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Larkins Et Al-2020-Cochrane Database of Systematic Reviews
Larkins Et Al-2020-Cochrane Database of Systematic Reviews
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Cochrane Database of Systematic Reviews
Non-corticosteroid immunosuppressive medications for steroid-
sensitive nephrotic syndrome in children (Review)
www.cochranelibrary.com
Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children
(Review)
Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.
Library Better health. Cochrane Database of Systematic Reviews
TABLE OF CONTENTS
HEADER......................................................................................................................................................................................................... 1
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
SUMMARY OF FINDINGS.............................................................................................................................................................................. 4
BACKGROUND.............................................................................................................................................................................................. 16
OBJECTIVES.................................................................................................................................................................................................. 16
METHODS..................................................................................................................................................................................................... 16
RESULTS........................................................................................................................................................................................................ 18
Figure 1.................................................................................................................................................................................................. 20
Figure 2.................................................................................................................................................................................................. 22
Figure 3.................................................................................................................................................................................................. 23
Figure 4.................................................................................................................................................................................................. 26
DISCUSSION.................................................................................................................................................................................................. 29
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 30
ACKNOWLEDGEMENTS................................................................................................................................................................................ 31
REFERENCES................................................................................................................................................................................................ 32
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 42
DATA AND ANALYSES.................................................................................................................................................................................... 103
Analysis 1.1. Comparison 1 Rituximab versus placebo or control, Outcome 1 Number with relapse.............................................. 103
Analysis 1.2. Comparison 1 Rituximab versus placebo or control, Outcome 2 Adverse effects....................................................... 104
Analysis 2.1. Comparison 2 Mycophenolate mofetil versus levamisole, Outcome 1 Relapse at 12 months.................................... 105
Analysis 2.2. Comparison 2 Mycophenolate mofetil versus levamisole, Outcome 2 Adverse effects............................................... 106
Analysis 3.1. Comparison 3 Mycophenolate mofetil versus cyclosporin, Outcome 1 Relapse at 12 months................................... 107
Analysis 3.2. Comparison 3 Mycophenolate mofetil versus cyclosporin, Outcome 2 Relapse rate/year.......................................... 107
Analysis 3.3. Comparison 3 Mycophenolate mofetil versus cyclosporin, Outcome 3 Adverse effects............................................. 107
Analysis 3.4. Comparison 3 Mycophenolate mofetil versus cyclosporin, Outcome 4 GFR at 12 months......................................... 108
Analysis 4.1. Comparison 4 Levamisole versus steroids or placebo or both, or no treatment, Outcome 1 Relapse during 109
treatment (4 to 12 months)..................................................................................................................................................................
Analysis 4.2. Comparison 4 Levamisole versus steroids or placebo or both, or no treatment, Outcome 2 Relapse at 6 to 12 110
months...................................................................................................................................................................................................
Analysis 4.3. Comparison 4 Levamisole versus steroids or placebo or both, or no treatment, Outcome 3 Mean relapse rate/ 110
patient/month.......................................................................................................................................................................................
Analysis 4.4. Comparison 4 Levamisole versus steroids or placebo or both, or no treatment, Outcome 4 Relapse during 110
treatment according to risk of bias.....................................................................................................................................................
Analysis 4.5. Comparison 4 Levamisole versus steroids or placebo or both, or no treatment, Outcome 5 Adverse effects............ 111
Analysis 5.1. Comparison 5 Levamisole versus cyclophosphamide, Outcome 1 Relapse................................................................ 112
Analysis 5.2. Comparison 5 Levamisole versus cyclophosphamide, Outcome 2 Adverse effects.................................................... 113
Analysis 6.1. Comparison 6 Cyclosporin and prednisone versus prednisone alone, Outcome 1 Relapse at 6 months................... 113
Analysis 6.2. Comparison 6 Cyclosporin and prednisone versus prednisone alone, Outcome 2 Relapse at 12 months................. 114
Analysis 6.3. Comparison 6 Cyclosporin and prednisone versus prednisone alone, Outcome 3 Number needing cytotoxic 114
agents.....................................................................................................................................................................................................
Analysis 6.4. Comparison 6 Cyclosporin and prednisone versus prednisone alone, Outcome 4 Creatinine at end of study.......... 114
Analysis 7.1. Comparison 7 Alkylating agents versus cyclosporin, Outcome 1 Relapse at end of therapy (6 to 9 months)............. 115
Analysis 7.2. Comparison 7 Alkylating agents versus cyclosporin, Outcome 2 Relapse at 12 to 24 months.................................... 115
Analysis 7.3. Comparison 7 Alkylating agents versus cyclosporin, Outcome 3 Adverse effects....................................................... 115
Analysis 8.1. Comparison 8 Alkylating agents versus steroids or placebo or both, Outcome 1 Relapse at 6 to 12 months............. 117
Analysis 8.2. Comparison 8 Alkylating agents versus steroids or placebo or both, Outcome 2 Relapse at 12 to 24 months........... 117
Analysis 8.3. Comparison 8 Alkylating agents versus steroids or placebo or both, Outcome 3 Leucopenia.................................... 118
Analysis 9.1. Comparison 9 Cyclophosphamide duration, Outcome 1 Relapse at 12 months......................................................... 119
Analysis 9.2. Comparison 9 Cyclophosphamide duration, Outcome 2 Relapse at 24 months......................................................... 119
Analysis 9.3. Comparison 9 Cyclophosphamide duration, Outcome 3 Leucopenia.......................................................................... 119
Analysis 10.1. Comparison 10 Cyclophosphamide dose, Outcome 1 Relapse at 12 months........................................................... 120
[Intervention Review]
Nicholas G Larkins1a, Isaac D Liu2b, Narelle S Willis3,4, Jonathan C Craig4,5, Elisabeth M Hodson3,4
1Department of Nephrology, Princess Margaret Hospital, Subiaco, Australia. 2Department of Paediatrics, National University Health
System, Singapore, Singapore. 3Sydney School of Public Health, The University of Sydney, Sydney, Australia. 4Cochrane Kidney and
Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia. 5College of Medicine and Public
Health, Flinders University, Adelaide, Australia
aThese authors contributed equally to this work. bThese authors contributed equally to this work
Contact address: Elisabeth M Hodson, Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at
Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia. elisabeth.hodson@health.nsw.gov.au.
Citation: Larkins NG, Liu ID, Willis NS, Craig JC, Hodson EM. Non-corticosteroid immunosuppressive medications for steroid-
sensitive nephrotic syndrome in children. Cochrane Database of Systematic Reviews 2020, Issue 4. Art. No.: CD002290. DOI:
10.1002/14651858.CD002290.pub5.
Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT
Background
About 80% of children with steroid-sensitive nephrotic syndrome (SSNS) have relapses. Of these children, half relapse frequently, and are at
risk of adverse effects from corticosteroids. While non-corticosteroid immunosuppressive medications prolong periods of remission, they
have significant potential adverse effects. Currently, there is no consensus about the most appropriate second-line agent in children who
are steroid sensitive, but who continue to relapse. In addition, these medications could be used with corticosteroids in the initial episode
of SSNS to prolong the period of remission. This is the fourth update of a review first published in 2001 and updated in 2005, 2008 and 2013.
Objectives
To evaluate the benefits and harms of non-corticosteroid immunosuppressive medications in SSNS in children with a relapsing course of
SSNS and in children with their first episode of nephrotic syndrome.
Search methods
We searched the Cochrane Kidney and Transplant Register of Studies up to 10 March 2020 through contact with the Information Specialist
using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE,
conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
Selection criteria
Randomised controlled trials (RCTs) or quasi-RCTs were included if they involved children with SSNS and compared non-corticosteroid
immunosuppressive medications with placebo, corticosteroids (prednisone or prednisolone) or no treatment; compared different non-
corticosteroid immunosuppressive medications or different doses, durations or routes of administration of the same non-corticosteroid
immunosuppressive medication.
Main results
We identified 43 studies (91 reports) and included data from 2428 children. Risk of bias assessment indicated that 21 and 24 studies were
at low risk of bias for sequence generation and allocation concealment respectively. Nine studies were at low risk of performance bias and
10 were at low risk of detection bias. Thirty-seven and 27 studies were at low risk of incomplete and selective reporting respectively.
Rituximab (in combination with calcineurin inhibitors (CNI) and prednisolone) versus CNI and prednisolone probably reduces the number
of children who relapse at six months (5 studies, 269 children: RR 0.23, 95% CI 0.12 to 0.43) and 12 months (3 studies, 198 children: RR
0.63, 95% CI 0.42 to 0.93) (moderate certainty evidence). At six months, rituximab resulted in 126 children/1000 relapsing compared with
548 children/1000 treated with conservative treatments. Rituximab may result in infusion reactions (4 studies, 252 children: RR 5.83, 95%
CI 1.34 to 25.29).
Mycophenolate mofetil (MMF) and levamisole may have similar effects on the number of children who relapse at 12 months (1 study, 149
children: RR 0.90, 95% CI 0.70 to 1.16). MMF may have a similar effect on the number of children relapsing compared to cyclosporin (2
studies, 82 children: RR 1.90, 95% CI 0.66 to 5.46) (low certainty evidence). MMF compared to cyclosporin is probably less likely to result
in hypertrichosis (3 studies, 140 children: RR 0.23, 95% CI 0.10 to 0.50) and gum hypertrophy (3 studies, 144 children: RR 0.09, 95% CI 0.07
to 0.42) (low certainty evidence).
Levamisole compared with steroids or placebo may reduce the number of children with relapse during treatment (8 studies, 474 children:
RR 0.52, 95% CI 0.33 to 0.82) (low certainty evidence). Levamisole compared to cyclophosphamide may make little or no difference to the
risk for relapse after 6 to 9 months (2 studies, 97 children: RR 1.17, 95% CI 0.76 to 1.81) (low certainty evidence).
Cyclosporin compared with prednisolone may reduce the number of children who relapse (1 study, 104 children: RR 0.33, 95% CI 0.13 to
0.83) (low certainty evidence). Alkylating agents compared with cyclosporin may make little or no difference to the risk of relapse during
cyclosporin treatment (2 studies, 95 children: RR 0.91, 95% CI 0.55 to 1.48) (low certainty evidence) but may reduce the risk of relapse at
12 to 24 months (2 studies, 95 children: RR 0.51, 95% CI 0.35 to 0.74), suggesting that the benefit of the alkylating agents may be sustained
beyond the on-treatment period (low certainty evidence).
Alkylating agents (cyclophosphamide and chlorambucil) compared with prednisone probably reduce the number of children, who
experience relapse at six to 12 months (6 studies, 202 children: RR 0.44, 95% CI 0.32 to 0.60) and at 12 to 24 months (4 studies, 59 children: RR
0.20, 95% CI 0.09 to 0.46) (moderate certainty evidence). IV cyclophosphamide may reduce the number of children with relapse compared
with oral cyclophosphamide at 6 months (2 studies, 83 children: RR 0.54, 95% CI 0.34 to 0.88), but not at 12 to 24 months (2 studies, 83
children: RR 0.99, 95% CI 0.76 to 1.29) and may result in fewer infections (2 studies, 83 children: RR 0.14, 95% CI 0.03 to 0.72) (low certainty
evidence). Cyclophosphamide compared to chlorambucil may make little or no difference in the risk of relapse after 12 months (1 study,
50 children: RR 1.31, 95% CI 0.80 to 2.13) (low certainty evidence).
Authors' conclusions
New studies incorporated in this review indicate that rituximab is a valuable additional agent for managing children with steroid-
dependent nephrotic syndrome. However, the treatment effect is temporary, and many children will require additional courses of
rituximab. The long-term adverse effects of this treatment are not known. Comparative studies of CNIs, MMF, levamisole and alkylating
agents have demonstrated little or no differences in efficacy but, because of insufficient power; clinically important differences in treatment
effects have not been completely excluded.
PLAIN LANGUAGE SUMMARY
Conclusions
Rituximab may be a valuable additional agent for the treatment of frequently relapsing nephrotic syndrome, where relapses persist
despite treatment with other non-corticosteroid agents. Because studies, directly comparing other medications, are too small to determine
whether any agents are more likely to maintain remission than any other, currently the use of levamisole, mycophenolate mofetil,
calcineurin inhibitors, or alkylating agents can be considered for children with relapsing nephrotic syndrome based on family and physician
preference. New larger studies are needed that compare different drug treatments to determine how these medicines should be used in
children with nephrotic syndrome.
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Rituximab versus placebo or control for SSNS in children
Better health.
Informed decisions.
Trusted evidence.
Comparison: placebo or control
Outcomes Anticipated absolute effects* (95% CI) Relative effect No. of par- Certainty of the
(95% CI) ticipants evidence
Risk with placebo or Risk with rituximab (studies) (GRADE)
control
Relapses at 3 months 530 per 1,000 170 per 1,000 RR 0.32 132 (3) ⊕⊕⊕⊝
(74 to 371) (0.14 to 0.70) MODERATE 1
Relapses at 6 months 548 per 1,000 126 per 1,000 RR 0.23 269 (5) ⊕⊕⊕⊝
(66 to 235) (0.12 to 0.43) MODERATE 2
Relapses at 12 months 606 per 1,000 382 per 1,000 RR 0.63 198 (3) ⊕⊕⊕⊝
(255 to 564) (0.42 to 0.93) MODERATE 1
Adverse effects: moderate to se- 8 per 1,000 46 per 1,000 RR 5.83 252 (4) ⊕⊕⊝⊝
vere Infusion reactions (11 to 201) (1.34 to 25.29) LOW 1
Adverse effects: arthropathy 12 per 1,000 47 per 1,000 RR 3.92 84 (2) ⊕⊕⊝⊝
(5 to 405) (0.45 to 33.98) LOW 1
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
SSNS: steroid-sensitive nephrotic syndrome; CI: confidence interval; RR: risk ratio
Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children (Review)
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is
substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
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Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
Better health.
Informed decisions.
Trusted evidence.
Summary of findings 2. Mycophenolate mofetil versus levamisole for steroid-sensitive nephrotic syndrome in children
Outcomes Anticipated absolute effects* (95% CI) Relative effect No. of par- Certainty of the evi-
(95% CI) ticipants dence
Risk with lev- Risk with MMF (studies) (GRADE)
amisole
Relapses at 12 months 658 per 1,000 592 per 1,000 RR 0.90 149 (1) ⊕⊕⊝⊝
(460 to 763) (0.70 to 1.16) LOW 1 2
Frequent relapses at 12 months 164 per 1,000 145 per 1,000 RR 0.88 149 (1) ⊕⊕⊝⊝
(67 to 307) (0.41 to 1.87) LOW 1 2
Adverse effects: abdominal pain 178 per 1,000 224 per 1,000 RR 1.26 149 (1) ⊕⊕⊝⊝
(118 to 427) (0.66 to 2.40) LOW 1 2
Adverse effects: anaemia 27 per 1,000 13 per 1,000 RR 0.48 149 (1) ⊕⊝⊝⊝
(1 to 142) (0.04 to 5.18) VERY LOW 1 2
Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children (Review)
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
** Event rate derived from the raw data. A 'per thousand' rate is non-informative in view of the scarcity of evidence and zero events in the levamisole group
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MMF: mycophenolate mofetil; SSNS: steroid-sensitive nephrotic syndrome; CI: confidence interval; RR: risk ratio
Better health.
Informed decisions.
Trusted evidence.
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
Outcomes Anticipated absolute effects* (95% CI) Relative effect No. of par- Certainty of the
(95% CI) ticipants evidence
Risk with CSA Risk with MMF (studies) (GRADE)
Relapse at 12 months 238 per 1,000 452 per 1,000 RR 1.90 82 (2) ⊕⊕⊝⊝
(157 to 1,000) (0.66 to 5.46) LOW 1 2
Relapse rate/year Mean relapse rate/year 0.83 higher with MMF compared to CSA - (3) ⊕⊕⊝⊝
(0.33 higher to 1.33 higher) LOW 1 2
Adverse effects: hypertension 292 per 1,000 88 per 1,000 RR 0.30 144 (3) ⊕⊕⊝⊝
(26 to 312) (0.09 to 1.07) LOW 1 2
Adverse effects: hypertrichosis 426 per 1,000 98 per 1,000 RR 0.23 140 (3) ⊕⊕⊕⊝
(43 to 213) (0.10 to 0.50) LOW 2 3
6
Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children (Review)
Adverse effects: lymphopenia 48 per 1,000 30 per 1,000 RR 0.64 84 (2) ⊕⊕⊝⊝
(4 to 231) (0.08 to 4.85) LOW 1 2
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Adverse effects: gum hypertrophy 208 per 1,000 19 per 1,000 RR 0.09 144 (3) ⊕⊕⊕⊝
(4 to 98) (0.02 to 0.47) LOW 1 2
Adverse effects: reduced GFR 83 per 1,000 28 per 1,000 RR 0.33 24 (1) ⊕⊕⊝⊝
(1 to 621) (0.01 to 7.45) LOW 1 2
Better health.
Informed decisions.
Trusted evidence.
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CSA: cyclosporin; MMF: mycophenolate mofetil; SSNS: steroid-sensitive nephrotic syndrome; CI: confidence interval; RR: risk ratio; GFR: glomerular filtration rate
Relapse during treatment (4 to 764 per 1,000 398 per 1,000 RR 0.52 474 (8) ⊕⊕⊝⊝
12 months) (252 to 627) (0.33 to 0.82) LOW 1 2
Relapse at 6 to 12 months 862 per 1,000 560 per 1,000 RR 0.65 462 (8) ⊕⊕⊝⊝
(414 to 758) (0.48 to 0.88) LOW 1 2
7
Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children (Review)
Frequent relapses not reported not reported -- -- --
Mean relapse rate/pa- The mean relapse rate/patient/year was 0.03 lower in the levamisole group - (2) ⊕⊝⊝⊝
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tient/month (0.27 lower to 0.2 higher) compared to the steroids or placebo or both, or no VERY LOW 1 3 4
treatment group
Adverse effects: leucopenia 10 per 1,000 41 per 1,000 RR 4.18 214 (3) ⊕⊕⊝⊝
(7 to 237) (0.72 to 24.21) LOW 1 2
Better health.
Informed decisions.
Trusted evidence.
Adverse effects: ANCA posi- 10 per 1,000 30 per 1,000 RR 3.00 100 (1) ⊕⊕⊝⊝
tive/arthritis (1 to 719) (0.13 to 71.92) LOW 1 2
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
SSNS: steroid-sensitive nephrotic syndrome; CI: confidence interval; RR: risk ratio; ANCA: anti-neutrophil cytoplasmic antibody
1 Heterogenous estimates of effect, smaller effect size among placebo-controlled studies; however, the consistent direction of effect indicates fewer relapses in the treatment arm
2 Unclear random sequence generation and/or allocation concealment (risk of selection bias)
3 The majority of studies were open-label, with unblinded outcome assessment (risk of performance and detection bias)
Summary of findings 5. Levamisole versus cyclophosphamide for steroid-sensitive nephrotic syndrome in children
Outcomes Anticipated absolute effects* (95% CI) Relative effect No. of par- Certainty of the
(95% CI) ticipants evidence
Risk with CPA Risk with levamisole (studies) (GRADE)
Relapse: at end of therapy 255 per 1,000 546 per 1,000 RR 2.14 97 (2) ⊕⊝⊝⊝
(56 to 1,000) (0.22 to 20.95) VERY LOW 1 2 3
8
Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children (Review)
Relapse: at 6 to 9 months after therapy 532 per 1,000 622 per 1,000 RR 1.17 97 (2) ⊕⊕⊝⊝
(404 to 963) (0.76 to 1.81) LOW 1 3
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Relapse: at 12 months after therapy 900 per 1,000 801 per 1,000 RR 0.89 40 (1) ⊕⊕⊝⊝
(612 to 1,000) (0.68 to 1.16) LOW 1 3
Relapse: at 24 months after therapy 950 per 1,000 845 per 1,000 RR 0.89 40 (1) ⊕⊕⊝⊝
(694 to 1,000) (0.73 to 1.10) LOW 1 3
Better health.
Informed decisions.
Trusted evidence.
Frequent relapses not reported not reported -- -- --
Adverse effects: infection 600 per 1,000 648 per 1,000 RR 1.08 40 (1) ⊕⊕⊝⊝
(402 to 1,000) (0.67 to 1.75) LOW 1 3
Adverse effects: leucopenia 106 per 1,000 27 per 1,000 RR 0.25 97 (2) ⊕⊕⊝⊝
(4 to 157) (0.04 to 1.48) LOW 1 3
Adverse effects: abnormal liver function 50 per 1,000 17 per 1,000 RR 0.33 40 (1) ⊕⊝⊝⊝
tests (1 to 386) (0.01 to 7.72) VERY LOW 3 4 5
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CPA: cyclophosphamide; SSNS: steroid-sensitive nephrotic syndrome; CI: confidence interval; RR: risk ratio
Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children (Review)
Summary of findings 6. Cyclosporin plus prednisolone versus prednisolone alone for steroid-sensitive nephrotic syndrome in children
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Patient or population: SSNS in children
Setting: Europe
Intervention: CSA plus prednisolone
Comparison: prednisolone alone
Outcomes Anticipated absolute effects* (95% CI) Relative effect No. of par- Certainty of the
Better health.
Informed decisions.
Trusted evidence.
(95% CI) ticipants evidence
Risk with prednisolone alone Risk with CSA plus prednisolone (studies) (GRADE)
Relapse at 6 months 309 per 1,000 102 per 1,000 RR 0.33 104 (1) ⊕⊕⊝⊝
(40 to 257) (0.13 to 0.83) LOW 1 2
Relapse at 12 months 509 per 1,000 367 per 1,000 RR 0.72 104 (1) ⊕⊕⊝⊝
(234 to 575) (0.46 to 1.13) LOW 1 3
Adverse effects: number needing cy- 218 per 1,000 103 per 1,000 RR 0.47 104 (1) ⊕⊝⊝⊝
totoxic agents (39 to 268) (0.18 to 1.23) VERY LOW 1 2 3
Adverse effects: creatinine at the end Mean creatinine was 2.00 µmol/L higher in the CSA plus prednisolone - 87 (1) ⊕⊝⊝⊝
of study (2.44 lower to 6.44 higher) than prednisolone alone VERY LOW 1 2 3
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CSA: cyclosporin; SSNS: steroid-sensitive nephrotic syndrome; CI: confidence interval; RR: risk ratio
1 Open-label study with unblinded outcome assessment (risk of performance and detection bias)
2 Wide confidence interval reduces certainty about effect size
3 At risk of attrition bias and reporting bias
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Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children (Review)
Summary of findings 7. Alkylating agents versus cyclosporin for steroid-sensitive nephrotic syndrome in children
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Alkylating agents versus CSA for SSNS in children
Better health.
Informed decisions.
Trusted evidence.
Outcomes Anticipated absolute effects* (95% CI) Relative effect No. of par- Certainty of the evi-
(95% CI) ticipants dence
Risk with CSA Risk with alkylating agents (studies) (GRADE)
Relapse at end of therapy (6 to 9 400 per 1,000 364 per 1,000 RR 0.91 95 (2) ⊕⊕⊝⊝
months) (220 to 592) (0.55 to 1.48) LOW 1 2
Relapse at 12 to 24 months 860 per 1,000 439 per 1,000 RR 0.51 95 (2) ⊕⊕⊝⊝
(301 to 636) (0.35 to 0.74) LOW 1 2
Adverse effects: serum creatinine 89 per 1,000 18 per 1,000 RR 0.20 106 (2) ⊕⊕⊝⊝
(2 to 151) (0.02 to 1.69) LOW 1 2
Adverse effects: hypertrichosis 339 per 1,000 20 per 1,000 RR 0.06 106 (2) ⊕⊕⊝⊝
(3 to 136) (0.01 to 0.40) LOW 1 2
Adverse effects: gum hypertrophy 232 per 1,000 19 per 1,000 RR 0.08 106 (2) ⊕⊕⊝⊝
(2 to 137) (0.01 to 0.59) LOW 1 2
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
** Event rate derived from the raw data. A 'per thousand' rate is non-informative in view of the scarcity of evidence and zero events in the CSA group
11
Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children (Review)
CSA: cyclosporin; SSNS: steroid-sensitive nephrotic syndrome; CI: confidence interval; RR: risk ratio
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High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is
substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
Better health.
Informed decisions.
Trusted evidence.
1 Open-label study with unblinded outcome assessment (risk of performance and detection bias)
2 Wide confidence interval reduces certainty about effect size
3 Unclear random sequence generation and allocation concealment (risk of selection bias)
4 Unclear random sequence generation (risk of selection bias)
Summary of findings 8. Alkylating agents versus steroids, placebo or both for steroid-sensitive nephrotic syndrome in children
Outcomes Anticipated absolute effects* (95% CI) Relative effect No. of par- Certainty of
(95% CI) ticipants the evidence
Risk with steroids, placebo Risk with alkylating agents (studies) (GRADE)
or both
Relapse at 6 to 12 months 740 per 1,000 326 per 1,000 RR 0.44 202 (6) ⊕⊕⊕⊝
(237 to 444) (0.32 to 0.60) MODERATE 1
(1.45 to 78.05)
Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children (Review)
(0.11 to 54.87)
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
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** Event rate derived from the raw data. A 'per thousand' rate is non-informative in view of the scarcity of evidence and zero events in the steroids, placebo or both group
SSNS: steroid-sensitive nephrotic syndrome; CI: confidence interval; RR: risk ratio
Better health.
Informed decisions.
Trusted evidence.
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is
substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
1 Open-label study with unblinded outcome assessment (risk of performance and detection bias)
2 Small number of participants and events
Summary of findings 9. Intravenous versus oral cyclophosphamide for steroid-sensitive nephrotic syndrome in children
Outcomes Anticipated absolute effects* (95% CI) Relative effect No. of par- Certainty of the
(95% CI) ticipants evidence
Risk with oral CPA Risk with IV CPA (studies) (GRADE)
Relapse at 6 months 524 per 1,000 283 per 1,000 RR 0.54 83 (2) ⊕⊕⊝⊝
Continuing frequently-relapsing or 571 per 1,000 229 per 1,000 RR 0.40 47 (1) ⊕⊕⊝⊝
(103 to 509) (0.18 to 0.89) LOW 1 2
steroid-dependent SSNS at 6 months
Relapse at end of study 619 per 1,000 613 per 1,000 RR 0.99 83 (2) ⊕⊕⊝⊝
(470 to 799) (0.76 to 1.29) LOW 1 2
Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children (Review)
Adverse events: leucopenia 143 per 1,000 53 per 1,000 RR 0.37 83 (2) ⊕⊕⊝⊝
(13 to 216) (0.09 to 1.51) LOW 1 3
Library
Cochrane
Adverse events: hair loss 381 per 1,000 72 per 1,000 RR 0.19 83 (2) ⊕⊕⊝⊝
(15 to 392) (0.04 to 1.03) LOW 1 3
Adverse events: all infections 238 per 1,000 33 per 1,000 RR 0.14 83 (2) ⊕⊕⊝⊝
(7 to 171) (0.03 to 0.72) LOW 1 3
Better health.
Informed decisions.
Trusted evidence.
Adverse events: nausea and vomiting no events 2/26** RR 4.07 47 (1) ⊕⊝⊝⊝
(0.21 to 80.51) VERY LOW 1 2 3
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
** Event rate derived from the raw data. A 'per thousand' rate is non-informative in view of the scarcity of evidence and zero events in the oral CPA group
IV: intravenous; CPA: cyclophosphamide; SSNS: steroid-sensitive nephrotic syndrome; CI: confidence interval; RR: risk ratio
1 Open-label study with unblinded outcome assessment (risk of performance and detection bias)
2 Small number of participants and events
3 Wide confidence interval reduces certainty about effect size
Summary of findings 10. Cyclophosphamide versus chlorambucil for steroid-sensitive nephrotic syndrome in children
Outcomes Anticipated absolute effects* (95% CI) Relative effect No. of par- Certainty of the evi-
(95% CI) ticipants dence
Risk with chlorambu- Risk with CPA (studies) (GRADE)
cil
14
Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children (Review)
Relapse at 12 months 500 per 1,000 575 per 1,000 RR 1.15 50 (1) ⊕⊕⊝⊝
(345 to 970) (0.69 to 1.94) LOW 1 2
Library
Cochrane
Relapse at 24 months 500 per 1,000 655 per 1,000 RR 1.31 50 (1) ⊕⊕⊝⊝
(400 to 1,000) (0.80 to 2.13) LOW 1 2
Better health.
Informed decisions.
Trusted evidence.
Adverse effects: lymphopenia 625 per 1,000 269 per 1,000 RR 0.43 50 (1) ⊕⊕⊝⊝
(131 to 544) (0.21 to 0.87) LOW 1 2
Adverse effects: thrombocytopenia 625 per 1,000 269 per 1,000 RR 0.43 50 (1) ⊕⊕⊝⊝
(131 to 544) (0.21 to 0.87) LOW 1 2
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
** Event rate derived from the raw data. A 'per thousand' rate is non-informative in view of the scarcity of evidence and zero events in the chlorambucil group
CPA: cyclophosphamide; SSNS: steroid-sensitive nephrotic syndrome; CI: confidence interval; RR: risk ratio
1 Open-label study with unblinded outcome assessment (risk of performance and detection bias)
2 Unclear random sequence generation (risk of selection bias)
3 Wide confidence interval reduces certainty about effect size
15
Cochrane Trusted evidence.
Informed decisions.
Library Better health. Cochrane Database of Systematic Reviews
carried out in children (aged from three months to 18 years) with 1. Monthly searches of the Cochrane Central Register of Controlled
SSNS and they compared non-corticosteroid immunosuppressive Trials (CENTRAL)
drugs with placebo, steroids or no treatment, compared different 2. Weekly searches of MEDLINE OVID SP
doses or durations of the same or compared different non- 3. Searches of kidney and transplant journals, and the proceedings
corticosteroid immunosuppressive medications. and abstracts from major kidney and transplant conferences
Types of participants 4. Searching of the current year of EMBASE OVID SP
5. Weekly current awareness alerts for selected kidney and
Inclusion criteria
transplant journals
Children aged from three months to 18 years with relapsing 6. Searches of the International Clinical Trials Register (ICTRP)
SSNS (i.e. the child became oedema-free and their urine protein Search Portal and ClinicalTrials.gov.
was 1+ on dipstick, or < 4 mg/m2/h, or urine protein/creatinine
ratio was < 0.02 g/mmol) for three consecutive days while Studies contained in the Register are identified through searches of
receiving corticosteroid therapy). Relapse of nephrotic syndrome CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane
was defined as the recurrence of proteinuria measured semi- Kidney and Transplant. Details of search strategies, as well as a
quantitatively on urine analysis or quantitatively using albumin or list of handsearched journals, conference proceedings and current
protein/creatinine ratios or timed urine specimens. A kidney biopsy awareness alerts, are available on the Cochrane Kidney and
diagnosis of minimal change disease was not required for study Transplant website.
inclusion.
See Appendix 1 for search terms used in strategies for this review.
Exclusion criteria
Searching other resources
Children with steroid-resistant nephrotic syndrome, children
1. Reference lists of review articles, relevant studies and clinical
with congenital nephrotic syndrome, and children with other
practice guidelines.
renal or systemic forms of nephrotic syndrome defined on
kidney biopsy, clinical features or serology (e.g. post-infectious 2. Contacting relevant individuals/organisations seeking
glomerulonephritis, Henoch-Schönlein nephritis, systemic lupus information about unpublished or incomplete studies.
erythematosus). 3. Grey literature sources (e.g. abstracts, dissertations and theses),
in addition to those already included in the Cochrane Kidney and
Types of interventions Transplant Register of Studies, were not searched.
• Non-corticosteroid immunosuppressive medications versus
Data collection and analysis
inactive placebo or no immunosuppressive treatment.
• Non-corticosteroid immunosuppressive medications (with or Selection of studies
without concomitant use of prednisone or prednisolone) versus The review was initially undertaken by five authors. The search
steroids used alone. methods described were used to obtain titles and abstracts of
• Two different non-corticosteroid immunosuppressive studies that could be relevant to the review. The titles and
medications (with or without concomitant use of steroids). abstracts were screened independently by four authors, who
• Different doses and durations of the same non-corticosteroid discarded studies that were irrelevant (e.g. studies of lipid lowering
immunosuppressive medication (with or without concomitant agents) although studies and reviews that might include relevant
use of steroids). data or information on studies were retained initially. Authors
independently assessed abstracts, and if necessary, the full text,
Types of outcome measures of these studies to determine which studies satisfied the inclusion
Primary outcomes criteria. Studies reported in non-English language journals were
translated before assessment. Any further information required
• Numbers of children with and without relapse at six or more from the original author(s) was included in the review. If necessary,
months. disagreements could be resolved in consultation.
Secondary outcomes Data extraction and management
• Mean relapse rates/patient/year Data extraction and risk of bias assessment was carried out
• Mean length of time to next relapse independently using standard data extraction forms by the same
• Serious adverse effects of therapy authors, who screened the studies for eligibility. Disagreements
were resolved in consultation among authors.
Search methods for identification of studies
Assessment of risk of bias in included studies
Electronic searches
The quality of studies to be included in the initial review and in the
We searched the Cochrane Kidney and Transplant Register of updates to 2008 was assessed independently by AD and EH or EH
Studies up to 10 March 2020 through contact with the Information and NW without blinding to authorship or journal of publication for
Specialist using search terms relevant to this review. The Register allocation concealment, blinding, intention-to-treat analysis and
contains studies identified from the following sources: completeness of follow-up (Crowther 2010). Discrepancies were
resolved in discussion with JC (Durkan 2001a; Durkan 2005; Hodson
2008).
For the 2013 and 2020 update, the following items were reduce reporting bias. There were insufficient studies to assess
independently assessed by two authors using the risk of bias publication bias for each group of interventions. Where more than
assessment tool (Higgins 2011) (see Appendix 2). one publication of the same study was identified, all reports were
reviewed to make sure that all available outcomes were included.
• Was there adequate sequence generation (selection bias)?
• Was allocation adequately concealed (selection bias)? Although we planned to construct funnel plots to assess for the
• Was knowledge of the allocated interventions adequately potential existence of small study bias, there were insufficient data
prevented during the study? reported to enable analysis (Higgins 2011).
* Participants and personnel (performance bias) Data synthesis
* Outcome assessors (detection bias)
Data were pooled using the random-effects model for dichotomous
• Were incomplete outcome data adequately addressed (attrition
and continuous outcomes.
bias)?
• Are reports of the study free of suggestion of selective outcome Subgroup analysis and investigation of heterogeneity
reporting (reporting bias)?
Subgroup analysis according to three possible sources of
• Was the study apparently free of other problems that could put
heterogeneity, participants, treatments and risk of bias was
it at a risk of bias?
planned but not performed because there were insufficient studies
Measures of treatment effect for any comparison. The summary measure data were translated
into absolute risk reductions (ARR) for a range of baseline risks for
For dichotomous outcomes (relapse or no relapse) results were alkylating agents and cyclosporin. Adverse effects were tabulated
expressed as risk ratio (RR) with 95% confidence intervals (95% CI). and assessed with descriptive techniques for alkylating agents and
Where continuous scales of measurement were used to assess the cyclosporin. Adverse effects for other medications were listed in the
effects of treatment (time to relapse), the mean difference (MD) was text and where possible included in the meta-analyses.
used, or the standardised mean difference (SMD) if different scales
had been used. Sensitivity analysis
Unit of analysis issues Sensitivity analysis was undertaken to assess the contribution of
individual studies to heterogeneity and to assess any changes in
Results of cross-over studies were reported in the text of the results. results following exclusion of that study.
It was planned to include data in meta-analyses if outcomes were
reported separately for the first part of the study and included 'Summary of findings' tables
information from all or most of the participants, who completed the
We presented the main results of the review in 'Summary of
first part of the study.
findings' tables. These tables present key information concerning
Dealing with missing data the quality of the evidence, the magnitude of the effects of
the interventions examined, and the sum of the available data
Where necessary we contacted study authors for additional for the main outcomes (Schunemann 2011a). The 'Summary of
information about their studies. Eight study authors provided findings' tables also include an overall grading of the evidence
additional information. We analysed available data and have related to each of the main outcomes using the GRADE (Grades
referred to areas of missing data in the text. of Recommendation, Assessment, Development and Evaluation)
approach (GRADE 2008; GRADE 2011). The GRADE approach defines
Assessment of heterogeneity the quality of a body of evidence as the extent to which one can be
We first assessed the heterogeneity by visual inspection of the confident that an estimate of effect or association is close to the
forest plot. We then quantified statistical heterogeneity using the true quantity of specific interest. The quality of a body of evidence
I2 statistic, which describes the percentage of total variation across involves consideration of within-trial risk of bias (methodological
studies that is due to heterogeneity rather than sampling error quality), directness of evidence, heterogeneity, precision of effect
(Higgins 2003). A guide to the interpretation of I2 values was as estimates and risk of publication bias (Schunemann 2011b). We
follows. presented the following outcomes in the 'Summary of findings'
tables.
• 0% to 40%: might not be important
• Relapse at different time points
• 30% to 60%: may represent moderate heterogeneity
• Number of patients with frequently relapsing disease
• 50% to 90%: may represent substantial heterogeneity
• Mean relapse rate per participant per month
• 75% to 100%: considerable heterogeneity.
• Adverse effects.
The importance of the observed value of I2 depends on the
magnitude and direction of treatment effects and the strength of RESULTS
evidence for heterogeneity (e.g. P-value from the Chi2 test, or a
Description of studies
confidence interval for I2) (Higgins 2011.
Results of the search
Assessment of reporting biases
• The initial review in 2001 included 18 studies (18 reports) with
The search strategy included major databases, conference 828 children (Durkan 2001a).
proceedings and prospective trial registries in an attempt to
Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children (Review) 18
Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.
Library Better health. Cochrane Database of Systematic Reviews
• The 2005 update (Durkan 2005) included 20 studies (24 reports) • The 2013 update (Pravitsitthikul 2013) included 31 studies (46
with 923 children. reports) with 1443 children.
• The 2008 update (Hodson 2008) included 26 studies (32 reports)
with 1173 children. For the 2020 update we identified 71 new reports. The results of the
literature search are shown in Figure 1.
Figure 1. (Continued)
The literature search identified 12 new included studies. Of these, • Levamisole
there were nine new studies (APN 2006; ATLANTIS 2018; Iijima * Levamisole versus steroids or placebo or both: eight studies
2014; NEPHRUTIX 2018; Ravani 2015; RITURNS 2018; Sinha 2019; (476 children) (Abeyagunawardena 2006a; Al-Saran 2006;
Uddin 2016; Zhang 2014). Three studies (Ahn 2018; Gruppen 2015; BAPN 1991; Dayal 1994; Gruppen 2015; Rashid 1996; Sural
Iijima 2011) were previously listed as awaiting assessment or 2001 (groups 1 and 3); Weiss 1993)
ongoing studies. APN 2006 was transferred from another Cochrane * Levamisole versus cyclophosphamide: two studies (97
review (Hahn 2015) because it evaluated a non-corticosteroid agent children) (Donia 2005; Sural 2001).
(cyclosporin). A total of 43 studies (91 reports) with 2541 children • Calcineurin inhibitors
enrolled and 2428 children analysed were included. * Cyclosporin and prednisone versus prednisone alone: one
study (106 children) (APN 2006). This study used cyclosporin
Nine new studies were excluded (Basu 2015; Khemani 2016; Liu
for eight weeks, in addition to steroids, for patients with an
2016c; Lou 2004; NCT02390362; Sasinka 1976; Wu 2015; Zedan 2016;
initial presentation of nephrotic syndrome.
Zhu 2013).
* Different dosing regimens of cyclosporin: two studies (141
There are 11 new ongoing studies (Hama 2018; Horinouchi children) (Ishikura 2008; Iijima 2014)
2018; INTENT 2018; JSKDC 10 2019; LEARNS 2019; NCT02818738; * Alkylating agents versus cyclosporin: two studies (112
NCT02972346; Ravani 2017; RITURNS II 2019; RITUXIVIG 2018; Sinha children) (Niaudet 1992; Edefonti 1988)
2019b) (Characteristics of ongoing studies) and three recently • Alkylating agents (cyclophosphamide, chlorambucil)
completed studies (NCT01092962; NCT01895894; Sawires 2019) * Alkylating agents versus steroids or placebo: six studies (202
(Characteristics of studies awaiting classification) which will be children) (Alatas 1978; Barratt 1970; Chiu 1973; Grupe 1976;
assessed in a future update of this review. ISKDC 1974; Sural 2001 (group 1 and 2))
The language used in this review has been updated to reflect * Different cyclophosphamide or chlorambucil regimens: six
uncertainty about findings per the Cochrane Consumer and studies (223 children) (Abeyagunawardena 2006b; Baluarte
Communication Guide (Glenton 2010). 1978; Barratt 1973; McCrory 1973; Prasad 2004; Ueda 1990)
* Cyclophosphamide versus chlorambucil: one study (50
Included studies children) (APN 1982)
The characteristics of the 43 completed studies are shown in * Cyclophosphamide versus vincristine: one study (39
Characteristics of included studies. One study enrolled children children) (Abeyagunawardena 2007)
with their initial episode of nephrotic syndrome (APN 2006) • Other agents
while the other studies enrolled children with relapsing nephrotic * Mizoribine versus placebo: one study (197 children) (Yoshioka
syndrome. 2000)
* Azithromycin versus steroids: one study (190 children)
• Rituximab (Zhang 2014)
* Rituximab versus placebo or standard care: 6 studies (326
children) (Ahn 2018; RITURNS 2018; Iijima 2011; NEPHRUTIX * Azathioprine versus steroids: two studies (60 children) (ISKDC
1970; Barratt 1977)
2018; Ravani 2011; Ravani 2015).
* ACTH versus placebo: one study (31 children) (ATLANTIS
• Mycophenolate mofetil
2018)
* MMF versus levamisole: one study (149 children) (Sinha 2019)
* Fusidic acid versus steroids: one study (18 children)
* MMF versus cyclosporin: three studies (144 children)
(Cerkauskiene 2005).
(Dorresteijn 2008; Gellermann 2013; Uddin 2016).
Figure 3. Risk of bias summary: review authors' judgements about each risk of bias item for each included study
Figure 3. (Continued)
Allocation Allocation concealment
Random sequence generation There was low risk of bias arising from allocation concealment in
24 studies (Abeyagunawardena 2006a; Abeyagunawardena 2006b;
We assessed that risk of bias arising from sequence generation was
Abeyagunawardena 2007; APN 1982; APN 2006; ATLANTIS 2018;
low in 21 studies (Abeyagunawardena 2006a; Abeyagunawardena
BAPN 1991; Barratt 1970; Barratt 1973; Barratt 1977; Chiu 1973;
2006b; Abeyagunawardena 2007; Ahn 2018; APN 2006; ATLANTIS
Dorresteijn 2008; Edefonti 1988; Gellermann 2013; Gruppen 2015;
2018; Chiu 1973; Dayal 1994; Donia 2005; Dorresteijn 2008;
Iijima 2011; ISKDC 1970; ISKDC 1974; Ravani 2011; Ravani 2015;
Gellermann 2013; Gruppen 2015; Iijima 2011; Iijima 2014; ISKDC
RITURNS 2018; Sinha 2019; Weiss 1993; Yoshioka 2000), at high risk
1970; Prasad 2004; Ravani 2011; Ravani 2015; RITURNS 2018; Sinha
of bias in two studies (McCrory 1973; Zhang 2014) and unclear in the
2019; Yoshioka 2000), at high risk of bias in two studies (McCrory
remaining 17 studies
1973; Zhang 2014) and unclear in the remaining 20 studies.
GFR, pneumonia and diarrhoea) (Analysis 3.3) (low certainty • Levamisole compared with steroids or placebo may make
evidence). little or no difference to the number of children developing
leucopenia or arthritis (Analysis 4.5) (low certainty evidence).
The evidence was downgraded due to risk of bias and imprecision
(Summary of findings 3). The evidence was downgraded because of risk of bias and
imprecision (Summary of findings 4).
Levamisole versus steroids or placebo or both, or no treatment
The heterogeneity between studies was investigated in sensitivity
Levamisole was administered for four months (BAPN 1991), six
analyses in which studies at low risk of bias for allocation
months (Rashid 1996; Sural 2001; Weiss 1993) and 12 months
concealment and blinding were separated from those at unclear or
(Abeyagunawardena 2006a; Al-Saran 2006; Dayal 1994; Gruppen
high risk of bias (Figure 4). This identifies that studies at unclear or
2015).
high risk of bias resulted in a greater benefit of levamisole (Analysis
• Levamisole compared with steroids or placebo may reduce the 4.4.2) compared with those studies at low risk of bias (Analysis
number of children with relapse during treatment (Analysis 4.1 4.4.1). These data are consistent with empirical evidence that lack
(8 studies, 474 children): RR 0.52, 95% CI 0.33 to 0.82; I2 = 89%) of blinding is associated with an increase in apparent treatment
and at 6 to 12 months (end of treatment) (Analysis 4.2 (8 studies, effect (Schulz 1995). Among the three studies at low risk of bias,
heterogeneity was eliminated when Weiss 1993 was excluded. This
462 children): RR 0.65, 95% CI 0.48 to 0.88; I2 = 87%). (low
study showed no apparent benefit of levamisole, but levamisole
certainty evidence).
was given on two consecutive days out of seven rather than on
• It is uncertain whether levamisole compared with placebo or no alternate days as in the other studies.
treatment alters the mean relapse rate because the certainty of
the evidence is very low (Analysis 4.3).
Figure 4. Forest plot of comparison: 6 Levamisole versus steroids or placebo or both, or no treatment, outcome: 6.4
Relapse during treatment according to risk of bias.
Levamisole versus cyclophosphamide with cyclophosphamide makes any difference to the number of
children with relapse at the end of therapy because the certainty
• Levamisole when compared with cyclophosphamide may make
of the evidence is very low (Analysis 5.1.1 (2 studies, 97 children):
little or no difference to the numbers of children at six to
RR 2.14, 95% CI 0.22 to 20.95; I2 = 79%).
nine months (Analysis 5.1.2 (2 studies, 97 children): RR 1.17,
95% CI 0.76 to 1.81; I2 = 43%), at 12 months (Analysis 5.1.3 • Adverse effects (infection, leucopenia) may not differ between
(1 study, 40 children): RR 0.89, 95% CI 0.68 to 1.16) and at treatment groups (Analysis 5.2).
24 months (Analysis 5.1.4 (1 study, 40 children): RR 0.89, 95%
CI 0.73 to 1.10). It is uncertain whether levamisole compared
The evidence was downgraded because of risk of bias issues, patients experiencing relapse at six to 12 months (Analysis 8.1
heterogeneity and imprecision (Summary of findings 5). (6 studies, 202 children): RR 0.44, 95% CI 0.32 to 0.60; I2 =
0%) (moderate certainty evidence) and may reduce the number
Cyclosporin and prednisone versus prednisone alone suffering relapse at 13 to 24 months (Analysis 8.2 (4 studies, 59
• The addition of cyclosporin to 12 weeks of prednisone therapy children): RR 0.20, 95% CI 0.09 to 0.46; I2 = 0%) (low certainty
for treatment of the first presentation of nephrotic syndrome evidence).
may reduce the risk of relapse at six months (Analysis 6.1 (1 • Leucopenia was reported in three studies (Analysis 8.3).
study, 104 children): RR 0.33, 95% CI 0.33 to 0.83) and but not Leucopenia developed in children receiving cyclophosphamide
at 12 months (Analysis 6.2 (1 study, 104 children): RR 0.72, or chlorambucil. However, because of small numbers of events
95% CI 0.46 to 1.13) (low certainty evidence). It is uncertain if and included children, It is uncertain whether alkylating agents
the number needing cytotoxic agents differed between groups compared with prednisone or placebo result in leucopenia
(Analysis 6.3) because the certainty of the evidence was very low. because the certainty of the evidence is very low.
• It is uncertain if cyclosporin added to prednisone makes any
difference to the end-of-follow-up serum creatinine (very low The evidence was downgraded because of increased risk of bias
certainty evidence). and imprecision (Summary of findings 8).
• Hypertrichosis and gum hypertrophy were seen in 60% and Cyclophosphamide: different durations, doses, route
9% of children given cyclosporin, respectively. Psychological
disturbances occurred in 27% of cyclosporin-treated patients • It is uncertain whether cyclophosphamide given for eight weeks
compared with 14% of patients treated with prednisone alone. compared with two weeks results in fewer children relapsing
within 12 months (Analysis 9.1.1 (1 study, 32 children): RR 0.15,
The evidence was downgraded due to risk of bias and imprecision 95% CI 0.04 to 0.57), because the certainty of the evidence is very
(Summary of findings 6). low.
• Cyclophosphamide given for 12 weeks compared to eight weeks
Alkylating agents versus cyclosporin may make little or no difference in the number of children
• Cyclosporin when compared to cyclophosphamide given for relapsing at 12 months (Analysis 9.1.2 (1 study, 73 children): RR
eight weeks or chlorambucil given for six weeks, may make 1.04, 95% CI 0.75 to 1.44) or 24 months (Analysis 9.2.1 (1 study,
little or no difference to the risk of relapse during cyclosporin 73 children): RR 0.98, 95% CI 0.74 to 1.28) or to the number of
treatment (6 to 9 months) (Analysis 7.1 (2 studies, 95 children): children with leucopenia (Analysis 9.3) (low certainty evidence).
RR 0.91, 95% CI 0.55 to 1.48; I2 = 0%) (low certainty evidence). • It is uncertain if cyclophosphamide given as 5 mg/kg/day over 6
• Alkylating agents may be more effective than cyclosporin in weeks versus 2.5 mg/kg/day over 12 weeks makes any difference
maintaining remission at 12 to 24 months after either has been to the number of children relapsing at 12 months (Analysis 10.1
ceased (Analysis 7.2 (2 studies, 95 children): RR 0.51, 95% CI 0.35 (1 study, 14 children): RR 2.33, 95% CI 0.11 to 48.99), or to adverse
to 0.74; I2 = 12%) (low certainty evidence). effects (Analysis 10.2), due to very low certainty evidence.
• Cyclosporin compared with alkylating agents may result in • IV cyclophosphamide (monthly for six months) when compared
raised serum creatinine, hypertrichosis and gum hypertrophy to oral cyclophosphamide (given for 12 weeks) may reduce the
(Analysis 7.3) (low certainty evidence). It is uncertain if number of children with relapse at 6 months (Analysis 11.1
cyclosporin makes any difference to hypertension, and it (2 studies, 83 children): RR 0.54, 95% CI 0.34 to 0.8; I2 = 0%)
is uncertain whether alkylating agents result in leucopenia but may make little or no difference to relapse at 12 to 24
because the certainty of the evidence is very low. months (Analysis 11.3 (2 studies, 83 children): RR 0.99, 95% CI
0.76 to 1.29; I2 = 0%) (low certainty evidence). Comparing IV
The evidence was downgraded due to risk of bias issues and cyclophosphamide with oral cyclophosphamide, infections may
imprecision (Summary of findings 7). be more common in the oral group (Analysis 11.4.3 (2 studies,
83 children): RR 0.14, 95% CI 0.03 to 0.72; I2 = 0%) (low certainty
Alkylating agents versus steroids or placebo or both evidence) (Summary of findings 9).
• Cyclophosphamide compared with prednisone or placebo
probably reduces the number of children relapsing at six to 12 The evidence was downgraded because of risk of bias issues and
months. (Analysis 8.1.1 (4 studies, 161 children): RR 0.47, 95% imprecision.
CI 0.33 to 0.66; I2 = 0%) (moderate certainty evidence), and may Chlorambucil (different dose regimens)
reduce the number of children relapsing at 13 to 24 months
(Analysis 8.2.1 (2 studies, 27 children): RR 0.21, 95% CI 0.07 to • Comparing chlorambucil regimens, it is uncertain if an
0.65; I2 = 0%) (low certainty evidence). increasing dose regimen versus a stable dose regimen makes
• Similarly, chlorambucil compared with placebo or prednisone any difference to relapse at 12 months (Analysis 12.1 (1
alone may reduce the number of children experiencing relapse study, 21 children): RR 0.18, 95% CI 0.01 to 3.41) or to the
at six months (Analysis 8.1.2 (2 studies, 41 children): RR 0.19, number with leucopenia or thrombocytopenia (Analysis 12.2)
(very low certainty evidence). However, there was a 34%
95% CI 0.03 to 1.09; I2 = 44%) and 12 months (Analysis 8.2.2 (2
increase in the incidence of leucopenia and an 18% increase in
studies, 32 children): RR 0.15, 95% CI 0.02 to 0.95; I2 = 39%) (low thrombocytopenia with the increasing dose regimen.
certainty evidence) .
• When the studies evaluating cyclophosphamide or The evidence was downgraded due to risk of bias and serious
chlorambucil were combined, alkylating agents when compared imprecision.
to prednisone or placebo probably reduce the number of
Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children (Review) 27
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Cyclophosphamide versus chlorambucil with placebo may make little or no difference to the risk of
relapse.
• Chlorambucil when compared with cyclophosphamide may
make little or no difference to relapse at 12 months (Analysis 13.1 • Mizoribine may increase the risk of hyperuricaemia (Analysis
(1 study, 50 children): RR 1.15, 95% CI 0.69 to 1.94) and 24 months 16.1.2 (1 study, 197 children): RR 3.96, 95% CI 1.37 to 11.42)
(Analysis 13.2 (1 study, 50 children): RR 1.31, 95% CI 0.80 to 2.13) but not leucopenia or hepatic dysfunction (Analysis 16.1) (low
(low certainty evidence). certainty evidence).
• Chlorambucil when compared with cyclophosphamide The evidence was downgraded for adverse effects due to risk of bias
may result in more children with lymphopenia and issues and imprecision .
thrombocytopenia (Analysis 13.3) (low certainty evidence)
Azithromycin and prednisone versus prednisone alone
The evidence was downgraded due to risk of bias and imprecision
(Summary of findings 10). • Azithromycin and prednisone when compared with prednisone
alone may make little or no difference to the risk of relapse by
Alkylating agents versus vincristine six months (Analysis 17.1 (1 study, 190 children): RR 0.55, 95% CI
0.30 to 1.02) (low certainty evidence).
• IV cyclophosphamide when compared to IV vincristine may
make little or no difference to the risk of relapse at 12 months • Adverse effects were not reported.
(Analysis 14.1 (1 study, 39 children): RR 0.54, 95% CI 0.26 to 1.12)
The evidence was downgraded due to risk of bias and imprecision.
and 24 months (Analysis 14.2 (1 study, 39 children): RR 0.73, 95%
CI 0.45 to 1.18) (low certainty evidence). Although no major side Azathioprine versus steroids
effects were reported, two children treated with vincristine had
abdominal cramps and constipation, and five children receiving • Azathioprine compared with steroids or placebo may make little
cyclophosphamide experienced vomiting that required anti- or no difference to the number of children who relapse at six
emetics. months (Analysis 18.1 (2 studies, 60 children): RR 0.90, 95% CI
0.59 to 1.38; I2 = 3%) (low certainty evidence).
The evidence was downgraded to low certainty due to increased
risk of bias and imprecision. The evidence was downgraded due to risk of bias issues and
imprecision.
Cyclosporin dose
Fusidic acid versus steroids
• After an initial 6-month course of cyclosporin, cyclosporin used
to maintain remission at doses to maintain levels at 60 to 80 ng/ Fusidic acid and prednisone was compared with prednisone alone
mL (mean dose 5.4 mg/kg/day), compared to cyclosporin at a in a cross-over study involving 18 children (Cerkauskiene 2005). The
fixed dose of 2.5 mg/kg/day, may reduce the number of children results for all courses of fusidic acid and prednisone (14 courses)
experiencing relapse at 12 months (Analysis 15.1.2 (1 study, 44 and prednisone alone (17 courses) were combined so no meta-
children): RR 0.33, 95% CI 0.16 to 0.70) and 24 months (Analysis analyses could be performed. There were no differences in the
15.1.3 (1 study, 44 children): RR 0.65, 95% CI 0.45 to 0.94) (low mean time to remission (12.6 ± 6.6 days for fusidic acid/prednisone
certainty evidence). versus 13.9 ± 7.4 days for prednisone alone) or in time to relapse
• The variable dose schedule compared with fixed dose may make (18.3 ± 23.9 weeks versus 17.8 ± 20.4 weeks). One child developed
little or no difference to adverse effects (Analysis 15.2). (low an allergic rash with fusidic acid.
certainty evidence).
ACTH
The evidence was considered of low certainty due to risk of bias and • ACTH when compared with placebo may make little or no
imprecision. difference to the risk of relapse at 6 months (Analysis 19.1 (1
study, 31 children): RR 1.00, 95% CI 0.83 to 1.20) (low certainty
• High-dose cyclosporin (target C2 levels 600 to 700 ng/mL for first evidence).
6 months followed by 450 to 550 ng/mL for the next 18 months)
compared with low-dose cyclosporin (target C2 levels 450 to 550 • Adverse effects were reported for all 28 children, who received
ng/mL for the first 6 months and 300 to 400 ng/mL for the next ACTH (those randomised to ACTH and those in the control arm
18 months) may make little or no difference to relapse at 2 years receiving ACTH after relapse). The most common adverse effects
(Analysis 15.3.1 (1 study, 85 children): RR 0.74, 95% CI 0.45 to were behavioural changes (25%), sleep disturbances (18%),
1.22) or to adverse effects including hypertension, hirsutism and cushingoid features (18%), injection site irritation (25%) and
nephrotoxicity (Analysis 15.4). (low certainty evidence). increased appetite (32%).
The evidence was considered of low certainty due to risk of bias and The evidence was downgraded due to risk of bias and imprecision.
imprecision. Subgroup analyses
Mizoribine versus placebo There were insufficient studies of any treatment combination to
enable conducting detailed subgroup analyses.
• Data on the number of children with relapse at 6 and 12 months
who had received mizoribine or placebo could not be extracted.
The reported hazard ratio of cumulative remission rate of 0.79
(95% CI 0.57 to 1.08) suggested that mizoribine when compared
were associated with lower risk of relapse. Future studies need Agreements and disagreements with other studies or
to include therapeutic drug monitoring, where this is available, to reviews
determine if monitoring impacts practice in a clinically meaningful
way. The findings of this review update are in keeping with three
of the four recently published guidelines (French NS Guideline
Currently prednisone is the immunosuppressive agent used for the 2008; IPNS-IAP 2008; KDIGO 2012) which do not suggest in what
first presentation of SSNS. Non corticosteroid immunosuppressive order corticosteroid sparing immunosuppressive drugs should
agents with prednisone at the first presentation of SSNS might be used. In contrast, Gipson 2009 suggest different orders of
lengthen the time to relapse and reduce steroid toxicity. One study administration for frequently-relapsing and steroid-dependent
(APN 2006) found no net-benefit of administering cyclosporin with SSNS with cyclophosphamide preferred as the initial medication
prednisone for two months at presentation, when balancing the for frequently-relapsing disease and a CNI preferred for steroid-
reduction in risk of relapse with adverse effects of therapy. A dependent disease. Updated guidelines on glomerulonephritis
study commenced in 2015 (INTENT 2018) is evaluating whether including SSNS from KDIGO are expected soon.
administration of MMF used for 12 weeks after remission is
achieved will reduce the risk of relapse compared with 12 weeks of AUTHORS' CONCLUSIONS
prednisone (Querfeld 2018).
Implications for practice
Quality of the evidence This systematic review of RCTs showed that oral or IV
This review has several potential problems because of the cyclophosphamide, oral chlorambucil, levamisole, cyclosporin,
limitations of the primary data. Overall, study quality was poor, and rituximab substantially reduce the incidence of relapse in
with only a third and a half of studies reporting sequence children with relapsing SSNS. Current evidence would suggest
generation and allocation concealment at low risk of bias there are limited differences in efficacy between different agents
respectively (Figure 2; Figure 3). Studies with inadequate allocation but there was low or very low certainty about these effect sizes,
concealment can exaggerate the efficacy of the experimental and it is possible that further studies would alter this conclusion.
treatment by 30% to 40% (Schulz 1995) and meta-analyses of low This update included additional data to support the efficacy
quality studies may overestimate the benefit of therapy (Moher of levamisole, MMF and rituximab. Levamisole is an attractive
1998). In addition, only 20% of studies were considered at low risk option in many settings because of a favourable side effect profile
of performance and detection bias. These observations make the and cost, though it is not available in some countries. MMF
need for adequately powered, well designed and reported studies appears to be as effective as cyclosporin. To date no studies
even more necessary. have compared tacrolimus with cyclosporin for FRNS and SDNS;
however, in practice the use of tacrolimus is common, partly
In many analyses there were little or no differences in outcomes based on the assumption that data indicating equivalent efficacy
between different treatment groups. However, the confidence in SRNS are generalisable (Choudhry 2009). Rituximab, while
intervals were often very wide, with the limits including the highly efficacious, is likely to be used as a second- or third-line
possibility of substantial benefit or lack of benefit from the corticosteroid-sparing agent until more long-term data on adverse
intervention(s) compared with the comparator(s). The results effects accumulate. Alkylating agents remain a reasonable option
in many studies for some outcomes were imprecise indicating in treating patients with frequently-relapsing or steroid-dependent
that if these interventions were analysed in new adequately SSNS, as approximately one third of children will have a prolonged
powered studies, the results could change the estimates of benefits period of remission following an initial course, although concerns
considerably. Assessment by GRADE shown in the Summary of regarding the long-term risk to fertility have led to more cautious
Findings Tables indicates that the certainty of evidence was recommendations from some international guideline groups and a
generally low to very low for most comparisons due to increased reduction in its use in some high-resource settings.
risk of bias and imprecision due to small patient numbers.
Implications for research
The effects of publication bias could not be formally assessed
because of the small number of studies for each medication. Multiple effective options in SSNS have been identified, but there
Subgroup analysis was not possible because of the small number are few, adequately-powered, head-to-head trials comparing the
of studies for each intervention. relative efficacy of different agents. Adaptive trial designs, including
platform trials, are another viable option to compare the effect
Potential biases in the review process of multiple therapeutic regimens in treating rare diseases. While
the establishing the initial trial infrastructure for a platform trial is
The search strategy was repeated several times to March 2020 currently more resource intensive than a traditional RCT, this may
and included conference proceedings. Nevertheless, it is possible prove a more efficient approach in the long-term to accumulate
that studies published in conference proceedings not routinely the data required to inform the best choice and/or combination of
searched for by Cochrane Kidney and Transplant, were not agents. There are few data about the relative impact of different
identified. Additional information which enabled the data to be treatment options on patient-centred outcomes. Since the last
entered into the meta-analysis was obtained for three studies publication of this review in 2013, efforts to develop registries for
(Abeyagunawardena 2007; Gellermann 2013; Ravani 2015). childhood nephrotic syndrome have intensified; for example, the
National Registry of Rare Kidney Disease project of the UK Renal
Registry, Large-scale observational studies are also underway in
Canada and the USA, which beyond advancing the understanding
of disease aetiology and prognosis in SSNS, also aim to be hubs for • Professor Remuzzi and Drs Koch and Narsipur and Ms Zelmer for
the development of future studies. their editorial advice during the preparation of this review and
its updates.
ACKNOWLEDGEMENTS
The authors are grateful to the following peer reviewers
We are grateful to Dr Ann Durkan who contributed to the for their time and comments: Dr Joshua Yehuda Kausman
original iteration of this review (Durkan 2001b), in terms of the (Department of Nephrology, Royal Children’s Hospital, Melbourne;
design, quality assessment, data collection, entry, analysis and Kidney Development, Disease and Regeneration, Murdoch
interpretation, and writing. We are grateful to Dr N Pravitsitthikul, Children’s Research Institute; Department of Paediatrics, University
who contributed to the 2013 update of this review. of Melbourne, Australia), Vera H Koch (Associate Professor,
Department of Pediatrics, University of Sao Paulo Medical School;
The authors wish to thank: Pediatric Nephrology Unit, Instituto da Criança – Hospital das
Clinicas, University of Sao Paulo Medical School, Brazil), Dr
• Professors Barratt, Brodehl, Hoyer, Ponticelli and Weiss and
Deirdre Hahn (Paediatric Nephrologist, The Children’s Hospital at
Drs Abeyagunawardena, Beattie and Donia for providing further
Westmead, Locked Bag 4001, Westmead, 2145, Australia).
information about their studies.
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Basu A, Sander A, Preussler S, Sinha Mahapatra T, Schaefer F.
syndrome in childhood [abstract]. Nephron 1971;8:95.
Long-term efficacy of rituximab & MMF maintenance - therapy
[CENTRAL: CN-00602053]
in childhood SDNS [abstract no: IPN11036-82]. Pediatric
ISKDC 1974 {published data only} Nephrology 2019;34(10):2003.
Prospective, controlled trial of cyclophosphamide therapy Basu B. Randomized clinical trial to compare efficacy and
in children with nephrotic syndrome. Report of the safety of rituximab to that of calcineurin inhibitor in children
International Study of Kidney Disease in Children. Lancet with steroid dependent nephrotic syndrome. Protocol
1974;304(7878):423-7. [MEDLINE: 4137139] version 1.2 (final version). www.jamanetwork.com/journals/
jamapediatrics/fullarticle/2685284?resultClick=24 (accessed 4
McCrory 1973 {published data only}
March 2020).
McCrory WW, Shibuya M, Lu WH, Lewy JE. Therapeutic and
toxic effects observed with different dosage programs of Basu B, Sander A, Roy B, Preussler S, Barua S, Mahapatra TK,
cyclophosphamide in treatment of steroid-responsive but et al. Efficacy of rituximab vs tacrolimus in pediatric
frequently relapsing nephrotic syndrome. Journal of Pediatrics corticosteroid-dependent nephrotic syndrome: a randomized
1973;82(4):614-8. [MEDLINE: 4698338] clinical trial. JAMA Pediatrics 2018;172(8):757-64. [MEDLINE:
29913001]
NEPHRUTIX 2018 {published data only}
Boumediene A, Vachin P, Sendeyo K, Oniszczuk J, Zhang SY, Schaefer F. Superior efficacy of rituximab vs tacrolimus in
Henique C, et al. NEPHRUTIX: A randomized, double-blind, pediatric steroid dependent nephrotic syndrome [abstract].
placebo vs rituximab-controlled trial assessing T-cell subset 54th ERA-EDTA Congress; 2017 June 3-6; Madrid, Spain. 2017.
changes in minimal change nephrotic syndrome. Journal of
Sinha 2019 {published data only}
Autoimmunity 2018;88:91-102. [MEDLINE: 29056249]
Bagga A, Bhatia D, Puraswani M, Hari P, Sinha A. Randomized
Niaudet 1992 {published data only} trial comparing efficacy & safety of mycophenolate mofetil
Niaudet P. Comparison of cyclosporin and chlorambucil in the and levamisole in frequently relapsing & steroid dependent
treatment of steroid-dependent idiopathic nephrotic syndrome: nephrotic syndrome [abstract no: P-SUN199]. Pediatric
a multicentre randomized controlled trial. The French Society Nephrology 2013;28(8):1599-600. [EMBASE: 71127678]
of Paediatric Nephrology. Pediatric Nephrology 1992;6(1):1-3.
Sinha A, Peruswami M, Rawat M, Hari P, Bagga A. Randomized
[MEDLINE: 1536727]
controlled trial to compare the efficacy and safety of
Prasad 2004 {published data only} mycophenolate mofetil versus levamisole in children with
frequently relapsing and steroid dependent nephrotic
Prasad N, Gulati S, Sharma RK, Singh U, Ahmed M. Pulse
syndrome [abstract]. Pediatric Nephrology 2015;29(12):2434.
cyclophosphamide therapy in steroid-dependent nephrotic
[CENTRAL: CN-01912558]
syndrome. Pediatric Nephrology 2004;19(5):494-8. [MEDLINE:
15015070]
Sinha A, Puraswani M, Kalaivani M, Goyal P, Hari P, Bagga A. children with nephrotic syndrome [abstract no: O-44]. Pediatric
Efficacy and safety of mycophenolate mofetil versus levamisole Nephrology 2013;28(8):1364. [EMBASE: 71126985]
in frequently relapsing nephrotic syndrome: an open-
label randomized controlled trial. Kidney International
2019;95(1):2010-8. [MEDLINE: 30497684] References to studies excluded from this review
Arun 2009 {published data only}
Sural 2001 {published data only}
Arun S, Bagga A, Bhatnagar S, Hari P, Menon S, Saini S. Efficacy
Sural S, Pahari DK, Mitra K, Bhattacharya S, Mondal S,
of zinc (Zn) in reducing relapses in steroid sensitive nephrotic
Taraphder A. Efficacy of levamisole compared to
syndrome (SSNS): double blind, randomized controlled trial
cyclophosphamide and steroid in frequently relapsing (FR)
(RCT) (CRG030600044) [abstract no: 184]. Pediatric Nephrology
minimal change nephrotic syndrome (MCNS) [abstract
2007;22(9):1481. [CENTRAL: CN-00724915]
no: A0660]. Journal of the American Society of Nephrology
2001;12(Program & Abstracts):126A. Arun S, Bhatnagar S, Menon S, Saini S, Hari P, Bagga A. Efficacy
of zinc supplements in reducing relapses in steroid-sensitive
Uddin 2016 {published data only}
nephrotic syndrome. Pediatric Nephrology 2009;24(8):1583-6.
Uddin GM, Rahman MA, Rahman MH, Roy RR, Begum A, [MEDLINE: 19347367]
Huque SS. Comparative efficacy of mycophenolate mofetil
and cyclosporine in children with frequent relapse nephrotic Basu 2015 {published data only}
syndrome [abstract no: PO-276]. Pediatric Nephrology Basu B, Pandey R, Mahapatra TK, Mondal N, Schaefer F.
2016;31(10):1852-3. [EMBASE: 612479647] WITHDRAWN: Efficacy and safety of mycophenolate mofetil
versus levamisole in children and adolescents with idiopathic
Ueda 1990 {published data only}
nephrotic syndrome: results of a randomized clinical trial.
Ueda N, Kuno K, Ito S. Eight and 12 week courses of American Journal of Kidney Diseases 2015 Jun 09. [MEDLINE:
cyclophosphamide in nephrotic syndrome. Archives of Disease 26071057]
in Childhood 1990;65(10):1147-59. [MEDLINE: 2248508]
Basu B, Pandey R, Mishra OP. WITHDRAWN: Randomized
Weiss 1993 {published and unpublished data} controlled trial to compare the efficacy & safety of
Weiss R. Results of a randomized, double-blind, placebo mycophenolate mofetil vs levamisole in children with frequent
controlled, multi-center clinical trial of levamisole for the relapsing & steroid dependent nephrotic syndrome [abstract
treatment of children with frequently relapsing or steroid no: O-18]. Pediatric Nephrology 2013;28(8):1353. [CENTRAL:
dependent nephrotic syndrome. Personal communication 2005. CN-01658385]
* Weiss R, NY, NJ, Phila. Pediatric Nephrology Study Group. Basu B, Pandey R, Mondal N, Schaefer F. WITHDRAWN: Efficacy
Randomized, double-blind, placebo (P) controlled trial of and safety of mycophenolate-mofetil vs levamisole in children
levamisole (L) for children (CH) with frequently relapsing/ with idiopathic nephrotic syndrome: results of a randomized
steroid dependant (FR/SD) nephrotic syndrome (NS) [abstract clinical trial [abstract]. Nephrology Dialysis Transplantation
no: 98P]. Journal of the American Society of Nephrology 2014;29(Suppl 3):iii7. [EMBASE: 71491485]
1993;4(Program & Abstracts):289. [CENTRAL: CN-00520404]
Beige 2003 {published data only}
Yoshioka 2000 {published data only} Beige J, Moosmayer I, Liefeldt L, Neumayer HH, Zidek W,
Yoshioka K, Ohashi Y, Sakai T, Ito H, Yoshikawa N, Nakamura H, Peters H. Effective and safe treatment of primary nephrotic
et al. A multicenter trial of mizoribine compared with placebo in syndrome with tacrolimus (FK 506) [abstract]. Nephrology
children with frequently relapsing nephrotic syndrome. Kidney Dialysis Transplantation 2003;18(Suppl 4):65. [CENTRAL:
International 2000;58(1):317-24. [MEDLINE: 10886577] CN-00444378]
Yoshioka K, Ohashi Y, Sakai T, Ito H, Yoshikawa N, Nakamura H, Cerkauskiene 2004 {published data only}
et al. Placebo-controlled trial of mizoribine (MZR) in children Cerkauskiene R, Jankauskiene A, Kaltenis P. Effect of omega-3
with frequently relapsing nephrotic syndrome (FRNS). fatty acids on serum homocysteine in childhood steroid-
The Pediatric Mizoribine Study Group [abstract]. Journal sensitive nephrotic syndrome [abstract no: P011]. Pediatric
of the American Society of Nephrology 1998;9(Program & Nephrology 2004;19(9):C95.
Abstracts):163A. [CENTRAL: CN-00448484]
Dharmaraj 2009 {published data only}
Zhang 2014 {published data only}
Dharmaraj R, Hari P, Bagga A. Randomized cross-over trial
* Zhang B, Liu T, Wang W, Zhang X, Fan S, Liu Z, et al. A comparing albumin and frusemide infusions in nephrotic
prospective randomly controlled clinical trial on azithromycin syndrome. Pediatric Nephrology 2009;24(4):775-82. [MEDLINE:
therapy for induction treatment of children with nephrotic 19142668]
syndrome. European Journal of Pediatrics 2014;173(4):509-15.
[MEDLINE: 24240666] Hari P, Bagga A. Does albumin infusion augment frusemide
induced diuresis in edematous children with nephrotic
Zhang BL, Liu T. A prospective clinical randomized controlled syndrome? [abstract no: M-PO-0834]. 4th World Congress of
trial on azithromycin therapy in induction treatment in Nephrology.19th International Congress of the International
Society of Nephrology (ISN); 2007 Apr 21-25; Rio de Janeiro, refractory nephrotic syndrome (RAMP). www.clinicaltrials.gov/
Brazil. 2007:285. ct2/show/NCT02390362 (first received 17 March 2015).
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Control group
• No treatment
Co-interventions
• Not reported
• Prednisone for relapses
Abeyagunawardena 2006a (Continued)
Outcomes • Number in relapse at completion of 12 months of therapy/no treatment (relapse: 3+ proteinuria on
3 consecutive days)
• Adverse effects
Risk of bias
Random sequence genera- Low risk Sealed envelope method (information from author)
tion (selection bias)
Allocation concealment Low risk Sealed envelopes. Participants or investigators could not influence group as-
(selection bias) signment (information from author)
Blinding of participants High risk No blinding and lack of blinding could influence the patient's management
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk No blinding and lack of blinding could influence assessment of outcome
sessment (detection bias)
All outcomes
Incomplete outcome data Low risk All participants included in analysis (information from author)
(attrition bias)
All outcomes
Abeyagunawardena 2006b
Methods • Study design: parallel RCT
• Time frame: 2002 to 2005
• Follow-up period: 12 months
• IV CPA: 500 mg/m2/dose 4 times/week for 6 months (total dose 132 mg/kg)
Abeyagunawardena 2006b (Continued)
Treatment group 2
Co-interventions
• Not reported
• Prednisone for relapses
Outcomes • Mean relapse rate at 6 months and 1 year follow-up from beginning of treatment
• Adverse effects
Risk of bias
Random sequence genera- Low risk Sealed envelope method (information from author)
tion (selection bias)
Allocation concealment Low risk Sealed envelopes. Not possible for participants/investigators to influence
(selection bias) group assignment (information from author)
Blinding of participants High risk No blinding. Different IV regimens/could Influence use of other medications
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk Outcome assessors not blinded and lack of blinding could influence the results
sessment (detection bias)
All outcomes
Incomplete outcome data Low risk All patients included in analyses (information from the author)
(attrition bias)
All outcomes
Selective reporting (re- Unclear risk Expected outcomes reported but only abstract data available
porting bias)
Abeyagunawardena 2007
Methods • Study design: parallel RCT
• Time frame: over 3 years
• Follow-up period: 24 months
Abeyagunawardena 2007 (Continued)
• Number: treatment group 1 (18); treatment group 2 (21)
• Mean age (years): treatment group 1 (6.4); treatment group 2 (7.2)
• Sex (M/F): treatment group 1 (11/7); treatment group 2 (15/6)
• Exclusion criteria: not reported
• IV CPA 500 mg/m2/dose monthly for 6 months (total dose 132 mg/kg)
Treatment group 2
• Vincristine: 1.5 mg/m2/dose weekly x 4 doses then monthly x 4 doses for 4 months (total duration 5
months)
Co-interventions
Risk of bias
Random sequence genera- Low risk "Envelope method containing same number of vincristine and CPA". Informa-
tion (selection bias) tion provided by author
Allocation concealment Low risk Allocation "this was done by a person not related to the trial. Until allocation is
(selection bias) done the investigators were not aware of the treatment regimen". Information
provided by author
Blinding of participants High risk No blinding. Different IV regimens/could Influence use of other medications
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk Outcome assessors not blinded and lack of blinding could influence diagnosis
sessment (detection bias) of relapse
All outcomes
Incomplete outcome data Low risk All patients completed study. Information provided by author
(attrition bias)
All outcomes
Abeyagunawardena 2007 (Continued)
Selective reporting (re- Unclear risk Limited information on results
porting bias)
Ahn 2018
Methods • Study design: parallel 2:1 RCT
• Time frame: not reported
• Follow-up period: 1 year
• RTX: single dose of 375 mg/m2 (maximum 500 mg), repeated after 2 weeks if CD19 depletion not
achieved
• CNI/steroids
Control group
• No RTX
• CNI/steroids
Co-interventions
• Not reported
Notes • Data analysed on 51 patients who received treatment without protocol violation
• 17/36 patients in the rituximab group experienced an infusion reaction, infection (any) occurred in
13/36 in the rituximab group and 3/18 in the control group, serious adverse events were reported in
3/36 in the rituximab group and 1/18 in the control group
Risk of bias
Random sequence genera- Low risk Computer generated, permuted block, stratified by sex and age
tion (selection bias)
Allocation concealment Unclear risk Methods comment on randomisation but not allocation.
(selection bias)
Ahn 2018 (Continued)
Blinding of participants High risk Open-label study
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- Unclear risk Data analysed on 51 patients who received treatment without protocol viola-
sessment (detection bias) tion
All outcomes
Incomplete outcome data Low risk From 61 randomised, 7 patients withdrew consent following randomisation
(attrition bias) or did not receive rituximab, 3 patients (1 in rituximab and 2 in control group)
All outcomes were excluded from analysis for unspecified protocol violations
Selective reporting (re- Low risk Safety was assessed using the Common Terminology Criteria for Adverse
porting bias) Events, version 4.0
Other bias Low risk Supported by a grant (11172MFDS298) from Ministry of Food and Drug Safety
in 2011-2012
Al-Saran 2006
Methods • Study design: parallel RCT
• Time frame: 1 January 2001 to 31 December 2003
• Follow-up period: 12 months
• Levamisole: 2.5 mg/kg on alternate days for 1 year started when child in remission
Control group
• Low dose prednisone: < 0.5 mg/kg/d on alternate days after achieving remission
Co-interventions
• Not reported
Notes • Exclusions post randomisation but pre-intervention: Unclear how many excluded from analysis be-
cause levamisole given for < 3 months
• Stop or end point/s: not reported
Al-Saran 2006 (Continued)
• Additional data requested from authors: Data on quality items and clarification of treatment regimens
sought but no response obtained
Risk of bias
Random sequence genera- Unclear risk Study described as randomised; method of randomisation not reported
tion (selection bias)
Blinding of participants High risk No blinding and lack of blinding could influence patient management
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk No blinding and lack of blinding could influence the outcome assessment
sessment (detection bias)
All outcomes
Other bias Low risk Funding support from King Abdulaziz City for Science and Technology(KACST),
Saudi Arabia, but not influence the outcome
Alatas 1978
Methods • Study design: parallel RCT
• Time frame: not reported
• Follow-up period: 20 followed to 6 months and 11 to 1 year
• Oral chlorambucil: 0.3 mg/kg/day (total dose 16.8 mg/kg) for 8 weeks
• Prednisone: 40 mg/m2/day for 8 weeks
Control group
• Placebo
• Prednisone: 40 mg/m2/day for 8 weeks
Alatas 1978 (Continued)
Co-interventions
• All treated with prednisone 60 mg/m2/day until remission and then randomised
Risk of bias
Random sequence genera- Unclear risk Study described as randomised; method of randomisation not reported
tion (selection bias)
Blinding of participants Low risk Both participants and investigators were blinded (used placebo)
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- Low risk No information provided but control group received placebo
sessment (detection bias)
All outcomes
Incomplete outcome data High risk Complete follow-up at 6 months; 5/11 patients (45.5%) of group I and 5/9 pa-
(attrition bias) tients (55.6%) of group II completed 12 months follow-up. This could influence
All outcomes the results at 12 months period
APN 1982
Methods • Study design: parallel RCT
• Time frame: 1977 to 1981
• Follow-up period: 2 years
APN 1982 (Continued)
• Exclusion criteria: previous treatment with cytotoxic agents; kidney biopsy-proven lesion other than
MCNS
Treatment group 2
Co-interventions
• All treated with prednisone 60 mg/m2/d until remission and then randomised
Risk of bias
Random sequence genera- Unclear risk Study described as randomised; method of randomisation not reported
tion (selection bias)
Blinding of participants High risk No blinding and lack of blinding could influence the management
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk No blinding and lack of blinding could influence outcome assessment
sessment (detection bias)
All outcomes
Incomplete outcome data Low risk Complete follow-up to 60 months (information from authors)
(attrition bias)
All outcomes
Selective reporting (re- Low risk Expected outcome data reported (information from authors)
porting bias)
Other bias Low risk Supported by grant (Ez. I-34844) from the VW-Foundation
APN 2006
Methods • Study design: parallel RCT
• Time frame: not reported
• Follow-up period: 2 years
• CSA: 150 mg/m2/day for 8 weeks; dose altered to achieve levels 80 to 150 ng/mL
• Prednisone: 60 mg/m2/day for 6 weeks; 40 mg/m2 on alternate days for 6 weeks (total duration 12
weeks)
Treatment group 2
• Prednisone 60 mg/m2/day for 6 weeks; 40 mg/m2 on alternate days for 6 weeks (total duration 12
weeks)
Co-interventions
• Not reported
Outcomes • Number of patients with relapse and mean relapse rate at 6 and 12 months
• Median time to relapse
• Number needing cytotoxic agents
• Adverse effects of CSA
• ISKDC and APN definitions of remission/relapse used
• Cumulative steroid dose
• Adverse effects
Risk of bias
Blinding of participants High risk No blinding reported and the outcome is likely to be influenced by lack of
and personnel (perfor- blinding
mance bias)
All outcomes
Blinding of outcome as- High risk No blinding of outcome assessment reported and outcome measurement like-
sessment (detection bias) ly to be influenced by lack of blinding
Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children (Review) 51
Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.
Library Better health. Cochrane Database of Systematic Reviews
APN 2006 (Continued)
All outcomes
Incomplete outcome data High risk 152 randomised, 25 withdrew consent (127 entered study)
(attrition bias)
All outcomes CSA/prednisone group: 13/62 (17%) excluded (SRNS (7), infection (3), throm-
bosis (2), protocol deviation (1))
Prednisone group: 10/65 (15%) excluded (infection (1), SRNS (7), protocol devi-
ation (1), unstated (1))
Selective reporting (re- High risk Not all of review's pre-specified outcomes have been reported. No report on
porting bias) number of FRNS. Adverse events and outcomes are reported in percentages
ATLANTIS 2018
Methods • Study design: parallel RCT
• Time frame: recruitment from May 2014 to November 2017, with follow-up until March 2018
• Follow-up period: 6 months
• ACTH: 80 U/1.73 m2 administered twice weekly for 6 months, followed by 40 U/1.73 m2 administered
twice weekly for 6 months (total duration 12 months)
Control group
Notes • The study was stopped at a preplanned interim analysis after enrolment of 31 participants because
of a lack of treatment efficacy
Risk of bias
ATLANTIS 2018 (Continued)
Bias Authors' judgement Support for judgement
Blinding of outcome as- High risk Open-label study; no information provided on how relapse was confirmed
sessment (detection bias)
All outcomes
Other bias High risk The study was supported by Mallinckrodt Pharmaceuticals and Questcor Phar-
maceuticals
Baluarte 1978
Methods • Study design: parallel RCT
• Time frame: not reported
• Follow-up period: average 28.6 months (stable dose) 1); 27.2 months (increasing dose)
• Oral chlorambucil (stable dose): 0.2 mg/kg/day for 8 weeks (total dose 11.2 mg/kg)
Treatment group 2
• Oral chlorambucil (increasing dose): 0.2 mg/kg/day increasing by about 0.1 mg/kg every 2 weeks for
6 to 11 weeks until leucopenia (maximum total dose up to 32.5 mg/kg)
Co-interventions
• Prednisone 60 mg/m2/d until urine protein-free for 5 to 7 days. Prednisone 60 mg/m2 on alternate
days until WCC > 4000 in both groups
Baluarte 1978 (Continued)
Outcomes • Number with relapse at 6 months (no definition provided)
• Adverse effects
Risk of bias
Random sequence genera- Unclear risk Study described as randomised; method of randomisation not reported
tion (selection bias)
Blinding of participants High risk No blinding and lack of blinding could influence the maintenance
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk No blinding and lack of blinding could influence the results
sessment (detection bias)
All outcomes
Incomplete outcome data Low risk All patients followed up for at least 12 months
(attrition bias)
All outcomes
Other bias Low risk Funding support from the National Institutes of Health General Clinical Re-
search Center
BAPN 1991
Methods • Study design: parallel RCT
• Time frame: not reported
• Follow-up period: 28 weeks
Control group
Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children (Review) 54
Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.
Library Better health. Cochrane Database of Systematic Reviews
BAPN 1991 (Continued)
• Placebo on alternate days for 16 weeks
Co-interventions
• Prednisone 2 mg/kg/day until remission; prednisone 1 mg/kg on alternate days for 28 days, reduced
by 0.25 mg/kg every 14 days and ceased at 8 weeks
Outcomes • Relapse at end of treatment (defined as 3+ proteinuria for 3 consecutive days, confirmed on ACR > 2
mg/mg or PCR > 200 mg/mmol)
• Relapse at 6 months
• Adverse effects
Risk of bias
Random sequence genera- Unclear risk Study described as randomised; method of randomisation not reported
tion (selection bias)
Blinding of outcome as- Low risk Double blinded placebo controlled study
sessment (detection bias)
All outcomes
Other bias High risk Help and support given by Janssen Pharmaceuticals Ltd. (UK)
Barratt 1970
Methods • Study design: parallel RCT
• Time frame: not reported
• Follow-up period: 18 to 123 weeks
Participants • Country: UK
• Setting: single tertiary centre
• Inclusion criteria: FR-SSNS (3+ relapses in at least 6 months, who had previously relapsed on at least
0.2 mg/kg of prednisolone on AD when they had been in prednisolone-maintained remission for at
least 2 weeks); age < 14 years
Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children (Review) 55
Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.
Library Better health. Cochrane Database of Systematic Reviews
Barratt 1970 (Continued)
• Number: treatment group (15); control group (15)
• Age range (years): treatment group (1.9 to 12.9); control group (2.9 to 12.6)
• Sex (M/F): not reported
• Exclusion criteria: unable to tolerate 8 weeks prednisone
Control group
Co-interventions
Outcomes • Relapse at 6 months (defined as oedema and ACR > 1.0 or Albustix 3+ or 4+ on 2 days)
• Relapse at 12 months
• Relapse at 2 years
Risk of bias
Random sequence genera- Unclear risk Study described as randomised; method of randomisation not reported
tion (selection bias)
Blinding of participants High risk No blinding and lack of blinding could influence the management
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk No blinding and lack of blinding could influence the outcome assessment
sessment (detection bias)
All outcomes
Incomplete outcome data Low risk 4/30 did not complete 1 year follow-up but unlikely to affect results
(attrition bias)
All outcomes
Other bias Low risk Funding support from The Medical Research Council
Barratt 1973
Methods • Study design: parallel RCT
• Time frame: not reported
• Follow-up period: 20 to 104 weeks
Participants • Country: UK
• Setting: single tertiary centre
• Inclusion criteria: FR-SSNS (3+ relapses in at least 6 months); age < 14 years
• Number: treatment group 1 (16); treatment group 2 (16)
• Age range (years): treatment group 1 (3.7 to 13.8); treatment group 2 (4.1 to 12.9)
• Sex (M/F): not reported
• Exclusion criteria: unable to tolerate 8 weeks prednisone
Co-interventions
• Maintenance prednisone for 8 weeks; taper for 8 weeks after CPA completed
Notes • Exclusions post randomisation but pre-intervention: 3 excluded from short CPA group
• Stop or end point/s: not reported
• Additional data requested from authors: none
• No information on adverse effects
Risk of bias
Random sequence genera- Unclear risk Study described as randomised; method of randomisation not reported
tion (selection bias)
Blinding of participants High risk No blinding and lack of blinding could influence the management
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk No blinding and lack of blinding could influence outcome assessment
sessment (detection bias)
All outcomes
Incomplete outcome data Low risk 4 patients withdrawn after randomisation and not included in analysis. 1/32
(attrition bias) patients did not complete 24 weeks to evaluation
All outcomes
Barratt 1973 (Continued)
Other bias Low risk Funding support by Ward Blenkinsop Ltd. (Private non-trading company in
London)
Barratt 1977
Methods • Study design: parallel RCT
• Time frame: not reported
• Follow-up period: 32 weeks
Participants • Country: UK
• Setting: single tertiary centre
• Inclusion criteria: SD-SSNS (previous relapse on at least 0.2 mg/kg of prednisone on alternate days);
age < 14 years
• Number: treatment group (12); control group (12)
• Mean age: not reported
• Sex (M/F): not reported
• Exclusion criteria: not reported
Control group
Co-interventions
• Not reported
Outcomes • Number in relapse at 32 weeks (defined as urine ACR > 1.0 in 2 specimens)
Risk of bias
Random sequence genera- Unclear risk Study described as randomised; method of randomisation not reported
tion (selection bias)
Allocation concealment Low risk Sealed cards (using 2 boxes containing 8 cards for each group)
(selection bias)
Blinding of participants High risk No blinding and lack of blinding could influence the management
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk No blinding and lack of blinding could influence assessment of outcome
sessment (detection bias)
Barratt 1977 (Continued)
All outcomes
Cerkauskiene 2005
Methods • Study design: cross-over RCT
• Time frame: May 1992 to March 1994
• Follow-up period: unclear
• Oral fusidic acid: 0.5 to 1.5 g/day according to age in 3 to 4 divided doses for 2 months
• Prednisone: 1.5 to 2 mg/kg/day until remission (negative urine on 3 consecutive days), alternate day
dose tapered over next 6 weeks
Control group
• Prednisone: 1.5 to 2 mg/kg/day until remission (negative urine on 3 consecutive days), alternate day
dose tapered over next 6 weeks
Co-interventions
Risk of bias
Cerkauskiene 2005 (Continued)
Random sequence genera- Unclear risk Study described as randomised; method of randomisation not reported
tion (selection bias)
Allocation concealment Unclear risk Envelopes used but unclear whether these were sealed, opaque envelopes
(selection bias)
Blinding of participants High risk No blinding and lack of blinding could influence the management
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk No blinding and lack of blinding could influence the outcome assessment
sessment (detection bias)
All outcomes
Incomplete outcome data Low risk 13/18 (72%) completed both courses of treatment. 31/36 (86%) (31/31) evalu-
(attrition bias) able courses of treatment
All outcomes
Selective reporting (re- High risk Expected outcomes reported. but data only available for combined groups so
porting bias) cannot be included in meta-analysis
Chiu 1973
Methods • Study design: parallel RCT
• Time frame: September 1967 to November 1971
• Follow-up period: 26.6 (20 to 38) months in control group. 25.7 (14 to 39) months in treatment group
Control group
• Prednisone: 60 mg/m2/day until urine protein-free for 2 weeks, then same dose on alternate days,
total 16 weeks
Co-interventions
• Not reported
Chiu 1973 (Continued)
• Number in relapse at 20 months
Risk of bias
Random sequence genera- Low risk Small lots (2 to 8) were set up by independent person
tion (selection bias)
Allocation concealment Low risk At allocation, independent person selected intervention at random from lot
(selection bias)
Blinding of participants High risk No blinding and lack of blinding could influence management
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk No blinding and lack of blinding could influence the assessment of outcomes
sessment (detection bias)
All outcomes
Incomplete outcome data Low risk Completeness of follow-up in both groups (12/12, 11/11 in groups I and II re-
(attrition bias) spectively)
All outcomes
Dayal 1994
Methods • Study design: parallel RCT
• Time frame: 1988 to 1990
• Follow-up period: 12 months in treatment group, 10.5 months in control group
Control group
Dayal 1994 (Continued)
• No treatment for 52 weeks
Co-interventions
• Prednisolone 60 mg/m2/day for 4 weeks, prednisolone 40 mg/m2 on alternate days for weeks to
achieve initial remission and for relapse
Outcomes • Number in relapse at end of treatment (12 months) (defined as oedema, urine protein > 1 g/m2/day
and serum albumin < 2.5 g/100 mL)
• Adverse effects
Risk of bias
Blinding of participants High risk No blinding and lack of blinding could influence management
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk No blinding and lack of blinding could influence outcome assessment
sessment (detection bias)
All outcomes
Incomplete outcome data Low risk Only one patient lost to follow-up but not included in analysis (3%)
(attrition bias)
All outcomes
Other bias Low risk Financial assistance given by the Fluid Research Fund, Christian Medical Col-
lege, Vellore, India
Donia 2005
Methods • Study design: parallel RCT
• Time frame: not reported
• Follow-up period: 2 years
Donia 2005 (Continued)
• Inclusion criteria: 40 consecutive patients with SD-SSNS recruited in relapse, allocated after remis-
sion; all had MCD on biopsy
• Number: treatment group 1 (20); treatment group 2 (20)
• Mean age ± SD (years): treatment group 1 (7.4 ± 2.89); treatment group 2 (7.38 ± 2.44)
• Sex (M/F): treatment group 1 (16/4); treatment group 2 (15/5)
• Exclusion criteria: not reported
Treatment group 2
• IV CPA: 500 mg/m2/dose monthly for 6 months (total dose 132 mg/kg)
• Prednisone: 1 mg/kg on alternate days for 14 days, reduce by 0.25 mg/kg every 14 days (total duration
2 months)
Co-interventions
• Not reported
Outcomes • Number in relapse at end of treatment (6 months), 6 months, 12 months, 24 months after the end of
therapy (relapse: 3+ proteinuria for 3 consecutive days/protein excretion > 50 mg/kg/d)
• Adverse effects
Notes • Exclusions post randomisation but pre-intervention: 2 children from levamisole group and one from
IV cyclophosphamide group excluded before intervention and replaced by next enrolled patient
• Stop or end point/s: not reported
• Additional data requested from authors: information on patient numbers, randomisation, allocation
concealment and loss to follow-up obtained from the authors
Risk of bias
Random sequence genera- Low risk Table of random numbers. Patients withdrawn before treatment were re-
tion (selection bias) placed in that group by next enrolled patient
Blinding of participants High risk Open-labelled study (no blinding and lack of blinding could influence the man-
and personnel (perfor- agement)
mance bias)
All outcomes
Blinding of outcome as- High risk Open-labelled study (no blinding and lack of blinding could influence the as-
sessment (detection bias) sessment of results)
All outcomes
Donia 2005 (Continued)
Other bias Unclear risk Insufficient information to permit judgement
Dorresteijn 2008
Methods • Study design: parallel RCT
• Time frame: enrolled January 2003 to June 2005
• Follow-up period: 12 months
Treatment group 2
• CSA: 4 to 5 mg/kg/day in 2 divided doses for 1 year (to maintain level 50 to 150 ng/dL)
Co-interventions
Risk of bias
Allocation concealment Low risk Opaque and sealed envelopes prepared by study statistician
(selection bias)
Blinding of participants High risk Open-label study. Lack of blinding could influence management
and personnel (perfor-
mance bias)
All outcomes
Dorresteijn 2008 (Continued)
Blinding of outcome as- High risk Open-label study. Lack of blinding could influence outcome assessment
sessment (detection bias)
All outcomes
Incomplete outcome data High risk 22.6% excluded; 3/15 children excluded from MMF group (FSGS (1), no biopsy
(attrition bias) (2)) and 4/16 children excluded from CSA group (no biopsy (2), did not receive
All outcomes CSA (2))
Edefonti 1988
Methods • Study design: parallel RCT
• Time frame: not reported
• Follow-up period: 3 months to 2 years
• Oral CSA: 6 mg/kg/day for 9 months (dose adjusted for trough level 200 to 600 ng/mL), reducing over
next 3 months (total duration 12 months)
Treatment group 2
• Oral CPA: 2.5 mg/kg/day for 8 weeks (total dose 140 mg/kg)
Co-interventions
• For relapse prednisone 60 mg/m2/day until remission, prednisone 40 mg/m2 on alternate days for 4
weeks
Outcomes • Number in relapse at 9 months (defined as urine protein > 4 mg/m2/h for 2 weeks)
• Number in relapse at 24 months
• Adverse effects
Edefonti 1988 (Continued)
Notes • Exclusions post randomisation but pre-intervention: 7 excluded post randomisation when did not re-
turn for follow-up
• Stop or end point/s: not reported
• Additional data requested from authors: detailed paediatric data requested but not obtained
Risk of bias
Random sequence genera- Unclear risk Study described as randomised; method of randomisation not reported
tion (selection bias)
Blinding of participants High risk No blinding and lack of blinding could influence management (open label)
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk No blinding and lack of blinding could influence assessment of outcomes
sessment (detection bias) (open label)
All outcomes
Incomplete outcome data High risk 4/66 (6%) lost to follow-up at 3 to 9 months and 1 changed to CSA after 10
(attrition bias) months, 43 of 55 children (78.2%) completed follow-up at 24 months
All outcomes
Gellermann 2013
Methods • Study design: cross-over RCT
• Time frame: December 2003 to April 2008
• Follow-up period: 2 years in total (1 year on each treatment)
• Oral MMF: starting dosage 1000 to 1200 mg/m2/day adjusted for target MPA trough of 1.5 to 2.5 µg/
mL for 1 year
Gellermann 2013 (Continued)
Treatment group 2
• Oral CSA: starting dose 150 mg/m2/day adjusted for target trough level 80 to 100 ng/mL for 1 year
Co-interventions
• Not reported
Notes • Authors kindly provided additional information for year one of trial prior to cross-over, allowing for
inclusion in meta-analysis as a RCT
Risk of bias
Allocation concealment Low risk Sequence held centrally under lock and key
(selection bias)
Blinding of participants High risk Open-label study. Lack of blinding could influence management
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk Open-label study. Lack of blinding could influence outcome assessment
sessment (detection bias)
All outcomes
Incomplete outcome data Low risk The analysis is not ITT. However, the number of patients excluded is small (7%)
(attrition bias) in MMF arm and the primary outcome continuous
All outcomes
Selective reporting (re- Low risk Authors have provided first year data separately for review
porting bias)
Grupe 1976
Methods • Study design: parallel RCT
• Time frame: not reported
• Follow-up period: 19.6 (12 to 34) months in treatment group; 20.0 (12 to 33) months in control group
Grupe 1976 (Continued)
• Number: treatment group (10); control group (11)
• Mean age, range (years): treatment group (11.0, 3 to 15.5); control group (7.0, 3.3 to 12)
• Sex (M/F): treatment group (6/4); control group (7/4)
• Exclusion criteria: not reported
• Oral chlorambucil: started at 0.1 to 0.2 mg/kg/day and increased every 2 weeks (average maximum
dose 0.33 mg/kg/day, range 0.26 to 0.41) until WCC fell (average 9.7 weeks, range 6 to 12 weeks) (total
average dose 16.9 mg/kg (range 9.5 to 23.7 mg/kg))
• Prednisone: 80 to 120 mg on alternate days for 2 months, taper over 4 to 6 weeks; given until WCC >
5000
Control group
Co-interventions
• To induce remission, both groups given prednisone 40 to 60 mg/d until urine protein free for 2 weeks
Outcomes • Number in relapse at 6 months (defined as urine protein 100 mg/24 hours for > 10 days)
• Number in relapse at 12 months
• Adverse effects
Risk of bias
Random sequence genera- Unclear risk Study described as randomised; method of randomisation not reported
tion (selection bias)
Blinding of participants High risk No blinding and lack of blinding could influence the management
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk No blinding and lack of blinding could influence the outcome assessment
sessment (detection bias)
All outcomes
Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children (Review) 68
Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.
Library Better health. Cochrane Database of Systematic Reviews
Gruppen 2015
Methods • Study design: parallel RCT
• Time frame: October 2007 to March 2012
• Follow-up period: 12 months
• Levamisole: 2.5 mg/kg on alternate days; maximum 150 mg. Commenced 3 to 21 days after remission
(total duration 12 months)
Control group
• Placebo: same dose given on alternate days. Commenced 3 to 21 days after remission (total duration
12 months)
Co-interventions
• To induce remission, both groups treated with prednisone using French Protocol (daily till remission,
alternate days for 4 months with monthly reduction in dose)
Risk of bias
Random sequence genera- Low risk Patients were randomly allocated by a computerized random number genera-
tion (selection bias) tor in a 1:1 ratio.
Allocation concealment Low risk Patients were randomly allocated by a computerized random number genera-
(selection bias) tor in a 1:1 ratio. Within the strata, the randomisation procedure was blocked.
Stratified for FRNS/SDNS, country, previous use of CPA
Blinding of participants Low risk Patients, parents, investigators, medical and nursing staff, outcome assessors,
and personnel (perfor- monitors, and data analysts were blinded to study medication.
mance bias)
All outcomes
Blinding of outcome as- Low risk Patients, parents, investigators, medical and nursing staff, outcome assessors,
sessment (detection bias) monitors, and data analysts were blinded to study medication.
Gruppen 2015 (Continued)
All outcomes
Selective reporting (re- Low risk Reported expected outcomes. Time to relapse, number with relapse, adverse
porting bias) effects
Other bias Low risk This study was funded by the Dutch Kidney Foundation, the Dutch Orphan Dis-
ease Foundation, Emma Foundation, the Dutch Health Insurance Achmea and
the French State Department of Health. The study performed in collaboration
with ACE Pharmaceuticals
Iijima 2011
Methods • Study design: parallel RCT
• Time Frame: November 2008 to November 2011
• Follow-up period: 1 year
Control group
Co-interventions
• Prednisolone for 6 weeks or for treatment of relapse and tapering doses of cyclosporin
Notes • Exclusion post randomisation but pre-intervention: 3 in RTX arm and 1 in placebo arm
• Stop or end-points: Randomisation was stopped early after pre-planned interim analysis (May 2010)
• Additional information requested from authors: number with relapse at 3 and 6 months provided for
meta-analysis
Risk of bias
Iijima 2011 (Continued)
Bias Authors' judgement Support for judgement
Random sequence genera- Low risk Minimisation method using SAS PROC PLAN
tion (selection bias)
Allocation concealment Low risk Allocation codes kept under lock until entire study completed
(selection bias)
Other bias Unclear risk Drug and placebo provided by pharmaceutical company but trial funded by
government. Trial stopped early but type one error unlikely given very small P-
value on primary outcome
Iijima 2014
Methods • Study design: parallel RCT
• Time frame: July 2005 to Jan 2009
• Follow-up period: 2 years
• Higher-level arm: CSA starting at 3 to 4 mg/kg/day in 2 divided doses, dose titrated for whole-blood
C2 level between 600 and 700 ng/mL for the first 6 months and then between 450 and 550 ng/mL for
the next 18 months
Treatment group 2
• Lower-level arm: CSA starting at 3 to 4 mg/kg/day in 2 divided doses, dose titrated for whole-blood
C2 level between 450 and 550 ng/mL for the first 6 months and then 300 to 400 ng/mL for the next
18 months
Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children (Review) 71
Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.
Library Better health. Cochrane Database of Systematic Reviews
Iijima 2014 (Continued)
Co-interventions
Notes
Risk of bias
Random sequence genera- Low risk QUOTE: "open-label, multicenter, prospective, randomised phase II controlled
tion (selection bias) trial".
Allocation concealment Unclear risk Unclear whether randomisation method could be influenced by investiga-
(selection bias) tors/participants
Blinding of outcome as- High risk Open-label study and primary outcome was relapse-free survival
sessment (detection bias)
All outcomes
Incomplete outcome data Low risk 8/94 (8.5%) excluded from analysis. Other patients accounted for
(attrition bias)
All outcomes
Other bias Unclear risk First author received funding from study drug manufacturer. However, given
nature of study unlikely to have a differential impact on the study groups
Ishikura 2008
Methods • Study design: parallel RCT
• Time frame: January 1996 to January 2002
• Follow-up period: 24 months
Ishikura 2008 (Continued)
• Number (randomised/analysed): treatment group 1 (29/24); treatment group 2 (27/20)
• Mean age (years): treatment group 1 (8.5); treatment group 2 (8.9)
• Sex (M/F): treatment group 1 (18/6); treatment group 2 (17/3)
• Exclusion criteria: previous treatment with CSA; renal insufficiency (CrCl ≤ 60 mL/min/1.73 m2); active
infection; secondary NS; pregnancy
• CSA: dose to maintain level 80 to 100 ng/mL (average dose 5.4 mg/kg/day) for 6 months then CSA to
maintain level 60 to 80 ng/mL (4.8 mg/kg/day) for 18 months
• CSA: dose to maintain level 80 to 100 ng/mL for 6 months then 2.5 mg/kg/day (fixed dose) for 18
months
Co-interventions
• Prednisone for relapse 2 mg/kg/day (maximum 80 mg) for 4 weeks then 2 mg/kg alternate day for 2
weeks, 1 mg/kg alternate day for 2 weeks and 0.5 mg/kg alternate day for 2 weeks
• ACEi in 4 patients in treatment group 1 and 1 patient in treatment group 2
Risk of bias
Random sequence genera- Unclear risk Randomisation list prepared by the steering committee but method not stated
tion (selection bias)
Blinding of participants High risk No blinding and lack of blinding could influence the management
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk Outcome assessors not blinded and lack of blinding could influence the as-
sessment (detection bias) sessment of outcomes
All outcomes
Incomplete outcome data Low risk Excluded patients unlikely to influence results. Inclusion of patients deliber-
(attrition bias) ately maintained on changing dose therapy though randomised to fixed dose
All outcomes therapy could have overestimated response in changing dose group; 12/56
(21.4%) (3 from changing dose group and 7 from fixed dose group excluded for
protocol violation from 3 centres as all patients received changing CSA dose
despite randomisation. 1 patient ineligible and data excluded; 1 lost to fol-
low-up and no data available)
Selective reporting (re- High risk Expected outcomes reported. Data provided as HR and data estimated from %
porting bias) to include in meta-analyses
Ishikura 2008 (Continued)
Other bias Low risk All patients received Sandimmune formulation of cyclosporin A. Patient re-
cruitment terminated when Neoral formulation became available
ISKDC 1970
Methods • Study design: parallel RCT
• Time frame: January 1967 to December 1969
• Follow-up period: 6 months
Control group
Co-interventions
• Not reported
Outcomes • Number in relapse at 6 months: defined as proteinuria > 4 mg/m2/day for 3 consecutive days out of 7
Notes • Exclusions post randomisation but pre-intervention: 4 withdrawn after randomisation (3 withdrawn
during treatment) and data not included in results
• Stop or end point/s: not reported
• Additional data requested from authors: none
Risk of bias
Blinding of participants Low risk Double-blind controlled study; "neither patients or caregivers knew which
and personnel (perfor- medication they were receiving"
mance bias)
All outcomes
ISKDC 1970 (Continued)
Blinding of outcome as- Low risk Double-blind study. Presumed that caregivers also assessed outcomes
sessment (detection bias)
All outcomes
Incomplete outcome data Low risk One patient excluded from placebo group, unlikely to alter results; 4% (8/197)
(attrition bias) were loss to follow-up
All outcomes
ISKDC 1974
Methods • Study design: parallel RCT
• Time frame: April 1970 to June 1972
• Follow-up period: 1.8 years in treatment group, 1.7 years in control group
• Oral CPA: 5 mg/kg/day until WCC 3000 to 5000/mm3 and then 1 to 3 mg/kg/day to maintain WCC 3000
to 5000/mm3 (total duration 42 days (6 weeks); total dose/kg not calculated)
• Prednisone: 10 mg/m2/day for 10 days
Control group
• Prednisone: 40 mg/m2 divided doses on 3 consecutive days out of 7 days for 180 days
Co-interventions
• None
Outcomes • Number in relapse at 6 months (defined as urine protein > 4 mg/m2/hour on 3 consecutive examina-
tions on 3 separated days during the course of not more than 7 days)
• Mean relapse rate/patient/year
• Adverse effects
Notes • Exclusions post randomisation but pre-intervention: 10 patients (18.9%) excluded before allocated
due to lost to follow-up or treated incorrectly
• Stop or end point/s: not reported
• Additional data requested from authors: none
Risk of bias
ISKDC 1974 (Continued)
Bias Authors' judgement Support for judgement
Random sequence genera- Unclear risk Study described as randomised; method of randomisation not reported
tion (selection bias)
Blinding of participants High risk No blinding and lack of blinding could influence the management
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk "Investigators decided if and when relapse has occurred"
sessment (detection bias)
All outcomes
Incomplete outcome data Low risk Completeness of follow-up (10 patients excluded before allocated)
(attrition bias)
All outcomes
Other bias Low risk Funding supported from the National Institutes of Health Research, Kidney
Foundation of New York, Kidney Disease Institute of the State of New York, Na-
tional Kidney Foundation, UK and the John Rath Foundation
McCrory 1973
Methods • Study design: parallel RCT
• Time frame: September 1969 to October 1970
• Follow-up period: 18 months
• Oral CPA: 2.5 mg/kg/day for 90 days (total dose 225 mg/kg)
• Prednisone: 1.5 mg/kg on alternate days for 90 days
Co-interventions
• Not reported
McCrory 1973 (Continued)
Outcomes • Number in relapse at 6, 12 and 18 months: defined as urine protein > 4 mg/m2/hour on 3 out of 7 days
• Duration of remission
• Adverse effects
Risk of bias
Random sequence genera- High risk Odds and even numbers from medical record numbers
tion (selection bias)
Allocation concealment High risk Odds and even numbers from medical record numbers
(selection bias)
Blinding of participants High risk No blinding and lack of blinding could influence the management
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk No blinding and lack of blinding could influence the outcome assessors
sessment (detection bias)
All outcomes
Other bias Low risk Funding support from the New York Kidney Disease Foundation.
NEPHRUTIX 2018
Methods • Study design: Parallel group RCT
• Time frame: not reported
• Follow-up period: not reported
NEPHRUTIX 2018 (Continued)
• RTX: 375 mg/m2 x 2 doses IV
Control group
• Placebo: x 2 doses IV
• Rituximab: 375 mg/m2 x 2 doses IV given after first relapse during study
Co-interventions
Notes • Unclear whether study presents data from all participants included in the study
• Reports studies T-cell subsets with limited clinical information
• NEPHRUTIX trial, NCT01268033
Risk of bias
Random sequence genera- Unclear risk Double-blind, randomised, placebo vs Rituximab controlled trial. No other in-
tion (selection bias) formation provided
Allocation concealment Unclear risk Double-blind, randomised, placebo vs Rituximab controlled trial. No other in-
(selection bias) formation provided
Blinding of outcome as- Unclear risk Unclear whether investigators blinded for outcome assessment
sessment (detection bias)
All outcomes
Incomplete outcome data Low risk 1 of 24 patients excluded (4%) from analysis
(attrition bias)
All outcomes
Selective reporting (re- High risk Few data on clinical outcomes provided
porting bias)
Other bias Low risk Supported by French Ministry of Health (PHRC, project number 16-03/2009)
Niaudet 1992
Methods • Study design: parallel RCT
• Time frame: October 1985 to May 1989
• Follow-up period: 2 to 3 years
Niaudet 1992 (Continued)
• Inclusion criteria: SD-SSNS (relapse on alt day prednisone) with evidence of steroid toxicity (e.g.
growth retardation, obesity, osteoporosis)
• Number: treatment group 1 (20); treatment group 2 (20)
• Mean age: not reported
• Sex (M/F): not reported
• Exclusion criteria: CrCl < 50 mL/min/1.73 m2; abnormal liver function tests; uncontrolled hyperten-
sion; previous cytotoxic therapy
• Oral CSA: 6 mg/kg/day for 3 months and then tapered over 3 months; dose adjusted to trough CSA
level of 50 to 150 ng/mL
Treatment group 2
Co-interventions
• For relapse prednisone 30 to 60 mg/m2 until remission, then same dose on alternate days and tapered
over 3 months
Risk of bias
Random sequence genera- Unclear risk Study described as randomised; method of randomisation not reported
tion (selection bias)
Blinding of participants High risk No blinding and lack of blinding could influence the management
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk No blinding and lack of blinding could influence the outcome assessment
sessment (detection bias)
All outcomes
Prasad 2004
Methods • Study design: parallel RCT
• Time frame: not reported
• Follow-up period: Median 24 months (treatment group); 21 months (control group)
• IV CPA: 500 mg/m2 monthly for 6 doses (total dose 100 mg/kg)
Treatment group 2
Co-interventions
• Prednisone 60 mg/m2 until remission for 3 days, 40 mg/m2 on alternate days for 4 weeks, tapering
dose of prednisone for 4 weeks
Outcomes • Number with relapse at 6 months after the end of therapy (relapse defined as 1+ proteinuria for 3
consecutive days or development of NS)
• Number with FR (2+ relapses in 6 months) or SD-SSNS
• Median protein-free days (± SE)
• Adverse effects (leucopenia, cystitis, hair loss, all infections, nausea and vomiting)
Notes • Exclusions post randomisation but pre-intervention: consecutive recruitment of patients reported
and no exclusions post randomisation
• Stop or end point/s: not reported
• Additional data requested from authors: none
Risk of bias
Random sequence genera- Low risk Randomised by the random number table
tion (selection bias)
Blinding of participants High risk No blinding and lack of blinding could influence the management
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk Outcome assessors not blinded and lack of blinding could influence the as-
sessment (detection bias) sessment of outcomes
Prasad 2004 (Continued)
All outcomes
Rashid 1996
Methods • Study design: parallel RCT
• Time frame: not reported
• Follow-up period: 44 weeks
Control group
• Prednisone: 2 mg/kg/day for 2 weeks, 1 mg/kg/day for 4 to 6 weeks, tapering dose to 6 months (total
duration 6 months)
Co-interventions
• Not reported
Risk of bias
Random sequence genera- Unclear risk Study described as randomised; method of randomisation not reported
tion (selection bias)
Rashid 1996 (Continued)
Allocation concealment Unclear risk Insufficient information to permit judgement
(selection bias)
Blinding of participants High risk No blinding and lack of blinding could influence the management
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk No blinding and lack of blinding could influence the outcome assessment
sessment (detection bias)
All outcomes
Incomplete outcome data Unclear risk Unclear whether all patients completed follow-up
(attrition bias)
All outcomes
Ravani 2011
Methods • Study design: parallel RCT
• Time frame: 2007 to 2008
• Follow-up period: 12 months
Control group
Co-interventions
Ravani 2011 (Continued)
Outcomes • Percentage change in proteinuria at 3 months
• Number with relapse at 3 months
• Numbers able to cease prednisolone at 3 months
• Number able to cease prednisolone and CNI at 3 months
• GFR
• Adverse effects of RTX
Risk of bias
Random sequence genera- Low risk Permuted blocks of variable size. Randomisation lists stratified by centre and
tion (selection bias) signs of toxicity
Blinding of participants Low risk Study staff facilitating follow-up data measurements were blinded to treat-
and personnel (perfor- ment group
mance bias)
All outcomes
Blinding of outcome as- Low risk Primary outcome (% change in proteinuria) was measured in central laborato-
sessment (detection bias) ry
All outcomes
Incomplete outcome data Low risk 25/27 of rituximab group and 27/27 of control group completed treatment but
(attrition bias) analysis included all patients
All outcomes
Ravani 2015
Methods • Study design: parallel RCT
• Time frame: April 2009 to April 2014
• Follow-up duration: median duration of follow-up 22 months (range 1 to 60 months)
Ravani 2015 (Continued)
• Exclusion criteria: history of treatment with CNI; received cyclophosphamide or MMF in the 6 months
prior; history of macro-haematuria; hepB/hepC/HIV, low C3; requiring albumin, diuretics or anticoag-
ulants; positive ANA/ENA/ANCA
Control group
• No additional therapy
Co-interventions
• Steroids were tapered in both groups by 0.3 mg/kg each week if proteinuria ≤ 1 g/m2; ACEi/ARB could
be used at physician discretion but were kept constant for duration of study.
• Relapses
* Treatment group: relapses were treated with RTX
* Control group: relapses were treated with prednisone (max dose 2 mg/kg) or steroid-sparing
agents (e.g. CNI, CPA). RTX could only be used following a failure of other steroid-sparing agents
Notes • Authors kindly provided additional data on number of patients with relapse at 3, 6 and 12 months for
meta-analysis
Risk of bias
Allocation concealment Low risk Sequence stored remotely, variable blocking size (4 to 6)
(selection bias)
Blinding of outcome as- Low risk No information regarding blinded outcome assessors. However, primary end-
sessment (detection bias) points are laboratory based and unlikely to be influenced by lack of blinding
All outcomes
Other bias Unclear risk "Investigator initiated and driven", author JR reports fees from Genentech and
Roche
RITURNS 2018
Methods • Study design: parallel RCT
• Time frame: May 2015 to September 2016
• Follow-up period: 12 months
• RTX: 2 infusions at weekly intervals (375 mg/m2, maximum dose 500 mg)
Treatment group 2
Co-interventions
• Alternate-day prednisolone
Notes
Risk of bias
Blinding of outcome as- Low risk Open label but outcomes were laboratory determined
sessment (detection bias)
All outcomes
Incomplete outcome data Low risk All randomised patients underwent intention-to-treat analysis
(attrition bias)
All outcomes
RITURNS 2018 (Continued)
Selective reporting (re- Low risk All expected outcomes reported
porting bias)
Sinha 2019
Methods • Study design: parallel RCT
• Time frame: February 2012 to December 2014
• Follow up: 12 months
Treatment group 2
Co-interventions
Notes
Risk of bias
Allocation concealment Low risk Centrally allocated with opaque sealed envelopes
(selection bias)
Sinha 2019 (Continued)
All outcomes
Blinding of outcome as- Unclear risk Open label and outcome was defined by dipstick tested by parents
sessment (detection bias)
All outcomes
Incomplete outcome data Low risk All patients included in intention-to-treat analysis
(attrition bias)
All outcomes
Sural 2001
Methods • Study design: parallel RCT
• Time frame: not reported
• Follow-up period: 12 months in all groups
Treatment group 2
Control group
• Prednisolone: 40 mg/m2 for 4 weeks and then tapered and stopped after 12 weeks
Co-interventions
• Not reported
Sural 2001 (Continued)
Risk of bias
Random sequence genera- Unclear risk Reported as "randomised prospective controlled study". No other information
tion (selection bias)
Allocation concealment Unclear risk Reported as "randomised prospective controlled study". No other information
(selection bias)
Blinding of participants High risk No blinding and lack of blinding could influence management
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk No blinding and lack of blinding could influence outcome assessment
sessment (detection bias)
All outcomes
Incomplete outcome data Low risk 85 patients consecutively enrolled and all accounted for in results
(attrition bias)
All outcomes
Uddin 2016
Methods • Study design: parallel RCT
• Time frame: not reported
• Follow-up period: 6 months
Treatment group 2
Co-interventions
• Prednisone: 60 mg/m2/day till protein free for 3 days, then taper 6 months
Uddin 2016 (Continued)
• Relapse rate at 6 months
• Adverse effects
Risk of bias
Random sequence genera- Unclear risk "Patients were randomly divided into two groups"
tion (selection bias)
Allocation concealment Unclear risk "Patients were randomly divided into two groups"
(selection bias)
Incomplete outcome data High risk 53/60 were analysed. 12% lost to follow-up or excluded from analysis
(attrition bias)
All outcomes
Ueda 1990
Methods • Study design: parallel RCT
• Time frame: February 1975 to August 1988
• Follow-up period: 8 weeks CPA group 66.2 (50.6) months; 12 weeks CPA group 63.1 (33.7) months
Treatment group 2
Ueda 1990 (Continued)
Co-interventions
• Relapses treated with prednisone 60 mg/m2/d for 4 weeks, then taper by 5 to 10 mg/m2 over 3 to 4
months
Outcomes • Number in relapse at 12 months (defined as urine protein > 40 mg/m2/h for 3 consecutive days)
• Number in relapse at 24 months
• Mean relapse rate/patient
• Adverse effects
Risk of bias
Random sequence genera- Unclear risk Study described as randomised; method of randomisation not reported
tion (selection bias)
Blinding of participants High risk No blinding and lack of blinding could influence the management
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk No blinding and lack of blinding could influence the outcome assessment
sessment (detection bias)
All outcomes
Weiss 1993
Methods • Study design: parallel RCT
• Time frame: not reported
• Follow-up period: 12 months
Weiss 1993 (Continued)
• Mean age ± SD (years): treatment group (7.3 ± 4.4); control group (7.5 ± 3.8)
• Sex (M/F): treatment group (19/4); control group (19/7)
• Exclusion criteria: prior treatment with an alkylating agent or other immunosuppressive agents with-
in 6 months of entry into the study; post menarchal girls; WCC < 4000/mm2 ;abnormal liver function
tests; CrCl < 90 mL/min/1.73 m2; C3 < 50 mg/dL; co-existent medical condition likely to interfere with
procedures and/or results
• Levamisole oral suspension: 2.5 mg/kg orally twice weekly (Saturday, Sunday) for 6 months
• Prednisone
Control group
Co-interventions
• Relapses treated with prednisone 60 mg/m2/day until remission and then 40 mg/m2 on alternate days
for 28 days (ISKDC protocol)
Outcomes • Mean relapse rate/patient by 6 months (defined as > 1+ proteinuria on 3 consecutive first morning
urine)
• Mean time to next relapse
• Mean number of days/month of prednisone treatment
• Number with relapse at end of treatment
• Number with relapse at 6 months after end of treatment
Notes • Exclusions post randomisation but pre-intervention: 7 withdrawn from Levamisole group (steroid tox-
icity (3), withdrew consent (1), administrative reasons (2), lost to follow-up (1)) before treatment com-
pleted; 8 withdrawn from placebo group (newly developed steroid resistance (2), acute kidney failure
(1), administrative reasons (5))
• Stop or end point/s: not reported
• Additional data requested from authors: Draft manuscript of study obtained from author
Risk of bias
Random sequence genera- Unclear risk No information provided except patients stratified to FR-SSNS or SD-SSNS and
tion (selection bias) by those who had received CPA
Allocation concealment Low risk "Randomization was centralised" Information from author
(selection bias)
Blinding of outcome as- Low risk Double blinded placebo controlled study
sessment (detection bias)
All outcomes
Incomplete outcome data Low risk Completeness of follow-up 89.1% (41/49) at 6 months but all patients included
(attrition bias) in ITT analysis
All outcomes
Weiss 1993 (Continued)
Selective reporting (re- High risk No information on adverse effects
porting bias)
Yoshioka 2000
Methods • Study design: parallel RCT
• Time frame: not reported
• Follow-up period: 18 months
Control group
Co-interventions
• Not reported
Outcomes • Number of relapses/patient-month of study (defined as urinary protein > 100 mg/L or 2+ on 3 or more
consecutive days)
• Cumulative remission rate
• Adverse effects
Notes • Exclusions post randomisation but pre-intervention: treatment group (3); control group (1)
• Stop or end point/s: not reported
• Additional data requested from authors: information on numbers relapsing sought but not obtained
Risk of bias
Yoshioka 2000 (Continued)
Blinding of participants Low risk Double-blind placebo-controlled study
and personnel (perfor-
mance bias)
All outcomes
Selective reporting (re- High risk Expected outcomes reported but data provided as relapse rate ratios and
porting bias) could not be entered in meta-analyses
Zhang 2014
Methods • Study design: parallel RCT
• Time frame: November 2009 to May 2012
• Follow-up period: 6 months
• Prednisone: 2 mg/kg daily (maximum 60 mg/kg/day) in divided doses for 4 weeks, 1.5 mg/kg on alter-
nate days for 4 weeks, decrease by 5 mg every 2 weeks till 30 mg/kg, then decrease by 2.5 mg very
every 2 weeks until withdrawal
• Azithromycin: 10 mg/kg daily for 3 days
Treatment group 2
• Prednisone: 2 mg/kg daily (maximum 60 mg/kg/day) in divided doses for 4 weeks, 1.5 mg/kg on alter-
nate days for 4 weeks, decrease by 5 mg every 2 weeks till 30 mg/kg, then decrease by 2.5 mg every
2 weeks every 2 weeks until withdrawal
Co-interventions
• Not reported
Zhang 2014 (Continued)
• Time to remission
Notes • Definitions
* Primary nephrotic syndrome: treated with prednisone for first time
* SRNS: no complete remission after treatment with 2 mg/kg/day for 8 weeks
* Relapse: morning urinalysis showed ≥ 3 + proteinuria after being negative for 3 days during fol-
low-up of 6 months
* Complete remission: negative or trace proteinuria for 3 consecutive days, serum albumin ≥ 2.5 g/L
Risk of bias
Random sequence genera- High risk QUOTE: "randomly categorized into intervention and control groups using a
tion (selection bias) random number table of odd or even numbers"
Blinding of participants High risk No blinding and lack of blinding could influence management
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk No blinding and lack of blinding could influence outcome assessment
sessment (detection bias)
All outcomes
Incomplete outcome data Low risk 21/208 (excludes 4 patients with SRNS); 10.1% lost to follow-up or excluded
(attrition bias) (15 lost to follow-up, 6 excluded for hypocomplementaemia)
All outcomes
Selective reporting (re- High risk Not all reviews prespecified outcomes are mentioned - no adverse events
porting bias) mentioned
Other bias Low risk Tiajin Bureau of Health Sciences and Technology Fund. Project number
09KZ34
ACEi - angiotensin converting-enzyme inhibitor/s; ACR - albumin/creatinine ratio; ACTH - adrenocorticotropic hormone; APN -
Arbeitsgemeinschaft fur Padiatrische Nephrologie; ARB - angiotensin receptor blocker/s; AZA - azathioprine; BP - blood pressure;
CNI - calcineurin inhibitor; CPA - cyclophosphamide; CrCl - creatinine clearance; CSA - cyclosporin; DM - diabetes mellitus; ESR -
erythrocyte sedimentation rate; FR - frequent relapsing; (e)GFR - (estimated) glomerular filtration rate; Hb - haemoglobin; HIV - human
immunodeficiency virus; IQR - interquartile range; ISKDC - International Study of Kidney Disease in Children; ITT - intention to treat; IV -
intravenous; MCD - minimal change disease; MC - minimal change; MMF - mycophenolate mofetil; MPA - mycophenolic acid; NS - nephrotic
syndrome; NSAID - nonsteroidal anti-inflammatory drug; PCR - protein/creatinine ratio; RCT - randomised controlled trial; RTX - rituximab;
SCr - serum creatinine; SD - standard deviation; SD-SSNS - steroid-dependent steroid-sensitive nephrotic syndrome; SE - standard error;
SEM - standard error of the mean; SR - steroid-resistant; SS - steroid-sensitive; TAC - tacrolimus; WCC - white cell count
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Basu 2015 This article has been withdrawn at the request of the author(s) and/or editor. Unclear how partici-
pant enrolment took place
Khemani 2016 Wrong population: includes both SDNS and SRNS participants and the results cannot be separated.
Authors emailed but no response obtained (CPA versus CSA)
Kirubakaran 1984 Other: reporting issue; study of levamisole however only available in abstract form and primary
outcome data could not be extracted
Li 2005a Wrong population: unclear whether included patients were adult or if the patients had primary NS
or secondary NS due to hepatitis B nephropathy (MMF)
Liu 2016c Wrong population. adults with refractory nephrotic syndrome (leflunomide combined with pred-
nisone)
Lou 2004 Wrong population: included adult patients and paediatric data could not be extracted (lefluno-
mide)
Naigui 1997 Wrong population: included adult patients and paediatric data could not be extracted (low dose
cyclosporin A with diltiazem)
NCT02390362 Other: study terminated for inadequate enrolment (RTX versus MMF)
Ni 2003 Wrong population: data for children and adults could not be separated. Includes diseases other
than idiopathic NS and data cannot be separated (leflunomide)
Nishiyama 1997 Wrong population: unclear whether participants had SSNS or SRNS
Samuels 2002 Wrong intervention: spirulina (unclear whether this was an RCT)
Sancewicz-Pach 1995 Wrong population. children with SRNS treated with CSA
Sasinka 1976 Wrong population: included patients with chronic GN, unable to separate data (CSA study)
Shendurnikar 2004 Wrong intervention: spirulina (unclear whether this was an RCT)
Tejani 1988 Wrong population: comparing CSA/prednisone with prednisone alone in children with new-onset
idiopathic NS (14) including unclear number with SRNS or relapsing SSNS (14) and data cannot be
separated for groups of SSNS versus SRNS patients
Wang 2005 Wrong population: includes children with NS associated with nephritic features including
hypocomplementaemia
Zhi-Hong 2004 Wrong intervention: astragalus (unclear whether this was an RCT)
Zhong 2007 Wrong intervention: Ginkgo biloba leaf extract (unclear whether this was an RCT)
ACEi - angiotensin converting-enzyme inhibitor; CPA - cyclophosphamide; CSA - cyclosporin; GN - glomerulonephritis; MMF -
mycophenolate mofetil; NS - nephrotic syndrome; SD - steroid-dependent; SR - steroid-resistant; RCT - randomised controlled trial; RTX
- rituximab; TAC - tacrolimus
Characteristics of studies awaiting assessment [ordered by study ID]
NCT01092962
Methods Parallel, open-label RCT
Notes • Study completed in 2015 but no results published. Authors contacted for information but no re-
sponse obtained
NCT01895894
Methods Parallel, open-label RCT
NCT01895894 (Continued)
• Control: no therapy
Notes Sponsors: Seoul National University Hospital and Chong Kun Dang Pharmaceutical. Study complet-
ed 2016 but no results published to date. Authors contacted for results but no response received
Sawires 2019
Methods Multicentre, open-label RCT
Notes Primarily a study of TNF-α levels with minimal information on clinical outcomes
Tohjoh 1994
Methods Not available
CNI - calcineurin inhibitor; CSA - cyclosporin; NS - nephrotic syndrome; RCT - randomised controlled trial; SD - steroid-dependent; SS -
steroid-sensitive
Characteristics of ongoing studies [ordered by study ID]
Hama 2018
Trial name or title JSKDC05 trial. UMIN000005103
Methods Parallel group, open-label, RCT of prednisolone versus prednisolone and high-dose mizoribine
Participants 120 children with first relapse of SSNS within 6 months of first treatment
Interventions High dose mizoribine ( six months) and prednisone versus prednisone alone
Hama 2018 (Continued)
Starting date Unclear
Horinouchi 2018
Trial name or title Mycophenolate mofetil as maintenance therapy after rituximab treatment for childhood-onset,
complicated, frequently-relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome:
a multicentre double-blind, randomised, placebo-controlled trial
Participants Children aged 2 years and older, with initial onset of NS at age 1 to 18 years with FRNS or SDNS
Interventions Intervention: RTX 4 x 375 mg/m2 doses given at weekly intervals plus MMF 1000 to 1200 mg/m2/day
twice daily, continued for 17 months after RTX
Comparator: RTX 4 x 375 mg/m2 doses given at weekly intervals plus placebo
Outcomes Time to treatment failure (development of frequent relapses, steroid dependence or steroid resis-
tance)
Notes Sponsor: Ministry of Health, Labor and Welfare, Japan and the Japan Agency for Medical Research
and Development
INTENT 2018
Trial name or title INTENT Study
Participants 340 children with initial episode of SSNS. 110 recruited to 10/2017
Control: 60mg/m2 prednisolone for 6 weeks followed by 40mg/m2 prednisolone on alternate days
for 6 weeks
Outcomes Primary outcome: number with relapse requiring treatment within 24 months (non-inferiority)
Secondary outcomes: time to relapse, relapse rate per person-year, incidence of FRNS, cumulative
prednisone dose, adverse effects
INTENT 2018 (Continued)
Starting date Aug 2015. Expected completion date 2020
JSKDC 10 2019
Trial name or title JSKDC10 Study: Multicentre, double-blind, randomised, placebo-controlled trial of rituximab
(IDECC-C2B8)for the treatment of childhood-onset early-stage uncomplicated frequently relapsing
or steroid-dependent nephrotic syndrome
Participants 40 children with FRNS or SDNS aged below 18 years at onset of NS with no previous immunosup-
pressive agents
Interventions Two doses of RTX 375 mg/m2 (maximum dose 500 mg) or placebo on day 1 and day 8
Outcomes Primary endpoint is duration of relapse free period during blinded period (365 days)
LEARNS 2019
Trial name or title The LEARNS Study: Prevention of relapses with levamisole as adjuvant therapy in children with first
episode of idiopathic nephrotic syndrome.
2. Levamisole 2.5 mg/kg or placebo on alternate days from week 4 in those in remission for 24
weeks
Notes 157 patients need to be enrolled to allow at least 82 children to complete 2 years of follow up
NCT02818738
Trial name or title Efficiency of levamisole for maintaining remission after the first flare of steroid sensitive nephrotic
syndrome in children (NEPHROVIR3)
Participants 156 children (2-16 years) from 36 centres in France with initial episode of SSNS
Interventions Experimental: Levamisole hydrochloride 2.5 mg/kg (maximum 150 mg) on alternate days for 6
months
Duration of remission
Adverse effects
Notes
NCT02972346
Trial name or title Availability Study of ACTH to Treat Children SRNS/SDNS
Interventions Intervention: ACTH 0.4 U/kg/day (maximum 25 U) for 3 consecutive days every 4 weeks + routine
treatment
Remission/relapse
Contact information Yufeng Li, Ph.D. mieuniversity@hotmail.com. Xinhua Hospital, Shanghai Jiao Tong University
School of Medicine
Notes Availability and Safety Study of ACTH to Treat Children with SRNS/SDNS
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Ravani 2017
Trial name or title Randomised controlled trial comparing of atumumab to rituximab in children with steroid-depen-
dent and calcineurin inhibitor-dependent idiopathic nephrotic syndrome
Participants 140 children aged 2 to 18 years in remission but with history of SDNS and CNI dependence
Relapse rate/year
Adverse effects
RITURNS II 2019
Trial name or title RITURNS II. Efficacy and Safety of Repeated Courses of Rituximab to that of Maintenance My-
cophenolate Mofetil Following Single Course of Rituximab among children with steroid dependent
nephrotic syndrome
Interventions Experimental group: RTX at randomisation and then at 9 and 16 months if B cell count normalises
Control group: RTX at randomisation and then MMF maintenance from four months onwards
Outcomes 1. The primary endpoint is the time to first relapse or death (whichever occurs first) till end of study
(follow-up phase of 24 months)
Starting date May 15, 2019. Estimated study completion date October 2021
Contact information Dr Biswanath basu, basuv3000@gmail.com. Nilratan Sircar Medical College, Kolkata, India
Notes NCT03899103
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RITUXIVIG 2018
Trial name or title Efficacy and safety of immunoglobulin associated with rituximab versus rituximab alone in child-
hood-onset steroid-dependent nephrotic syndrome (RITUXIVIG)
Participants Childhood onset nephrotic syndrome (first flair at age > 2 years and < 18 years)
Steroid-dependent:
- Patient with at least 2 relapses confirmed during the decay of corticosteroids or within 2 weeks
following steroids discontinuation
- Patient with at least 2 relapses including one under steroid-sparing agent (MMF, CNI, CPA) or fol-
lowing treatment withdrawal.
- 2 or more relapses within 6 months after initial remission or 4 or more relapses within any 12-
month period.
Notes
Sinha 2019b
Trial name or title Levamisole on alternate days compared to steroids made daily during infections to prevent disease
relapses in patients with frequently relapsing nephrotic syndrome
Participants 156 children aged 2 to 18 years with FRNS or SDNS and requiring ≤ 1 mg/kg prednisolone on alter-
nate days to maintain remission
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Sinha 2019b (Continued)
Interventions Intervention: Low dose prednisolone (0.5 to 0.7 mg/kg) on alternate days given daily for 7 days dur-
ing infections
ACTH - adrenocorticotropic hormone; CNI - calcineurin inhibitor/s; CPA - cyclophosphamide; FR - frequently-relapsing; IV - intravenous;
MCD - minimal change disease; MMF - mycophenolate mofetil; NS - nephrotic syndrome; RCT - randomised controlled trial; RTX - rituximab;
SD - steroid-dependent
DATA AND ANALYSES
Comparison 1. Rituximab versus placebo or control
1 Number with relapse 6 Risk Ratio (M-H, Random, 95% CI) Subtotals only
1.1 Three months 3 132 Risk Ratio (M-H, Random, 95% CI) 0.32 [0.14, 0.70]
1.2 Six months 5 269 Risk Ratio (M-H, Random, 95% CI) 0.23 [0.12, 0.43]
1.3 Twelve months 3 198 Risk Ratio (M-H, Random, 95% CI) 0.63 [0.42, 0.93]
2 Adverse effects 4 Risk Ratio (M-H, Random, 95% CI) Subtotals only
2.1 Moderate to severe Infusion 4 252 Risk Ratio (M-H, Random, 95% CI) 5.83 [1.34, 25.29]
reactions
2.2 Severe Infection 3 222 Risk Ratio (M-H, Random, 95% CI) 0.90 [0.26, 3.15]
2.3 Arthropathy 2 84 Risk Ratio (M-H, Random, 95% CI) 3.92 [0.45, 33.98]
Analysis 1.1. Comparison 1 Rituximab versus placebo or control, Outcome 1 Number with relapse.
Study or subgroup Rituximab Control group Risk Ratio Weight Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
1.1.1 Three months
Ravani 2015 0/15 11/15 8.01% 0.04[0,0.68]
Iijima 2011 4/24 11/24 42.57% 0.36[0.13,0.98]
Ravani 2011 5/27 13/27 49.42% 0.38[0.16,0.93]
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Study or subgroup Rituximab Control group Risk Ratio Weight Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
Subtotal (95% CI) 66 66 100% 0.32[0.14,0.7]
Total events: 9 (Rituximab), 35 (Control group)
Heterogeneity: Tau2=0.14; Chi2=2.7, df=2(P=0.26); I2=25.84%
Test for overall effect: Z=2.81(P=0)
1.1.2 Six months
RITURNS 2018 0/59 10/58 4.73% 0.05[0,0.78]
Ravani 2015 1/15 13/15 9.46% 0.08[0.01,0.52]
NEPHRUTIX 2018 1/10 13/13 14.05% 0.14[0.03,0.63]
Iijima 2011 6/24 22/24 34.79% 0.27[0.13,0.55]
Ahn 2018 9/35 11/16 36.96% 0.37[0.19,0.72]
Subtotal (95% CI) 143 126 100% 0.23[0.12,0.43]
Total events: 17 (Rituximab), 69 (Control group)
Heterogeneity: Tau2=0.18; Chi2=6.24, df=4(P=0.18); I2=35.94%
Test for overall effect: Z=4.54(P<0.0001)
1.1.3 Twelve months
Ravani 2015 5/15 15/15 22.07% 0.35[0.18,0.7]
RITURNS 2018 16/60 22/60 29.38% 0.73[0.43,1.24]
Iijima 2011 17/24 23/24 48.55% 0.74[0.56,0.97]
Subtotal (95% CI) 99 99 100% 0.63[0.42,0.93]
Total events: 38 (Rituximab), 60 (Control group)
Heterogeneity: Tau2=0.07; Chi2=4.23, df=2(P=0.12); I2=52.75%
Test for overall effect: Z=2.3(P=0.02)
Test for subgroup differences: Chi2=7.72, df=1 (P=0.02), I2=74.11%
Analysis 1.2. Comparison 1 Rituximab versus placebo or control, Outcome 2 Adverse effects.
Study or subgroup Rituximab Control group Risk Ratio Weight Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
1.2.1 Moderate to severe Infusion reactions
Iijima 2011 5/24 1/24 50.23% 5[0.63,39.67]
Ravani 2011 4/27 0/27 26.08% 9[0.51,159.43]
Ravani 2015 0/15 0/15 Not estimable
RITURNS 2018 2/60 0/60 23.69% 5[0.25,102]
Subtotal (95% CI) 126 126 100% 5.83[1.34,25.29]
Total events: 11 (Rituximab), 1 (Control group)
Heterogeneity: Tau2=0; Chi2=0.12, df=2(P=0.94); I2=0%
Test for overall effect: Z=2.35(P=0.02)
1.2.2 Severe Infection
Iijima 2011 3/24 2/24 30.48% 1.5[0.27,8.19]
Ravani 2011 2/27 0/27 13.97% 5[0.25,99.51]
RITURNS 2018 8/60 18/60 55.55% 0.44[0.21,0.94]
Subtotal (95% CI) 111 111 100% 0.9[0.26,3.15]
Total events: 13 (Rituximab), 20 (Control group)
Heterogeneity: Tau2=0.59; Chi2=3.72, df=2(P=0.16); I2=46.21%
Test for overall effect: Z=0.16(P=0.87)
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Study or subgroup Rituximab Control group Risk Ratio Weight Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
1.2.3 Arthropathy
Ravani 2011 2/27 0/27 52.19% 5[0.25,99.51]
Ravani 2015 1/15 0/15 47.81% 3[0.13,68.26]
Subtotal (95% CI) 42 42 100% 3.92[0.45,33.98]
Total events: 3 (Rituximab), 0 (Control group)
Heterogeneity: Tau2=0; Chi2=0.05, df=1(P=0.82); I2=0%
Test for overall effect: Z=1.24(P=0.22)
Test for subgroup differences: Chi2=3.91, df=1 (P=0.14), I2=48.89%
Comparison 2. Mycophenolate mofetil versus levamisole
1 Relapse at 12 months 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
1.1 Relapses at 12 months 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
1.2 Frequent relapses at 12 months 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
1.3 Infrequent relapses at 12 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
months
2 Adverse effects 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
2.1 Peritonitis 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
2.2 Abdominal pain 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
2.3 Anaemia 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
2.4 Leucopenia 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
Analysis 2.1. Comparison 2 Mycophenolate mofetil versus levamisole, Outcome 1 Relapse at 12 months.
Study or subgroup MMF Levamisole Risk Ratio Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
2.1.1 Relapses at 12 months
Sinha 2019 45/76 48/73 0.9[0.7,1.16]
2.1.2 Frequent relapses at 12 months
Sinha 2019 11/76 12/73 0.88[0.41,1.87]
2.1.3 Infrequent relapses at 12 months
Sinha 2019 34/76 36/73 0.91[0.64,1.28]
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Analysis 2.2. Comparison 2 Mycophenolate mofetil versus levamisole, Outcome 2 Adverse effects.
Study or subgroup MMF Levamisole Risk Ratio Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
2.2.1 Peritonitis
Sinha 2019 1/76 3/73 0.32[0.03,3.01]
2.2.2 Abdominal pain
Sinha 2019 17/76 13/73 1.26[0.66,2.4]
2.2.3 Anaemia
Sinha 2019 1/76 2/73 0.48[0.04,5.18]
2.2.4 Leucopenia
Sinha 2019 1/76 0/73 2.88[0.12,69.65]
Comparison 3. Mycophenolate mofetil versus cyclosporin
1 Relapse at 12 months 2 82 Risk Ratio (M-H, Random, 95% CI) 1.90 [0.66, 5.46]
2 Relapse rate/year 3 142 Mean Difference (IV, Random, 95% CI) 0.83 [0.33, 1.33]
3 Adverse effects 3 Risk Ratio (M-H, Random, 95% CI) Subtotals only
3.1 Hypertension 3 144 Risk Ratio (M-H, Random, 95% CI) 0.30 [0.09, 1.07]
3.2 Hypertrichosis 3 140 Risk Ratio (M-H, Random, 95% CI) 0.23 [0.10, 0.50]
3.3 Lymphopenia 2 84 Risk Ratio (M-H, Random, 95% CI) 0.64 [0.08, 4.85]
3.4 Gum hypertrophy 3 144 Risk Ratio (M-H, Random, 95% CI) 0.09 [0.02, 0.47]
3.5 Reduced GFR 1 24 Risk Ratio (M-H, Random, 95% CI) 0.33 [0.01, 7.45]
3.6 Pneumonia 1 24 Risk Ratio (M-H, Random, 95% CI) 3.0 [0.13, 67.06]
3.7 Diarrhoea 1 60 Risk Ratio (M-H, Random, 95% CI) 9.00 [0.51, 160.17]
4 GFR at 12 months 1 Mean Difference (IV, Random, 95% CI) Totals not selected
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Analysis 3.1. Comparison 3 Mycophenolate mofetil versus cyclosporin, Outcome 1 Relapse at 12 months.
Study or subgroup MMF CSA Risk Ratio Weight Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
Dorresteijn 2008 5/12 1/12 22.67% 5[0.68,36.66]
Gellermann 2013 12/28 9/30 77.33% 1.43[0.71,2.86]
Total (95% CI) 40 42 100% 1.9[0.66,5.46]
Total events: 17 (MMF), 10 (CSA)
Heterogeneity: Tau2=0.25; Chi2=1.43, df=1(P=0.23); I2=30.23%
Test for overall effect: Z=1.19(P=0.24)
Analysis 3.2. Comparison 3 Mycophenolate mofetil versus cyclosporin, Outcome 2 Relapse rate/year.
Study or subgroup MMF CSA Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) Random, 95% CI Random, 95% CI
Uddin 2016 30 3 (2.9) 30 1.4 (2.6) 12.91% 1.56[0.17,2.95]
Gellermann 2013 28 1.1 (2) 30 0.4 (0.7) 41.1% 0.7[-0.08,1.48]
Dorresteijn 2008 12 0.8 (1.3) 12 0.1 (0.3) 45.99% 0.75[0.01,1.49]
Total *** 70 72 100% 0.83[0.33,1.33]
Heterogeneity: Tau2=0; Chi2=1.21, df=2(P=0.55); I2=0%
Test for overall effect: Z=3.27(P=0)
Analysis 3.3. Comparison 3 Mycophenolate mofetil versus cyclosporin, Outcome 3 Adverse effects.
Study or subgroup MMF CSA Risk Ratio Weight Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
3.3.1 Hypertension
Dorresteijn 2008 1/12 4/12 25.68% 0.25[0.03,1.92]
Uddin 2016 1/30 11/30 26.67% 0.09[0.01,0.66]
Gellermann 2013 4/30 6/30 47.66% 0.67[0.21,2.13]
Subtotal (95% CI) 72 72 100% 0.3[0.09,1.07]
Total events: 6 (MMF), 21 (CSA)
Heterogeneity: Tau2=0.51; Chi2=3.35, df=2(P=0.19); I2=40.26%
Test for overall effect: Z=1.86(P=0.06)
3.3.2 Hypertrichosis
Dorresteijn 2008 0/12 3/8 7.62% 0.1[0.01,1.69]
Gellermann 2013 0/30 8/30 7.78% 0.06[0,0.98]
Uddin 2016 5/30 18/30 84.6% 0.28[0.12,0.65]
Subtotal (95% CI) 72 68 100% 0.23[0.1,0.5]
Total events: 5 (MMF), 29 (CSA)
Heterogeneity: Tau2=0; Chi2=1.6, df=2(P=0.45); I2=0%
Test for overall effect: Z=3.7(P=0)
3.3.3 Lymphopenia
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Analysis 3.4. Comparison 3 Mycophenolate mofetil versus cyclosporin, Outcome 4 GFR at 12 months.
Study or subgroup MMF CSA Mean Difference Mean Difference
N Mean(SD) N Mean(SD) Random, 95% CI Random, 95% CI
Dorresteijn 2008 12 131 (40) 12 109 (16) 22[-2.38,46.38]
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1 Relapse during treatment (4 to 12 8 474 Risk Ratio (M-H, Random, 95% CI) 0.52 [0.33, 0.82]
months)
2 Relapse at 6 to 12 months 8 462 Risk Ratio (M-H, Random, 95% CI) 0.65 [0.48, 0.88]
3 Mean relapse rate/patient/month 2 90 Mean Difference (IV, Random, 95% CI) -0.03 [-0.27, 0.20]
4 Relapse during treatment according 8 Risk Ratio (M-H, Random, 95% CI) Subtotals only
to risk of bias
4.1 Studies at low risk of bias 3 208 Risk Ratio (M-H, Random, 95% CI) 0.84 [0.57, 1.25]
4.2 Studies at unclear or high risk of 5 266 Risk Ratio (M-H, Random, 95% CI) 0.36 [0.25, 0.53]
bias
5 Adverse effects 3 Risk Ratio (M-H, Random, 95% CI) Subtotals only
5.1 Leucopenia 3 214 Risk Ratio (M-H, Random, 95% CI) 4.18 [0.72, 24.21]
5.2 ANCA positive/arthritis 1 100 Risk Ratio (M-H, Random, 95% CI) 3.0 [0.13, 71.92]
Analysis 4.1. Comparison 4 Levamisole versus steroids or placebo or both,
or no treatment, Outcome 1 Relapse during treatment (4 to 12 months).
Study or subgroup Levamisole Control Risk Ratio Weight Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
Al-Saran 2006 3/32 12/24 7.88% 0.19[0.06,0.59]
Rashid 1996 6/20 12/20 10.96% 0.5[0.23,1.07]
Abeyagunawardena 2006a 8/42 26/34 11.91% 0.25[0.13,0.48]
Sural 2001 8/30 23/28 12.2% 0.32[0.17,0.6]
Dayal 1994 9/22 10/14 12.35% 0.57[0.31,1.05]
BAPN 1991 17/31 26/30 14.39% 0.63[0.45,0.9]
Gruppen 2015 33/50 42/49 15.1% 0.77[0.61,0.97]
Weiss 1993 21/22 21/26 15.2% 1.18[0.96,1.46]
Total (95% CI) 249 225 100% 0.52[0.33,0.82]
Total events: 105 (Levamisole), 172 (Control)
Heterogeneity: Tau2=0.35; Chi2=65.89, df=7(P<0.0001); I2=89.38%
Test for overall effect: Z=2.83(P=0)
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Analysis 4.3. Comparison 4 Levamisole versus steroids or placebo or
both, or no treatment, Outcome 3 Mean relapse rate/patient/month.
Study or subgroup Levamisole Control Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) Random, 95% CI Random, 95% CI
Weiss 1993 16 0.7 (0.2) 18 0.6 (0.3) 44.4% 0.1[-0.08,0.28]
Al-Saran 2006 32 0.1 (0.2) 24 0.2 (0.2) 55.6% -0.14[-0.22,-0.06]
Total *** 48 42 100% -0.03[-0.27,0.2]
Heterogeneity: Tau2=0.02; Chi2=5.92, df=1(P=0.02); I2=83.1%
Test for overall effect: Z=0.28(P=0.78)
Lower with levamisole -0.5 -0.25 0 0.25 0.5 Lower with control
Analysis 4.4. Comparison 4 Levamisole versus steroids or placebo or both, or
no treatment, Outcome 4 Relapse during treatment according to risk of bias.
Study or subgroup Levamisole Control Risk Ratio Weight Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
4.4.1 Studies at low risk of bias
BAPN 1991 17/31 26/30 30% 0.63[0.45,0.9]
Gruppen 2015 33/50 42/49 34.64% 0.77[0.61,0.97]
Weiss 1993 21/22 21/26 35.36% 1.18[0.96,1.46]
Subtotal (95% CI) 103 105 100% 0.84[0.57,1.25]
Total events: 71 (Levamisole), 89 (Control)
Heterogeneity: Tau2=0.1; Chi2=14.27, df=2(P=0); I2=85.98%
Test for overall effect: Z=0.84(P=0.4)
4.4.2 Studies at unclear or high risk of bias
Al-Saran 2006 3/32 12/24 9.62% 0.19[0.06,0.59]
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Analysis 4.5. Comparison 4 Levamisole versus steroids or
placebo or both, or no treatment, Outcome 5 Adverse effects.
Study or subgroup Levamisole Control Risk Ratio Weight Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
4.5.1 Leucopenia
Al-Saran 2006 0/32 0/24 Not estimable
Sural 2001 1/30 0/28 30.85% 2.81[0.12,66.17]
Gruppen 2015 5/50 1/50 69.15% 5[0.61,41.28]
Subtotal (95% CI) 112 102 100% 4.18[0.72,24.21]
Total events: 6 (Levamisole), 1 (Control)
Heterogeneity: Tau2=0; Chi2=0.09, df=1(P=0.77); I2=0%
Test for overall effect: Z=1.6(P=0.11)
4.5.2 ANCA positive/arthritis
Gruppen 2015 1/50 0/50 100% 3[0.13,71.92]
Subtotal (95% CI) 50 50 100% 3[0.13,71.92]
Total events: 1 (Levamisole), 0 (Control)
Heterogeneity: Not applicable
Test for overall effect: Z=0.68(P=0.5)
Test for subgroup differences: Chi2=0.03, df=1 (P=0.86), I2=0%
Comparison 5. Levamisole versus cyclophosphamide
1.1 Relapse at end of therapy 2 97 Risk Ratio (M-H, Random, 95% CI) 2.14 [0.22, 20.95]
1.2 Relapse at 6 to 9 months after ther- 2 97 Risk Ratio (M-H, Random, 95% CI) 1.17 [0.76, 1.81]
apy
1.3 Relapse at 12 months after therapy 1 40 Risk Ratio (M-H, Random, 95% CI) 0.89 [0.68, 1.16]
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1.4 Relapse at 24 months after therapy 1 40 Risk Ratio (M-H, Random, 95% CI) 0.89 [0.73, 1.10]
2 Adverse effects 2 Risk Ratio (M-H, Random, 95% CI) Subtotals only
2.1 Infection 1 40 Risk Ratio (M-H, Random, 95% CI) 1.08 [0.67, 1.75]
2.2 Leucopenia 2 97 Risk Ratio (M-H, Random, 95% CI) 0.25 [0.04, 1.48]
2.3 Abnormal liver function tests 1 40 Risk Ratio (M-H, Random, 95% CI) 0.33 [0.01, 7.72]
Analysis 5.1. Comparison 5 Levamisole versus cyclophosphamide, Outcome 1 Relapse.
Study or subgroup Levamisole CPA Risk Ratio Weight Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
5.1.1 Relapse at end of therapy
Sural 2001 8/30 1/27 41.37% 7.2[0.96,53.89]
Donia 2005 10/20 11/20 58.63% 0.91[0.5,1.64]
Subtotal (95% CI) 50 47 100% 2.14[0.22,20.95]
Total events: 18 (Levamisole), 12 (CPA)
Heterogeneity: Tau2=2.22; Chi2=4.88, df=1(P=0.03); I2=79.49%
Test for overall effect: Z=0.65(P=0.51)
5.1.2 Relapse at 6 to 9 months after therapy
Sural 2001 17/30 10/27 37.13% 1.53[0.85,2.74]
Donia 2005 15/20 15/20 62.87% 1[0.7,1.43]
Subtotal (95% CI) 50 47 100% 1.17[0.76,1.81]
Total events: 32 (Levamisole), 25 (CPA)
Heterogeneity: Tau2=0.05; Chi2=1.76, df=1(P=0.18); I2=43.11%
Test for overall effect: Z=0.71(P=0.48)
5.1.3 Relapse at 12 months after therapy
Donia 2005 16/20 18/20 100% 0.89[0.68,1.16]
Subtotal (95% CI) 20 20 100% 0.89[0.68,1.16]
Total events: 16 (Levamisole), 18 (CPA)
Heterogeneity: Not applicable
Test for overall effect: Z=0.88(P=0.38)
5.1.4 Relapse at 24 months after therapy
Donia 2005 17/20 19/20 100% 0.89[0.73,1.1]
Subtotal (95% CI) 20 20 100% 0.89[0.73,1.1]
Total events: 17 (Levamisole), 19 (CPA)
Heterogeneity: Not applicable
Test for overall effect: Z=1.04(P=0.3)
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Comparison 6. Cyclosporin and prednisone versus prednisone alone
1 Relapse at 6 months 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
2 Relapse at 12 months 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
3 Number needing cytotoxic agents 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
4 Creatinine at end of study 1 Mean Difference (IV, Random, 95% Totals not selected
CI)
Analysis 6.1. Comparison 6 Cyclosporin and prednisone versus prednisone alone, Outcome 1 Relapse at 6 months.
Study or subgroup CSA + pred Prednisone Risk Ratio Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
APN 2006 5/49 17/55 0.33[0.13,0.83]
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Analysis 6.2. Comparison 6 Cyclosporin and prednisone versus prednisone alone, Outcome 2 Relapse at 12 months.
Study or subgroup CSA + pred Prednisone Risk Ratio Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
APN 2006 18/49 28/55 0.72[0.46,1.13]
Analysis 6.3. Comparison 6 Cyclosporin and prednisone versus
prednisone alone, Outcome 3 Number needing cytotoxic agents.
Study or subgroup CSA + pred Prednisone Risk Ratio Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
APN 2006 5/49 12/55 0.47[0.18,1.23]
Analysis 6.4. Comparison 6 Cyclosporin and prednisone versus
prednisone alone, Outcome 4 Creatinine at end of study.
Study or subgroup CSA + pred Prednisone Mean Difference Mean Difference
N Mean(SD) N Mean(SD) Random, 95% CI Random, 95% CI
APN 2006 44 48.2 (11.1) 43 46.2 (10) 2[-2.44,6.44]
Comparison 7. Alkylating agents versus cyclosporin
1 Relapse at end of therapy (6 to 9 2 95 Risk Ratio (M-H, Random, 95% CI) 0.91 [0.55, 1.48]
months)
2 Relapse at 12 to 24 months 2 95 Risk Ratio (M-H, Random, 95% CI) 0.51 [0.35, 0.74]
3 Adverse effects 2 Risk Ratio (M-H, Random, 95% CI) Subtotals only
3.1 Serum creatinine 2 106 Risk Ratio (M-H, Random, 95% CI) 0.20 [0.02, 1.69]
3.2 Hypertrichosis 2 106 Risk Ratio (M-H, Random, 95% CI) 0.06 [0.01, 0.40]
3.3 Gum hypertrophy 2 106 Risk Ratio (M-H, Random, 95% CI) 0.08 [0.01, 0.59]
3.4 Hypertension 1 40 Risk Ratio (M-H, Random, 95% CI) 0.33 [0.01, 7.72]
3.5 Leucopenia 1 66 Risk Ratio (M-H, Random, 95% CI) 29.84 [1.84, 483.93]
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Less with alkylating agents 0.1 0.2 0.5 1 2 5 10 Less with CSA
Analysis 7.2. Comparison 7 Alkylating agents versus cyclosporin, Outcome 2 Relapse at 12 to 24 months.
Study or subgroup Alkylat- Cyclosporin Risk Ratio Weight Risk Ratio
ing agents
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
Edefonti 1988 8/25 24/30 33.94% 0.4[0.22,0.73]
Niaudet 1992 11/20 19/20 66.06% 0.58[0.38,0.87]
Total (95% CI) 45 50 100% 0.51[0.35,0.74]
Total events: 19 (Alkylating agents), 43 (Cyclosporin)
Heterogeneity: Tau2=0.01; Chi2=1.13, df=1(P=0.29); I2=11.69%
Test for overall effect: Z=3.61(P=0)
Less with alkylating agents 0.1 0.2 0.5 1 2 5 10 Less with CSA
Analysis 7.3. Comparison 7 Alkylating agents versus cyclosporin, Outcome 3 Adverse effects.
Study or subgroup Alkylat- Cyclosporin Risk Ratio Weight Risk Ratio
ing agents
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
7.3.1 Serum creatinine
Niaudet 1992 0/20 1/20 45.69% 0.33[0.01,7.72]
Edefonti 1988 0/30 4/36 54.31% 0.13[0.01,2.37]
Subtotal (95% CI) 50 56 100% 0.2[0.02,1.69]
Total events: 0 (Alkylating agents), 5 (Cyclosporin)
Heterogeneity: Tau2=0; Chi2=0.19, df=1(P=0.67); I2=0%
Test for overall effect: Z=1.48(P=0.14)
7.3.2 Hypertrichosis
Edefonti 1988 0/30 11/36 49.94% 0.05[0,0.85]
Niaudet 1992 0/20 8/20 50.06% 0.06[0,0.96]
Subtotal (95% CI) 50 56 100% 0.06[0.01,0.4]
Total events: 0 (Alkylating agents), 19 (Cyclosporin)
Heterogeneity: Tau2=0; Chi2=0, df=1(P=0.95); I2=0%
Test for overall effect: Z=2.88(P=0)
Less with alkylating agents 0.002 0.1 1 10 500 Less with CSA
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Less with alkylating agents 0.002 0.1 1 10 500 Less with CSA
Comparison 8. Alkylating agents versus steroids or placebo or both
1 Relapse at 6 to 12 months 6 202 Risk Ratio (M-H, Random, 95% CI) 0.44 [0.32, 0.60]
1.1 Cyclophosphamide versus pred- 4 161 Risk Ratio (M-H, Random, 95% CI) 0.47 [0.34, 0.66]
nisone (6 or 12 months)
1.2 Chlorambucil versus prednisone 2 41 Risk Ratio (M-H, Random, 95% CI) 0.19 [0.03, 1.09]
or placebo (at 6 months)
2 Relapse at 12 to 24 months 4 59 Risk Ratio (M-H, Random, 95% CI) 0.20 [0.09, 0.46]
2.1 Cyclophosphamide versus pred- 2 27 Risk Ratio (M-H, Random, 95% CI) 0.21 [0.07, 0.65]
nisone (12 to 24 months)
2.2 Chlorambucil versus prednisone 2 32 Risk Ratio (M-H, Random, 95% CI) 0.15 [0.02, 0.95]
or placebo (at 12 months)
3.1 Cyclophosphamide 2 78 Risk Ratio (M-H, Random, 95% CI) 10.63 [1.45, 78.05]
3.2 Chlorambucil 1 20 Risk Ratio (M-H, Random, 95% CI) 2.5 [0.11, 54.87]
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Analysis 8.1. Comparison 8 Alkylating agents versus steroids
or placebo or both, Outcome 1 Relapse at 6 to 12 months.
Study or subgroup Alkylat- Control Risk Ratio Weight Risk Ratio
ing agents
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
8.1.1 Cyclophosphamide versus prednisone (6 or 12 months)
Chiu 1973 1/12 5/11 2.51% 0.18[0.03,1.33]
Barratt 1970 5/15 13/15 17.96% 0.38[0.18,0.81]
ISKDC 1974 9/27 16/26 26.29% 0.54[0.29,1]
Sural 2001 11/27 23/28 41.84% 0.5[0.3,0.81]
Subtotal (95% CI) 81 80 88.6% 0.47[0.34,0.66]
Total events: 26 (Alkylating agents), 57 (Control)
Heterogeneity: Tau2=0; Chi2=1.43, df=3(P=0.7); I2=0%
Test for overall effect: Z=4.42(P<0.0001)
8.1.2 Chlorambucil versus prednisone or placebo (at 6 months)
Grupe 1976 0/10 9/11 1.34% 0.06[0,0.87]
Alatas 1978 3/11 8/9 10.06% 0.31[0.11,0.83]
Subtotal (95% CI) 21 20 11.4% 0.19[0.03,1.09]
Total events: 3 (Alkylating agents), 17 (Control)
Heterogeneity: Tau2=0.86; Chi2=1.78, df=1(P=0.18); I2=43.94%
Test for overall effect: Z=1.86(P=0.06)
Total (95% CI) 102 100 100% 0.44[0.32,0.6]
Total events: 29 (Alkylating agents), 74 (Control)
Heterogeneity: Tau2=0; Chi2=4.73, df=5(P=0.45); I2=0%
Test for overall effect: Z=5.14(P<0.0001)
Test for subgroup differences: Chi2=0.99, df=1 (P=0.32), I2=0%
Less with alkylating agents 0.002 0.1 1 10 500 Less with control
Analysis 8.2. Comparison 8 Alkylating agents versus steroids
or placebo or both, Outcome 2 Relapse at 12 to 24 months.
Study or subgroup Alkylat- Control Risk Ratio Weight Risk Ratio
ing agents
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
8.2.1 Cyclophosphamide versus prednisone (12 to 24 months)
Barratt 1970 0/4 3/3 9.84% 0.11[0.01,1.63]
Chiu 1973 2/9 10/11 45.38% 0.24[0.07,0.84]
Subtotal (95% CI) 13 14 55.22% 0.21[0.07,0.65]
Total events: 2 (Alkylating agents), 13 (Control)
Heterogeneity: Tau2=0; Chi2=0.26, df=1(P=0.61); I2=0%
Test for overall effect: Z=2.7(P=0.01)
8.2.2 Chlorambucil versus prednisone or placebo (at 12 months)
Grupe 1976 0/10 11/11 9.44% 0.05[0,0.71]
Alatas 1978 1/5 6/6 35.34% 0.27[0.07,1.09]
Subtotal (95% CI) 15 17 44.78% 0.15[0.02,0.95]
Total events: 1 (Alkylating agents), 17 (Control)
Less with alkylating agents 0.002 0.1 1 10 500 Less with control
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Less with alkylating agents 0.002 0.1 1 10 500 Less with control
Analysis 8.3. Comparison 8 Alkylating agents versus steroids or placebo or both, Outcome 3 Leucopenia.
Study or subgroup Alkylat- Control Risk Ratio Weight Risk Ratio
ing agents
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
8.3.1 Cyclophosphamide
Sural 2001 4/27 0/28 48.09% 9.32[0.53,165.26]
Chiu 1973 6/12 0/11 51.91% 12[0.75,191]
Subtotal (95% CI) 39 39 100% 10.63[1.45,78.05]
Total events: 10 (Alkylating agents), 0 (Control)
Heterogeneity: Tau2=0; Chi2=0.02, df=1(P=0.9); I2=0%
Test for overall effect: Z=2.32(P=0.02)
8.3.2 Chlorambucil
Alatas 1978 1/11 0/9 100% 2.5[0.11,54.87]
Subtotal (95% CI) 11 9 100% 2.5[0.11,54.87]
Total events: 1 (Alkylating agents), 0 (Control)
Heterogeneity: Not applicable
Test for overall effect: Z=0.58(P=0.56)
Test for subgroup differences: Chi2=0.6, df=1 (P=0.44), I2=0%
Less with alkylating agents 0.005 0.1 1 10 200 Less with control
Comparison 9. Cyclophosphamide duration
1 Relapse at 12 months 2 Risk Ratio (M-H, Random, 95% CI) Totals not selected
1.1 8 weeks versus 2 weeks 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
1.2 12 weeks versus 8 weeks 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
2 Relapse at 24 months 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
2.1 12 weeks versus 8 weeks 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
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3 Leucopenia 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
Analysis 9.1. Comparison 9 Cyclophosphamide duration, Outcome 1 Relapse at 12 months.
Study or subgroup Long Short Risk Ratio Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
9.1.1 8 weeks versus 2 weeks
Barratt 1973 2/16 13/16 0.15[0.04,0.57]
9.1.2 12 weeks versus 8 weeks
Ueda 1990 28/41 21/32 1.04[0.75,1.44]
Less with long duration 0.02 0.1 1 10 50 Less with short duration
Analysis 9.2. Comparison 9 Cyclophosphamide duration, Outcome 2 Relapse at 24 months.
Study or subgroup Long Short Risk Ratio Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
9.2.1 12 weeks versus 8 weeks
Ueda 1990 30/41 24/32 0.98[0.74,1.28]
Less with long duration 0.1 0.2 0.5 1 2 5 10 Less with short duration
Analysis 9.3. Comparison 9 Cyclophosphamide duration, Outcome 3 Leucopenia.
Study or subgroup Long duration Short duration Risk Ratio Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
Ueda 1990 14/41 9/32 1.21[0.6,2.44]
Comparison 10. Cyclophosphamide dose
1 Relapse at 12 months 1 Risk Ratio (M-H, Random, 95% CI) Subtotals only
2 Adverse effects 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
2.1 Leukopenia 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
2.2 Lymphopenia 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
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2.3 Alopecia 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
2.4 Gastrointestinal 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
2.5 Genitourinary 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
Analysis 10.1. Comparison 10 Cyclophosphamide dose, Outcome 1 Relapse at 12 months.
Study or subgroup 2.5 mg/kg/d 5 mg/kg/d Risk Ratio Weight Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
McCrory 1973 1/8 0/6 0% 2.33[0.11,48.99]
Less with 2.5 mg/kg/d 0.01 0.1 1 10 100 Less with 5 mg/kg/d
Analysis 10.2. Comparison 10 Cyclophosphamide dose, Outcome 2 Adverse effects.
Study or subgroup 2.5 mg/kg/d 5 mg/kg/d Risk Ratio Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
10.2.1 Leukopenia
McCrory 1973 2/8 5/6 0.3[0.09,1.05]
10.2.2 Lymphopenia
McCrory 1973 5/8 6/6 0.66[0.38,1.15]
10.2.3 Alopecia
McCrory 1973 0/8 4/6 0.09[0.01,1.35]
10.2.4 Gastrointestinal
McCrory 1973 1/8 3/6 0.25[0.03,1.85]
10.2.5 Genitourinary
McCrory 1973 1/8 3/6 0.25[0.03,1.85]
Less with 2.5 mg/kg/d 0.005 0.1 1 10 200 Less with 5 mg/kg/d
Comparison 11. Intravenous versus oral cyclophosphamide
1 Relapse at 6 months 2 83 Risk Ratio (M-H, Random, 95% CI) 0.54 [0.34, 0.88]
2 Continuing frequently relapsing or 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
steroid dependent SSNS at 6 months
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3 Relapse at end of study 2 83 Risk Ratio (M-H, Random, 95% CI) 0.99 [0.76, 1.29]
4 Adverse effects 2 Risk Ratio (M-H, Random, 95% CI) Subtotals only
4.1 Leucopenia 2 83 Risk Ratio (M-H, Random, 95% CI) 0.37 [0.09, 1.51]
4.2 Hair loss 2 83 Risk Ratio (M-H, Random, 95% CI) 0.19 [0.04, 1.03]
4.3 All infections 2 83 Risk Ratio (M-H, Random, 95% CI) 0.14 [0.03, 0.72]
4.4 Nausea and vomiting 1 47 Risk Ratio (M-H, Random, 95% CI) 4.07 [0.21, 80.51]
Analysis 11.1. Comparison 11 Intravenous versus oral cyclophosphamide, Outcome 1 Relapse at 6 months.
Study or subgroup IV CPA Oral CPA Risk Ratio Weight Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
Abeyagunawardena 2006b 2/15 6/21 10.86% 0.47[0.11,2]
Prasad 2004 11/26 16/21 89.14% 0.56[0.33,0.92]
Total (95% CI) 41 42 100% 0.54[0.34,0.88]
Total events: 13 (IV CPA), 22 (Oral CPA)
Heterogeneity: Tau2=0; Chi2=0.05, df=1(P=0.82); I2=0%
Test for overall effect: Z=2.48(P=0.01)
Less with IV CPA 0.1 0.2 0.5 1 2 5 10 Less with oral CPA
Analysis 11.2. Comparison 11 Intravenous versus oral cyclophosphamide,
Outcome 2 Continuing frequently relapsing or steroid dependent SSNS at 6 months.
Study or subgroup IV CPA Oral CPA Risk Ratio Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
Prasad 2004 6/26 12/21 0.4[0.18,0.89]
Less with IV CPA 0.1 0.2 0.5 1 2 5 10 Less with oral CPA
Analysis 11.3. Comparison 11 Intravenous versus oral cyclophosphamide, Outcome 3 Relapse at end of study.
Study or subgroup IV CPA Oral CPA Risk Ratio Weight Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
Abeyagunawardena 2006b 6/15 9/21 11.08% 0.93[0.42,2.06]
Prasad 2004 21/26 17/21 88.92% 1[0.75,1.32]
Total (95% CI) 41 42 100% 0.99[0.76,1.29]
Total events: 27 (IV CPA), 26 (Oral CPA)
Heterogeneity: Tau2=0; Chi2=0.03, df=1(P=0.86); I2=0%
Less with IV CPA 0.1 0.2 0.5 1 2 5 10 Less with oral CPA
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Study or subgroup IV CPA Oral CPA Risk Ratio Weight Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
Test for overall effect: Z=0.07(P=0.94)
Less with IV CPA 0.1 0.2 0.5 1 2 5 10 Less with oral CPA
Analysis 11.4. Comparison 11 Intravenous versus oral cyclophosphamide, Outcome 4 Adverse effects.
Study or subgroup IV CPA Oral CPA Risk Ratio Weight Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
11.4.1 Leucopenia
Abeyagunawardena 2006b 0/15 2/21 22.46% 0.28[0.01,5.35]
Prasad 2004 2/26 4/21 77.54% 0.4[0.08,1.99]
Subtotal (95% CI) 41 42 100% 0.37[0.09,1.51]
Total events: 2 (IV CPA), 6 (Oral CPA)
Heterogeneity: Tau2=0; Chi2=0.05, df=1(P=0.82); I2=0%
Test for overall effect: Z=1.38(P=0.17)
11.4.2 Hair loss
Abeyagunawardena 2006b 0/15 11/21 30.25% 0.06[0,0.94]
Prasad 2004 2/26 5/21 69.75% 0.32[0.07,1.5]
Subtotal (95% CI) 41 42 100% 0.19[0.04,1.03]
Total events: 2 (IV CPA), 16 (Oral CPA)
Heterogeneity: Tau2=0.43; Chi2=1.33, df=1(P=0.25); I2=24.96%
Test for overall effect: Z=1.92(P=0.05)
11.4.3 All infections
Abeyagunawardena 2006b 0/15 3/21 32.67% 0.2[0.01,3.54]
Prasad 2004 1/26 7/21 67.33% 0.12[0.02,0.87]
Subtotal (95% CI) 41 42 100% 0.14[0.03,0.72]
Total events: 1 (IV CPA), 10 (Oral CPA)
Heterogeneity: Tau2=0; Chi2=0.09, df=1(P=0.77); I2=0%
Test for overall effect: Z=2.35(P=0.02)
11.4.4 Nausea and vomiting
Prasad 2004 2/26 0/21 100% 4.07[0.21,80.51]
Subtotal (95% CI) 26 21 100% 4.07[0.21,80.51]
Total events: 2 (IV CPA), 0 (Oral CPA)
Heterogeneity: Not applicable
Test for overall effect: Z=0.92(P=0.36)
Less with IV CPA 0.002 0.1 1 10 500 Less with oral CPA
Comparison 12. Chlorambucil dose
1 Relapse at 12 months 1 Risk Ratio (M-H, Random, 95% CI) Subtotals only
2 Adverse effects 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
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2.1 Leucopenia 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
2.2 Thrombocytopenia 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
Analysis 12.1. Comparison 12 Chlorambucil dose, Outcome 1 Relapse at 12 months.
Study or subgroup Increasing dose Stable dose Risk Ratio Weight Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
Baluarte 1978 0/11 2/10 0% 0.18[0.01,3.41]
Less with increasing dose 0.005 0.1 1 10 200 Less with stable dose
Analysis 12.2. Comparison 12 Chlorambucil dose, Outcome 2 Adverse effects.
Study or subgroup Increasing dose Stable dose Risk Ratio Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
12.2.1 Leucopenia
Baluarte 1978 7/11 3/10 2.12[0.74,6.04]
12.2.2 Thrombocytopenia
Baluarte 1978 2/11 0/10 4.58[0.25,85.33]
Less with increasing dose 0.01 0.1 1 10 100 Less with stable dose
Comparison 13. Cyclophosphamide versus chlorambucil
1 Relapse at 12 months 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
2 Relapse at 24 months 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
3 Adverse effects 1 300 Risk Ratio (M-H, Fixed, 95% CI) 0.65 [0.42, 1.01]
3.1 Leucopenia 1 50 Risk Ratio (M-H, Fixed, 95% CI) 0.92 [0.21, 4.14]
3.2 Lymphopenia 1 50 Risk Ratio (M-H, Fixed, 95% CI) 0.43 [0.21, 0.87]
3.3 Thrombocytopenia 1 50 Risk Ratio (M-H, Fixed, 95% CI) 0.43 [0.21, 0.87]
3.4 Severe infection 1 50 Risk Ratio (M-H, Fixed, 95% CI) 4.63 [0.23, 91.81]
3.5 Hair loss 1 50 Risk Ratio (M-H, Fixed, 95% CI) 8.33 [0.47, 147.07]
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3.6 Haematuria 1 50 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
Analysis 13.1. Comparison 13 Cyclophosphamide versus chlorambucil, Outcome 1 Relapse at 12 months.
Study or subgroup CPA Chlorambucil Risk Ratio Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
APN 1982 15/26 12/24 1.15[0.69,1.94]
Analysis 13.2. Comparison 13 Cyclophosphamide versus chlorambucil, Outcome 2 Relapse at 24 months.
Study or subgroup CPA Chlorambucil Risk Ratio Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
APN 1982 17/26 12/24 1.31[0.8,2.13]
Analysis 13.3. Comparison 13 Cyclophosphamide versus chlorambucil, Outcome 3 Adverse effects.
Study or subgroup CPA Chlorambucil Risk Ratio Weight Risk Ratio
n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI
13.3.1 Leucopenia
APN 1982 3/26 3/24 8.82% 0.92[0.21,4.14]
Subtotal (95% CI) 26 24 8.82% 0.92[0.21,4.14]
Total events: 3 (CPA), 3 (Chlorambucil)
Heterogeneity: Not applicable
Test for overall effect: Z=0.1(P=0.92)
13.3.2 Lymphopenia
APN 1982 7/26 15/24 44.12% 0.43[0.21,0.87]
Subtotal (95% CI) 26 24 44.12% 0.43[0.21,0.87]
Total events: 7 (CPA), 15 (Chlorambucil)
Heterogeneity: Not applicable
Test for overall effect: Z=2.34(P=0.02)
13.3.3 Thrombocytopenia
APN 1982 7/26 15/24 44.12% 0.43[0.21,0.87]
Subtotal (95% CI) 26 24 44.12% 0.43[0.21,0.87]
Total events: 7 (CPA), 15 (Chlorambucil)
Heterogeneity: Not applicable
Test for overall effect: Z=2.34(P=0.02)
13.3.4 Severe infection
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Comparison 14. Cyclophosphamide versus vincristine
1 Relapse at 12 months 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
2 Relapse at 24 months 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
Analysis 14.1. Comparison 14 Cyclophosphamide versus vincristine, Outcome 1 Relapse at 12 months.
Study or subgroup IV CPA Vincristine Risk Ratio Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
Abeyagunawardena 2007 6/18 13/21 0.54[0.26,1.12]
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Comparison 15. Cyclosporin dose
1 Changing versus fixed dose: re- 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
lapse
1.1 6 months 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
1.2 12 months 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
1.3 24 months 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
2 Changing versus fixed dose: ad- 2 Risk Ratio (M-H, Random, 95% CI) Totals not selected
verse effects
2.1 Hypertension 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
2.2 Psychological disorder 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
2.3 Obesity 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
2.4 Hirsutism 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
2.5 Transient elevated creatinine 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
2.6 Gum hypertrophy 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
2.7 GIT effects 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
2.8 Convulsions 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
2.9 Fatigue 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
3 High versus lower CSA target level: 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
2-year outcomes
3.1 Number with relapse 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
3.2 Number with FRNS and SDNS 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
4 High versus lower CSA target level: 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
adverse effects
4.1 Encephalopathy 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
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4.2 Infection 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
4.3 Pneumonia 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
4.4 Renal toxicity 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
4.5 Hirsutism 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
4.6 Gum hypertrophy 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
4.7 Hypertension 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
Analysis 15.1. Comparison 15 Cyclosporin dose, Outcome 1 Changing versus fixed dose: relapse.
Study or subgroup Changing dose Fixed dose Risk Ratio Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
15.1.1 6 months
Ishikura 2008 3/24 8/20 0.31[0.1,1.02]
15.1.2 12 months
Ishikura 2008 6/24 15/20 0.33[0.16,0.7]
15.1.3 24 months
Ishikura 2008 14/24 18/20 0.65[0.45,0.94]
Less with changing dose 0.05 0.2 1 5 20 Less with fixed dose
Analysis 15.2. Comparison 15 Cyclosporin dose, Outcome 2 Changing versus fixed dose: adverse effects.
Study or subgroup Changing dose Fixed dose Risk Ratio Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
15.2.1 Hypertension
Ishikura 2008 6/24 2/20 2.5[0.57,11.05]
15.2.2 Psychological disorder
Ishikura 2008 0/24 1/20 0.28[0.01,6.52]
15.2.3 Obesity
Ishikura 2008 1/24 0/20 2.52[0.11,58.67]
15.2.4 Hirsutism
Ishikura 2008 4/24 2/20 1.67[0.34,8.18]
15.2.5 Transient elevated creatinine
Ishikura 2008 2/24 1/20 1.67[0.16,17.06]
Less with changing dose 0.01 0.1 1 10 100 Less with fixed dose
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Study or subgroup Changing dose Fixed dose Risk Ratio Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
15.2.6 Gum hypertrophy
Ishikura 2008 2/24 4/20 0.42[0.08,2.04]
15.2.7 GIT effects
Ishikura 2008 2/24 2/20 0.83[0.13,5.4]
15.2.8 Convulsions
Ishikura 2008 1/24 0/20 2.52[0.11,58.67]
15.2.9 Fatigue
Dorresteijn 2008 1/12 0/12 3[0.13,67.06]
Less with changing dose 0.01 0.1 1 10 100 Less with fixed dose
Analysis 15.3. Comparison 15 Cyclosporin dose, Outcome 3 High versus lower CSA target level: 2-year outcomes.
Study or subgroup High target Lower target Risk Ratio Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
15.3.1 Number with relapse
Iijima 2014 16/43 21/42 0.74[0.45,1.22]
15.3.2 Number with FRNS and SDNS
Iijima 2014 6/43 14/42 0.42[0.18,0.99]
Less with high target 0.1 0.2 0.5 1 2 5 10 Less with lower target
Analysis 15.4. Comparison 15 Cyclosporin dose, Outcome 4 High versus lower CSA target level: adverse effects.
Study or subgroup High target Lower target Risk Ratio Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
15.4.1 Encephalopathy
Iijima 2014 2/43 1/42 1.95[0.18,20.74]
15.4.2 Infection
Iijima 2014 15/43 13/42 1.13[0.61,2.07]
15.4.3 Pneumonia
Iijima 2014 3/43 1/42 2.93[0.32,27.06]
15.4.4 Renal toxicity
Iijima 2014 2/43 0/42 4.89[0.24,98.85]
15.4.5 Hirsutism
Iijima 2014 23/43 20/42 1.12[0.74,1.71]
15.4.6 Gum hypertrophy
Iijima 2014 4/43 7/42 0.56[0.18,1.77]
15.4.7 Hypertension
Less with high target 0.01 0.1 1 10 100 Less with lower target
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Study or subgroup High target Lower target Risk Ratio Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
Iijima 2014 7/43 5/42 1.37[0.47,3.97]
Less with high target 0.01 0.1 1 10 100 Less with lower target
Comparison 16. Mizoribine versus placebo
1 Adverse effects 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
1.1 During treatment 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
1.2 Hyperuricaemia 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
1.3 Hepatic dysfunction 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
1.4 Leucopenia 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
Analysis 16.1. Comparison 16 Mizoribine versus placebo, Outcome 1 Adverse effects.
Study or subgroup Mizoribine Placebo Risk Ratio Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
16.1.1 During treatment
Yoshioka 2000 33/99 21/98 1.56[0.97,2.49]
16.1.2 Hyperuricaemia
Yoshioka 2000 16/99 4/98 3.96[1.37,11.42]
16.1.3 Hepatic dysfunction
Yoshioka 2000 9/99 9/98 0.99[0.41,2.39]
16.1.4 Leucopenia
Yoshioka 2000 2/99 1/98 1.98[0.18,21.48]
Comparison 17. Azithromycin versus steroids
Outcome or subgroup title No. of No. of par- Statistical method Effect size
studies ticipants
1 Relapse at 6 months 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
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Comparison 18. Azathioprine versus steroids
Outcome or subgroup title No. of No. of partici- Statistical method Effect size
studies pants
1 Relapse at 6 months 2 60 Risk Ratio (M-H, Random, 95% CI) 0.90 [0.59, 1.38]
Analysis 18.1. Comparison 18 Azathioprine versus steroids, Outcome 1 Relapse at 6 months.
Study or subgroup AZA Placebo/Pred Risk Ratio Weight Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
ISKDC 1970 5/18 8/18 21.59% 0.63[0.25,1.55]
Barratt 1977 9/12 9/12 78.41% 1[0.63,1.59]
Total (95% CI) 30 30 100% 0.9[0.59,1.38]
Total events: 14 (AZA), 17 (Placebo/Pred)
Heterogeneity: Tau2=0; Chi2=1.03, df=1(P=0.31); I2=3.32%
Test for overall effect: Z=0.47(P=0.64)
Comparison 19. ACTH versus placebo
Outcome or subgroup title No. of No. of par- Statistical method Effect size
studies ticipants
1 Relapse at 6 months 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
Analysis 19.1. Comparison 19 ACTH versus placebo, Outcome 1 Relapse at 6 months.
Study or subgroup ACTH No treatment Risk Ratio Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
ATLANTIS 2018 14/15 15/16 1[0.83,1.2]
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APPENDICES
Appendix 2. Risk of bias assessment tool
Potential source of bias Assessment criteria
Random sequence genera- Low risk of bias: Random number table; computer random number generator; coin tossing; shuf-
tion fling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be imple-
mented without a random element, and this is considered to be equivalent to being random).
Selection bias (biased alloca-
tion to interventions) due to High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; se-
inadequate generation of a quence generated by hospital or clinic record number; allocation by judgement of the clinician; by
randomised sequence preference of the participant; based on the results of a laboratory test or a series of tests; by avail-
ability of the intervention.
Unclear: Insufficient information about the sequence generation process to permit judgement.
Allocation concealment Low risk of bias: Randomisation method described that would not allow investigator/participant to
know or influence intervention group before eligible participant entered in the study (e.g. central
allocation, including telephone, web-based, and pharmacy-controlled, randomisation; sequential-
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(Continued)
Selection bias (biased alloca- ly numbered drug containers of identical appearance; sequentially numbered, opaque, sealed en-
tion to interventions) due to velopes).
inadequate concealment of al-
locations prior to assignment High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); as-
signment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or
non-opaque or not sequentially numbered); alternation or rotation; date of birth; case record num-
ber; any other explicitly unconcealed procedure.
Blinding of participants and Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome
personnel is not likely to be influenced by lack of blinding; blinding of participants and key study personnel
ensured, and unlikely that the blinding could have been broken.
Performance bias due to
knowledge of the allocated High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by
interventions by participants lack of blinding; blinding of key study participants and personnel attempted, but likely that the
and personnel during the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
study
Unclear: Insufficient information to permit judgement
Blinding of outcome assess- Low risk of bias: No blinding of outcome assessment, but the review authors judge that the out-
ment come measurement is not likely to be influenced by lack of blinding; blinding of outcome assess-
ment ensured, and unlikely that the blinding could have been broken.
Detection bias due to knowl-
edge of the allocated interven- High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be
tions by outcome assessors. influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could
have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
Incomplete outcome data Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be relat-
ed to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome
Attrition bias due to amount, data balanced in numbers across intervention groups, with similar reasons for missing data across
nature or handling of incom- groups; for dichotomous outcome data, the proportion of missing outcomes compared with ob-
plete outcome data. served event risk not enough to have a clinically relevant impact on the intervention effect esti-
mate; for continuous outcome data, plausible effect size (difference in means or standardized dif-
ference in means) among missing outcomes not enough to have a clinically relevant impact on ob-
served effect size; missing data have been imputed using appropriate methods.
High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either
imbalance in numbers or reasons for missing data across intervention groups; for dichotomous
outcome data, the proportion of missing outcomes compared with observed event risk enough to
induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausi-
ble effect size (difference in means or standardized difference in means) among missing outcomes
enough to induce clinically relevant bias in observed effect size; ‘as-treated’ analysis done with
substantial departure of the intervention received from that assigned at randomisation; potentially
inappropriate application of simple imputation.
Selective reporting Low risk of bias: The study protocol is available and all of the study’s pre-specified (primary and
secondary) outcomes that are of interest in the review have been reported in the pre-specified way;
Reporting bias due to selective the study protocol is not available but it is clear that the published reports include all expected out-
outcome reporting comes, including those that were pre-specified (convincing text of this nature may be uncommon).
High risk of bias: Not all of the study’s pre-specified primary outcomes have been reported; one or
more primary outcomes is reported using measurements, analysis methods or subsets of the data
(e.g. subscales) that were not pre-specified; one or more reported primary outcomes were not pre-
specified (unless clear justification for their reporting is provided, such as an unexpected adverse
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Informed decisions.
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(Continued)
effect); one or more outcomes of interest in the review are reported incompletely so that they can-
not be entered in a meta-analysis; the study report fails to include results for a key outcome that
would be expected to have been reported for such a study.
Other bias Low risk of bias: The study appears to be free of other sources of bias.
Bias due to problems not cov- High risk of bias: Had a potential source of bias related to the specific study design used; stopped
ered elsewhere in the table early due to some data-dependent process (including a formal-stopping rule); had extreme base-
line imbalance; has been claimed to have been fraudulent; had some other problem.
Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient ra-
tionale or evidence that an identified problem will introduce bias.
WHAT'S NEW
Date Event Description
10 March 2020 New citation required but conclusions New interventions included
have not changed
10 March 2020 New search has been performed Updated review with new included studies
HISTORY
Protocol first published: Issue 3, 2000
Review first published: Issue 4, 2001
Date Event Description
17 October 2013 New search has been performed New studies included
17 October 2013 New citation required and conclusions New interventions included
have changed
13 October 2013 New search has been performed Search strategies updated
18 March 2010 New search has been performed Contact details updated.
Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children (Review) 133
Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.
Library Better health. Cochrane Database of Systematic Reviews
CONTRIBUTIONS OF AUTHORS
Initial review
• AM Durkan: wrote the protocol, literature searching, assessment for eligibility and quality, data extraction, data synthesis, wrote the
review
DECLARATIONS OF INTEREST
None known.
SOURCES OF SUPPORT
Internal sources
• No sources of support supplied
External sources
• Australian Kidney Foundation, Australia.
INDEX TERMS
Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children (Review) 134
Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.