1 s2.0 S016147541400205X

ORIGINAL ARTICLES
MANUAL AND MANIPULATIVE THERAPY IN

ADDITION TO REHABILITATION FOR
OSTEOARTHRITIS OF THE KNEE: ASSESSOR-BLIND
RANDOMIZED PILOT TRIAL
Lauren Dwyer, MTech(Chiro), a Gregory F. Parkin-Smith, MTech(Chiro), MBBS, MSc, DrHC, b
James W. Brantingham, DC, PhD, c, 1 Charmaine Korporaal, MTech(Chiro), d Tammy K. Cassa, DC, e
Gary Globe, PhD, MBA, f Debra Bonnefin, DC, MAppSc, g and Victor Tong, DC, MBA h
ABSTRACT
Objectives: The purpose of this study was to examine the methodological integrity, sample size requirements, and
short-term preliminary clinical outcomes of manual and manipulative therapy (MMT) in addition to a rehabilitation
program for symptomatic knee osteoarthritis (OA).
Methods: This was a pilot study of an assessor-blinded, randomized, parallel-group trial in 2 independent university-
based outpatient clinics. Participants with knee OA were randomized to 3 groups: 6 MMT sessions alone, training in
rehabilitation followed by a home rehabilitation program alone, or MMT plus the same rehabilitation program,
respectively. Six MMT treatment sessions (provided by a chiropractic intern under supervision or by an experienced
chiropractor) were provided to participants over the 4-week treatment period. The primary outcome was a description
of the research methodology and sample size estimation for a confirmatory study. The secondary outcome was the
short-term preliminary clinical outcomes. Data were collected at baseline and 5 weeks using the Western Ontario and
McMasters Osteoarthritis Index questionnaire, goniometry for knee flexion/extension, and the McMaster Overall
Therapy Effectiveness inventory. Analysis of variance was used to compare differences between groups.
Results: Eighty-three patients were randomly allocated to 1 of the 3 groups (27, 28, and 28, respectively). Despite 5
dropouts, the data from 78 participants were available for analysis with 10% of scores missing. A minimum of 462
patients is required for a confirmatory 3-arm trial including the respective interventions, accounting for cluster effects
and a 20% dropout rate. Statistically significant and clinically meaningful changes in scores from baseline to week 5
were found for all groups for the Western Ontario and McMasters Osteoarthritis Index (P ≤ .008), with a greater
change in scores for MMT and MMT plus rehabilitation. Between-group comparison did not reveal statistically
significant differences between group scores at week 5 for any of the outcome measures (P ≥ .46).
Conclusions: This pilot trial suggests that a confirmatory trial is feasible. There were significant changes in scores from
baseline to week 5 across all groups, suggesting that all 3 treatment approaches may be of benefit to patients with mild-to-
moderate knee OA, justifying a confirmatory trial to compare these interventions. (J Manipulative Physiol Ther 2015;38:1-21.e2)
Key Indexing Terms: Pilot Projects; Osteoarthritis; Knee; Musculoskeletal Manipulations; Rehabilitation
steoarthritis (OA) is the most common form of than 65 years, with a propensity for symptomatic OA to
O chronic arthritis, with radiologic evidence of joint

degeneration in more than 50% of people older
occur in women. 1,2 The knee joint is one of the most
commonly affected by OA, leading to a burden on the
a h
Private Practice, Department of Chiropractic, Durban University Radiologist, Rowland Heights, CA.
of Technology, Durban, South Africa. Submit requests for reprints to: James W. Brantingham, DC,
b
Adjunct Senior Lecturer, Murdoch University, Murdoch, Australia. PhD, Adjunct Associate Professor, 250 Whiteside Place, Thousand
c
Adjunct Associate Professor, School of Chiropractic and Oaks, CA 91362. (e-mail: Jimbrant2002@yahoo.com).
1
Sports Science, Murdoch University, Murdoch, Australia. Formerly Director of Research and Associate Professor, Cleveland
d
Senior Lecturer in Chiropractic, Department of Chiropractic, Chiropractic College, Los Angeles, CA.
Durban University of Technology, Durban, South Africa. Paper submitted September 28, 2013; in revised form October
e
Practicing Chiropractor, Erie, PA. 10, 2014; accepted October 13, 2014.
f
Director, Global Health Economics, Amgen Inc, Thousand 0161-4754
Oaks, CA. Copyright © 2015 by National University of Health Sciences.
g
Associate Professor, Texas Chiropractic College, Pasadena, TX. http://dx.doi.org/10.1016/j.jmpt.2014.10.002
Downloaded for Anonymous User (n/a) at Univ Andres Bello Natl from ClinicalKey.com by Elsevier on May 17, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
2 Dwyer et al Journal of Manipulative and Physiological Therapeutics
Manual Therapy and Rehabilitation for Knee OA January 2015
individual and the community through reduced quality of recruitment problems. Therefore, this trial is presented as a
life, diminished capacity for employment, and an increase 2-center, assessor-blind, parallel-group short-term clinical
in health care costs. 3 With an aging population globally, the trial with balanced randomization (1:1). The results and
problem of OA of the knee will likely worsen, which has recommendations of this pilot trial may be considered a
prompted the development of clinical practice guidelines template for a fully-powered confirmatory trial. The study
that now recommend treatment at an early stage of the protocol was not updated as regularly as was desired on
disease, using health promotion/exercise to reduce progres- ClinicalTrials.gov. However, third-party access resulted in
sion, and optimization of both pharmacologic and non- premature cancellation/closure of the study on the website.
pharmacologic treatment. 4 The recommendation for future trials is to limit third-party
For mild to moderate OA, clinical practice guidelines access to the protocol on ClinicalTrials.gov and to ensure
promote a multimodal treatment approach that includes drug regular updating, to facilitate transparency in the conduct of
therapy and nonpharmacologic treatment, such as patient the trial. This project received approval from the relevant
education, exercise, and weight optimization. 5 Physical institutional review board of Cleveland Chiropractic College
therapies, such as manual and manipulative therapy (IRB No. 08132010) and the Research Ethics Committee of
(MMT), are also emerging as a viable treatment option, 6–8 Durban University of Technology. The trial was registered
particularly in combination with other interventions like with Clinical.Trials.gov (NCT01188837).
exercise, 9 health promotion, and simple analgesia. 10 Manual
and manipulative therapy can offer positive outcomes for
knee OA 8,11,12 but needs to be explored further within the Evaluation of the Research Integrity and Methodological Rigor
context of multimodal care. The primary outcomes of this study included the
Combining treatments to form a package of care for a following: patient recruitment, enrollment, and allocation;
specific disorder implies the delivery of a complex data collection and patient retention; acceptability of
intervention, the outcome of which may be confounded by interventions; sample size calculations; and research design
internal and external factors. 13 Therefore, the trials testing alternative. Sample size calculations were performed and
complex interventions require modeling or piloting prior to a reported using the data from this external pilot trial. Initial
confirmatory trial with a view to optimize the research design calculations were based on the F test (analysis of covariance
and determine feasibility. 14–16 [ANCOVA]) for fixed effects, main effects, and interaction
The purpose of this trial was to conduct an external pilot effects at a 95% level of confidence to achieve statistical
trial and compare MMT, a rehabilitation program, and the Power of 80% (using G* Power software, www.psycho.uni-
combination of MMT plus the rehabilitation program for dusseldorf.de, Dusseldorf, Germany) taking into account the
mild to moderate OA of the knee. The primary outcome effect size, the number of groups, the number of covariates,
was to assess the design integrity, with a view to provide a and the degrees of freedom for the outcome measure
critique of the research design, offer design recommenda- (Western Ontario and McMasters Osteoarthritis Index
tions, and provide a sample size estimate for a larger [WOMAC]). For research design alternative, multisite or
confirmatory trial. The secondary outcome was to gain cluster randomized trials as a potential research design were
insight into preliminary clinical outcomes. The research discussed. Accordingly, a sample size estimate is offered
hypothesis was that the 3 treatment approaches would with this design in mind.
show significant change in scores from baseline to week 5
and that there would be a significant difference between Selection Criteria
treatment groups. To achieve the primary end-point, the Inclusion Criteria. All eligible participants had a diagnosis
following objectives were covered by descriptive analysis of of mild-moderate knee OA based on the diagnostic
(a) patient recruitment, enrollment, and allocation; (b) data criteria of the American College of Rheumatology and the
collection and patient retention; (c) acceptability of interven- Kellgren-Lawrence grade for knee OA, suitable grades for
tions; and (d) sample size calculations. this study being grades 0 to 3. 17,18 This diagnosis was
reached after assessment by the lead clinician and radio-
graphic investigation of each eligible participant. The
METHODS radiographs were read and interpreted by a Diplomate in
Chiropractic Radiology who was blind to the study criteria,
Trial Design and Changes to the Methods After Commencement data, and randomization.
This study was initially designed as an assessor-blind, Inclusion and exclusion criteria are in Figure 1.
parallel-group clinical trial with 1-, 3-, and 6-month follow-up.
However, toward the latter part of this study, access to funding
became more difficult, which impacted recruitment and data Setting, Practitioners, and Participants
collection. The authors realized that a pilot study was needed This study was implemented across 2 chiropractic
to inform the design of future trials to account for financial and university-based outpatient teaching clinics, 1 in the city of
Journal of Manipulative and Physiological Therapeutics Dwyer et al 3
Volume 38, Number 1 Manual Therapy and Rehabilitation for Knee OA
Inclusion Criteria: in the study. Eligible patients who volunteered for the study
1. Age ≥38 and ≤80 years;
2. Knee pain ≥ 1 year and able to stand and walk without were offered a cooling-off period of up to 3 days, with those
severe varus/valgus deformity and/or severe instability choosing to proceed giving written informed consent and
(instability being defined as a significant increase in randomly allocated to 1 of the treatment groups. 21 The
anterior drawer or varus/valgus movement when
compared to the opposite knee); rationale for the cooling-off period was 2-fold—firstly, to
3. A minimum of1of the 3 clinical criteria below for allow the potential participant to make an informed,
diagnosis of knee OA (sensitivity 89% and specificity considered decision about joining the study (ie, no coercion
88%) 17 :
a. Knee pain and crepitus with active motion to join the study), and to ensure participants were genuinely
and morning stiffness ≤30 min; or experiencing an episode of symptoms, because knee OA
b. Knee pain and crepitus with active motion often has a relapsing/remitting course or acute or chronic
and morning stiffness >30 minutes and
bony enlargement; or
symptoms. Treatment was provided by a senior chiropractic
c. Knee pain and no crepitus and bony intern under supervision or by an experienced chiropractor.
enlargement – bony enlargement being Supervising and treating chiropractors had more than 5 years
determined on palpation and supplemented
by observations of radiographs.
of clinical experience and specific experience in either sports-
4. No history of knee surgery in the past 6 months;19 type and/or extremity injuries. Most patients were treated by
5. Kellgren and Lawrence grade of 0-3 on plain-film the same treating clinician at each site.
radiographs; 18
6. Ability to stand and walk without assistance for most
(≥¾) of the day, as keeping active and performing
exercises would otherwise be difficult; Interventions
7. A participant was required to have a score of Group 1: MMT Alone. Participants were required to undergo 6
≥720/2400 (≥30%) on the WOMAC; and
8. No previous manual and/or manipulative therapy for treatments sessions over the 4-week treatment period, then a
their knee pain. final consultation during week 5 for data collection only. The
limit of absence was 3 or more missed appointments. The
Exclusion Criteria:
1. Kellgren-Lawrence grade 4 knee degenerative frequency of treatment was approximately twice per week.
changes on plain-film radiographs, indicating severe Each treatment session was approximately 20 minutes, during
knee OA; which time each participant was also assessed for adverse signs
2. Possibility of serious pathological or psychiatric
disorders; such as pain, joint swelling, or redness. The treatment would
3. Possibility of a disorder that would prevent the then be adjusted to participant tolerance, at the discretion of the
participant performing exercises or contraindications clinician. Each participant in this group had 6 treatment
to MMT.
sessions with a total treatment dose of around 120 minutes
(2 hours). Patient education about the diagnosis and prognosis
Fig 1. Inclusion and exclusion criteria. MMT, manual and was provided, alongside lifestyle advice, as described in the
manipulative therapy; OA, osteoarthritis; WOMAC, a 24-question informed consent and other handouts given to the patients.
survey used to measure pain, joint stiffness, and function (disability).
The treatment comprised joint mobilization (grades 1-4)
and joint manipulation (grade 5; high-velocity, low-amplitude,
Durban, South Africa, at Durban University of Technology thrust-type manipulation) of the affected kinematic chain
and the other in Los Angeles, California, at Cleveland (knee, hip, foot, and spine). Manipulation, mobilization, and
Chiropractic College, Los Angeles, in the United States. soft tissue treatment were based on techniques previously
Participants were recruited over a 6-month period, from described. 19,22,23 Manipulation was applied to joints with
September 2010 to February 2011, with the study being restricted range of motion (ROM), identified by joint motion
advertised on campus, on local radio, and in local palpation by the treating clinician, using the high-velocity
newspapers. Potential study candidates with knee pain who low-amplitude manipulations noted above or, as described
were seeking care responded to the advertising by contacting in textbooks and other peer-reviewed papers. 24–26 Forced
the clinical lead at each study site. The lead clinician screened end-ROM grade 4 mobilizations or grade 5 thrust manipula-
each potential participant by telephone or in person for tions were avoided, particularly in flexion and extension,
eligibility, the screening criteria being the following: (a) knee where it was likely to worsen symptoms or could not be
pain ≥ 1 year, (b) no history of knee surgery in the past tolerated by the participant. 22,23
6 months, (c) aged ≥ 38 and ≤ 80 years, (d) the knee pain was A description of the 3 most commonly used mobilization
not to be due to an acute injury, and (e) had no previous and manipulation techniques were as follows:
manual and/or manipulative therapy for their knee Manual 1: second oscillating mobilization of the knee in
pain. 17,19,20 The patient information sheet and consent form flexion (and separately into extension) starting at the point of
is offered in Appendix A which is available online. stiffness with lesser grades II to III and progressing to IV++
Potential patients made an appointment with the lead or rarely to grade V if safe and appropriate; 2 to 6 sets of
clinician at the study site to undergo a full assessment and 30 repetitions. As appropriate a light—varus (adduction
complete an information sheet and were invited to participate stress), valgus, (abduction stress), or gentle—internal rotation
may be added if felt indicated per motion palpation technique Education consisted of information about the diagnosis
(applied at any joint that might be a candidate for MMT) as and prognosis, and advice on health promotion and lifestyle.
described and noted in commonly used textbooks, now The content and timing of treatment were important in that
further supported by the recently published review of advice, education, and training were provided to participants
methods used by chiropractors to determine the site for at the onset of their treatment program (week 1) and
applying manipulation. 23,27,28 reinforced at 2 other points during the treatment period
Patellar mobilization used could be applied with various (weeks 2 and 4). This was to reinforce the need for
techniques developed at Macquarie University using their rehabilitation and to encourage compliance.
patellar myofascial mobilization procedure where the The home-exercise prescription was standardized for use
participant is seated on an examination table with their knee across the trial centers, yet still allowing for minor case by
over the practitioner's ipsilateral knee and in relaxed flexion. case variations. The exercise program was similar to that
The practitioner places a web contact (or pincer with thumb described previously. 22 At the first treatment session during
and index finger) against the superior pole of the patella while week 1, participants received training in the exercise
the participant extends the knee and the patella is gently program, which was to be performed at home for around
stressed superior to inferior with a bias toward medial or 20 minutes, at least 3 times per week. Participants were
lateral rotation. This is repeated up to 10 times (additionally a required to return for a second and third treatment sessions
light thrust may be applied at any time throughout the during weeks 2 and 4 to reinforce the treatment approach,
mobilizations; see the published peer-reviewed paper for ensure exercises were being done correctly, and encourage
complete details). 19 Patellar mobilization was also performed compliance. Participants were provided a pamphlet of
as per a previous trial from Durban University of Technology information with written descriptions and drawings of the
(with the supine participant's knee slightly flexed and with exercises, alongside direct supervision/training.
the participant's knee between the practitioner's legs); the The aim of the rehabilitation program was to keep it
thumbs of the practitioner remove the slack from superior to simple, to encourage compliance, and to contain costs by
inferior and either lateral to medial or medial to lateral against keeping supervision to the minimum. This is likely to
and slightly lifting up the edge of the patella. As the knee is replicate clinical practice more closely because patients do not
brought into extension, the patella is stressed inferiorly or necessarily have the motivation, time, or finances to undertake
distally with a combined lateral or medial stress. Based on the regular supervised rehabilitation. Recommendations on the
experience of 1 of the authors (J.W.B.), it was suggested that rehabilitation program are provided latterly.
the patella be most often mobilized with a bias of lateral to Each treatment session was approximately 20 minutes,
medial then superior to inferior. However, the patellar could during which time each participant was also assessed for
also be simply mobilized from lateral to medial from the side adverse signs such as pain, joint swelling, or redness. The
of the participant and/or in any direction of apparent exercise regime would then be adjusted to participant
restriction. 23,28,29 If the technique developed at Macquarie tolerance, performing less exercise if there were adverse
was not used, then as per the 2005 trial previously noted, the symptoms. Each participant in this group had 3 treatment
patella was mobilized for 2 to 6 sets of 30 repetitions. 30 sessions (of around 20 minutes each) with a total treatment
Axial elongation of the knee in extension was frequently dose of around 60 minutes (1 hour), and total exercise dose
performed as nonthrust (as a lesser grade of mobilization) was approximately 240 minutes (4 hours; 12 exercise
but often initially as a grade IV or IV++ as a light thrust 2 sessions of 20 minutes each) over the treatment period. A
to 3 times, and if no side effects were detected within a diary was kept by all patients in the exercise group to
few treatments, it was delivered as a full high-velocity, monitor at home exercise compliance.
low-amplitude (HVLA) grade V thrust manipulation, 1 up Group 2: Rehabilitation Program
to 3 times. Axial elongation or distractive thrust (pulling/ The rehabilitation program included patient education,
tractioning or thrusting the femur and tibia apart) was done exercise prescription, soft tissue treatment, and passive
without any combined forced knee extension. 23,29,31 stretches (on treatment days) to the knee and elsewhere
Other manipulations could be applied if strongly along the full kinetic chain, where needed, based on
indicated (presenting with pain and/or functional deficit or functional assessment. 22 Functional examination included
both) per the lumbar spine, sacroiliac joint, the hip (per a active and passive ROM, manual muscle strength and
specific protocol if OA was present), 32 or full lower length, reflex, sensory and myofascial restriction or tender-
extremity as per the literature previously indicated. 26,27,31 ness and palpation of the lumbar spine, hip, ankle, foot, and
knee joints. In addition, squatting, performance of step-ups,
Group 2: Rehabilitation Program. The rehabilitation program and similar evaluation were also checked to determine the
included patient education, exercise prescription, soft tissue ability of participants to participate in exercise and manual
treatment, and passive stretches (on treatment days only) to therapy protocols.
the knee and elsewhere along the full kinetic chain, where Education consisted of information about the diagnosis
needed, based on functional assessment. and prognosis, and advice on health promotion and lifestyle.
The participant was reassured that knee OA is not an Outcome Measures

immediately life-threatening or serious problem, although it The outcome measures were as follows:
could be painful. The participant was advised to stay active as
The WOMAC, a 24-question survey, was used to measure
much as possible and that nonaggravating physical activity
pain, joint stiffness, and function (disability). Each
was helpful and to return to normal activities, including work,
parameter was scored out of 100, with a maximum total
as soon as possible leads to better recovery and function.
Participants were informed that exercise was important for score of 2400 (pain 500, stiffness 200, function 1700). 33,34
The WOMAC index is a valid and reliable measure of
OA of the knee as it helped to reduce pain and maintain
changes in pain and function, and used in various knee OA
general health. Low-impact activities, where there was less
trials, where a 20% overall change in score (ie, ≥ 480/2400)
weight going through the hips and knees were recommended.
is reported as being clinically meaningful; 33,34
Participants were advised that being overweight could lead to
more pain and damage to hips and knees affected by OA. Knee ROMs (flexion/extension) were measured by the
The content and timing of treatment were important in same research assistant at each study site. Knee
that advice, education, and training were provided to flexion and extension were performed 3 times per
participants at the onset of their treatment program (week 1) each evaluation, as described by Norkin and White
and reinforced at 2 other points during the treatment period and using a Saunders digital inclinometer (Saunders
(weeks 2 and 4). This was to reinforce the need for Equipment Company 1998, Florida, CA). The mean of
rehabilitation and to encourage compliance. these measurements was then obtained. 35–37 Digital
Most of the soft-tissue therapy and passive stretching, Inclinometry or goniometry has adequate intraexami-
which was used on 3 occasions over the treatment period ner reliability including for OA of the knee (intratester
during weeks 1, 2 and 4, was applied in the following reliability with an interexaminer correlation coefficient
manner: focused soft tissue treatment was applied similar to of 0.75-0.88 or higher). 38–40
a previous trial, including circular finger and palm pressure
(forms of point pressure, petrissage, and effleurage), and The McMaster Overall Therapy Effectiveness (OTE)
stretch to the knee and other joints along the full kinetic inventory, which measures global patient-perceived satis-
chain based on functional assessment. 22,32 faction and improvement with care, is based on a 15-point
The home-exercise program was similar to that described Likert scale where 0 indicates no change; − 7, maximum
in a previous trial, 22 which included strengthening exercises, deterioration; and + 7, maximum improvement. 41–43 The
stretching, supine ROMs exercises, and walking. minimal important difference of quality of life score per
At the first treatment session during week 1, participants item on a 15-point scale (− 7 to + 7) is very close to 0.5
received training in the exercise program, which was to be (range, 0.42-0.58), where differences of approximately 1.0
performed at home, at least 3 times per week. Participants represented a moderate change (range, 0.77-1.51) and
were required to return for a second and third treatment differences greater than 1.5 represented large changes. 41
sessions during weeks 2 and 4 to reinforce the treatment For the OTE, a clinically meaningful posttreatment score is
approach, ensure exercises were being done correctly, and a change of 14% (≥ 1/7). 41
encourage compliance. Each participant was also assessed Baseline demographic data and statistics were reported
for adverse signs such as pain, joint swelling, or redness. in Table 1, for total or cumulative WOMAC in Table 2,
The exercise regime would then be adjusted to participant for knee ROM in Tables 3 and 4, and, finally, for the OTE
tolerance, performing less exercise if there were adverse in Table 5.
symptoms. Each participant in all 3 groups had 3 treatment Adverse events were monitored in each participant and
sessions. A diary was kept by all patients to monitor at determined at each treatment consultation by interview;
home exercise compliance. patient notes were specifically designed to prompt such
Group 3: MMT Plus Rehabilitation. Participants in group 3 questions each visit. Participants had been previously
received a combination of the treatments described for group informed that transient, benign side effects are often
1 and group 2. Participants were required to skip exercise on encountered with exercise and MMT, such as stiffness and
the days they received MMT. The duration of each session discomfort and normally resolve. Although recorded in the
was around 20 minutes, with an additional 20 minutes for patient notes, these were not reported as adverse effects.
patient education and training during 3 sessions, with the total However, participants were informed that side effects of
treatment dose approximately 180 minutes (3 hours) and total treatment, such as persistent or escalation of pain, or
exercise dose of around 240 minutes (4 hours). Each unintended effects, such as but not limited to, joint
participant in this group had 6 treatment sessions over the swelling/redness or inability to weight-bear, were considered
4-week treatment period, with additional time during a adverse events and were to be immediately reported to the
treatment session in weeks 1, 2, and 4 to reinforce patient assessing/treating clinician because the participant was not to
education and the exercise program. Participants were continue further treatment or perform exercises until it was
required to skip exercise on the days they received MMT. determined safe to do so.
Table 1. Sample Characteristics and Descriptive Statistics the full trial is likely to be inadequate, whereas another
Group 1 a Group 2 c Group 3 d author suggests that a sample size for a pilot trial should be
Variable (n b=26) (n = 26) (n = 26) 30 or more participants per group, so that sufficient data are
Age (y) available to assess the study parameters accuracy. 44,45
Mean (SD) 63.5 (10.9) 60.9 (10.3) 62.2 (11.8) Regarding sample size determination for pilot trials, “If the
95% CI 59.1-67.9 56.7-65.0 57.4-66.9 aim of a pilot study is to demonstrate intervention efficacy
Sex, female (frequency) 19 (73%) 15 (58%) 15 (58%)
in a single group, a sample in the range of 20-25 will
Height (cm)
Mean (S) 165.9 (9.8) 167.1 (15.5) 165.9 (8.5) probably be adequate when population effect sizes are
95% CI 162.0-169.9 160.8-173.4 162.4-169.3 likely to be moderate or larger….” 44 The authors agreed on
Weight (kg) a minimum sample size of ≈ 25 per group (3 groups), while
Mean (SD) 78.6 (15.2) 85.8 (20.4) 84.3 (21.2) considering available funding, practical constraints, and the
95% CI 72.5-84.8 77.6-94.1 75.7-92.8
available time frame for recruitment. 44,45
BMI
Mean (SD) 28.6 (5.2) 30.8 (6.4) 30.6 (7.6)
95% CI 26.5-30.7 28.2-33.4 27.5-33.7
Onset (frequency) Randomization and Data Management
Insidious 22 (85%) 23 (88%) 20 (77%) Randomization was conducted using a random numbers
Traumatic 4 3 6
Duration of symptoms (mo)
process where a sequence of random numbers with
Mean (SD) 89.3 (81.4) 58.4 (53.4) 104.1 (131.0) sequence boundaries was generated using computer
95% CI 56.4-122.1 36.8-80.0 51.2-157.0 software. This randomization process was conducted by
Side (frequency) 1 of the authors who did not participate as a clinician in the
Left 13 (50%) 13 (50%) 17 (65%) trial or collect data. 21 Each study site had its own
Right 11 10 7
Both 2 3 2
randomization set/sequence, generated in the same way
Occupation (frequency) for each site. Each random treatment assignment was
Not working 9 14 (54%) 16 (62%) placed in a sealed opaque envelope, producing a series of
Nonmanual work 15 (58%) 12 7 sequentially numbered sealed envelopes, thus conferring
Manual work 2 0 3 allocation concealment. As each volunteer consented to
Regular exercise (frequency)
None 14 (54%) 12 (46%) 16 (62%)
participate, the clinic manager for each site, who was
Mild intensity 9 7 9 independent of the study, then opened an envelope and
Moderate intensity 3 7 1 identified the treatment group to which the participant was
High intensity 0 0 0 assigned. This trial, therefore, followed an individually
Grade of knee OA (frequency) randomized design, with the clinical lead being informed of
Grade 0 0 0 0
Grade 1 22 (85%) 16 (62%) 16 (62%)
the allocation of participants, post hoc. This randomization
Grade 2 4 10 10 process was adopted at both clinic sites.
Grade 3 0 0 0 Data were collected by an independent research assistant
No. of treatment sessions 6 4 6 who was not aware of the treatment groups or randomization.
No. of exercise sessions n/a 10 9 Treatment was provided by either the lead clinician or other
during trial
vetted, participating clinicians, none of whom collected any
BMI, body mass index; CI, confidence interval; OA, osteoarthritis. data and were masked from the data and randomization.
a
Manipulative therapy alone.
b
Sample size.
c
Exercise prescription alone.
d
Manipulative therapy plus exercise. Data Analysis
Intention-to-treat analysis was performed by replacing
missing data using a multiple imputations method (WinMICE
prototype version 0.1; TNO Quality of Life, Leiden, the
Netherlands, http://www.multiple-imputation.com). The
calculations were performed using a multilevel regression
model that created 5 multilevel imputations 46,47 . The mean
The Pilot Trial Sample Size of the 5 imputed values was then used to replace missing
Usually, a definitive sample size is not required for a scores, and the data were then analyzed using standard
pilot trial, because hypothesis testing is not the primary end- statistical tests.
point. However, as a secondary outcome, this trial intended To address the secondary outcome of this trial, clinical
to offer insight into preliminary clinical outcomes to outcomes, data analysis was conducted. The data sets were
determine the need for a larger confirmatory trial. It has amenable to the F test (MedCalc software; www.medcal.org)
been suggested that the traditional sample size for a pilot using weighted 2-tailed ANCOVA at a 95% confidence level,
trial of 10 per group or 10% of the expected sample size of using data from baseline and the final consultation (week 5).
Table 2. Comparison of Cumulative or Total WOMAC Data of the 3 Treatment Groups

Sphericity
Greenhouse-Geisser ε = 0.48
Sphericity assumed P ≤ .001
Summary Statistics Mean SE 95% CI

Group 1 baseline 1113.1 68.9 971.2-1255.0
Group 2 baseline 997.1 59.6 874.2-1120.0
Group 3 baseline 1165.0 74.8 1011.1-1319.1
Group 1 4th visit 790.5 79.7 626.4-954.7
Group 2 4th visit 710.8 66.2 574.4-847.2
Group 3 4th visit 696.9 66.0 561.0-832.7
Group 1 1wFU 553.0 80.7 386.8-719.3
Group 2 1wFU 633.5 63.4 502.9-764.2
Group 3 1wFU 570.3 86.7 391.7-748.8
Mean Difference SE Pa 95% CI a

Within-group comparison
Group 1
Baseline–4th visit 322.5 54.7 .0001 126.0 to 519.1
4th visit–1wFU 237.5 43.8 .0005 80.0 to 395.0
Baseline–1wFU 560.0 65.4 b.0001 324.8 to 795.2
Group 2
4th visit–1wFU 77.2 38.4 1.0 − 60.7 to 215.1
Baseline–1wFU 363.5 78.1 .0033 82.8 to 644.3
Group 3
Baseline–4th visit 374.5 110.8 .0860 − 24.0 to 773.0
4th visit–1wFU 126.6 45.2 .3462 − 35.7 to 289.0
Baseline–1wFU 570.3 109.6 .0003 218.1 to 1006.0
Between-group comparison
Group 1–Group 2
Baseline 116.0 88.7 1.0 − 202.8 to 434.8
4th visit 79.8 102.1 1.0 − 287.3 to 446.9
1wFU − 80.5 92.1 1.0 − 411.5 to 250.5
Group 2–Group 3
Baseline − 168.0 107.1 1.0 − 553.1 to 217.2
4th visit 13.9 95.7 1.0 − 330.2 to 358.0
1wFU 63.3 105.0 1.0 − 314.1 to 440.7
Group 1–Group 3
Baseline − 52.0 109.4 1.0 − 445.3 to 341.4
4th visit 93.7 101.2 1.0 − 270.3 to 458.0
1wFU − 17.2 113.4 1.0 − 425.0 to 391.0
A significant change in cumulative or total WOMAC scores was found from baseline and to the 1-week follow-up for all 3 groups, suggesting that all
3treatments had a meaningful beneficial clinical effect over the study treatment period of 1 month and at the fifth-week follow-up. When comparing the 3
groups, no statistically significant differences were found in scores across all 3 time-points.
P values less than 0.05 are statistically significant.
1wkFU, 1-week follow-up; CI, confidence interval; SE, standard error.
a
Boneferroni corrected.
Differences in baseline data and regression toward the mean difference analyses were performed to establish where the
were considered potential confounding factors and were differences lay.
accounted for statistically using the ANCOVA analysis. The
data were statistically adjusted using the covariates of
age, duration of symptoms, and body mass index. These RESULTS
covariates were chosen because they appeared dissimilar Evaluation of the Research Integrity and Methodological Rigor
when examining the patient characteristics and confidence Recruitment, Enrollment, Allocation, and Patients. Flow diagram of
intervals, although they may not have been statistically participant recruitment and retention (CONSORT diagram)
different (Table 1). If significant differences between are found in Figure 2. Initial data analysis (Table 1)
data sets were discovered, Tukey honestly significant indicated that 13 and 70 participants were recruited at the
Table 3. Comparison of Knee Flexion ROM Data of the 3 Treatment Groups

Sphericity
Sphericity assumed P≤ .0029

Group 1 baseline 99.0 3.8 91.1 to 106.9
Group 1 4th visit 105.5 3.5 98.3 to 112.6
Group 2 4th visit 106.0 3.6 98.5 to 113.4
Group 3 4th visit 103.6 2.9 97.7 to 109.5
Group 1 1wFU 106.1 3.6 98.7 to 113.5
Group 2 1wFU 105.5 3.5 98.4 to 112.6
Group 3 1wFU 109.7 3.0 103.5 to 115.9

Group 1
Baseline–4th visit − 6.4 1.6 .0143 − 12.095 to − 0.774
4th visit–1wFU − 0.7 1.5 1.0 − 6.068 to 4.737
Baseline–1wFU − 7.1 2.2 .106 − 14.844 to 0.644
Group 2
Baseline–4th visit − 5.2 1.6 .149 − 11.074 to 0.720
4th visit–1wFU 0.5 2.5 1.0 − 8.666 to 9.590
Baseline–1wFU − 4.7 2.8 1.0 − 14.905 to 5.475
Group 3
Baseline–4th visit − 9.7 4.8 1.0 − 27.005 to 7.520
4th visit–1wFU − 6.2 3.0 1.0 − 16.912 to 4.604
Baseline–1wFU − 15.9 4.7 .086 − 32.817 to 1.025
Group 1–Group 2
Baseline − 1.7 4.2 1.0 − 16.8 to 13.3
4th visit − 0.5 4.2 1.0 − 15.6 to 14.6
1wFU 0.6 4.6 1.0 − 15.8 to 17.1
Group 2–Group 3
Baseline 6.9 6.3 1.0 − 15.8 to 29.7
4th visit 2.4 4.2 1.0 − 12.8 to 17.5
1wFU − 4.2 3.3 1.0 − 16.1 to 7.6
Group 1–Group 3
Baseline 5.2 6.8 1.0 − 19.3 to 29.6
4th visit 1.9 4.5 1.0 − 14.2 to 18.0
1wFU − 3.6 5.0 1.0 − 21.4 to 14.2
a
American and South African study sites, respectively. underwent unrelated surgery), and there was a total of 10%
Between-group analysis of variance did not reveal any (79/780) missing data, with the data from 78 participants
significant difference between the 2 study site groups in available for analysis (26/group) after missing data were
terms of age, height, grade of knee OA, or duration of replaced. Examination of the descriptive and patient
symptoms (P ≥ .17), although there was a significant characteristics suggests that the 3 groups were similar at
difference for weight and body mass index (P ≤ .01). This baseline (Table 1) as well for the WOMAC, ROM, and the
analysis was conducted prior to amalgamating the data into patient satisfaction or global OTE score (see Tables 2, 3, 4,
the 3 treatment groups (Table 1). The flow of participants is and 5). The baseline scores for the individual WOMAC
shown in the Consort Figure 2. Of the 111 participants domains of pain, stiffness, and disability can be found in
screened, 91 were assessed, with 83 eligible participants Tables 6, 7, and 8.
volunteering for the study. Five participants dropped out of The average number of exercise sessions undertaken in
the study (3 “no shows”, 1 moved to another town, 1 group 2s and 3 over the treatment period was 9 and 10,
Table 4. Comparison of Knee Extension ROM Data of the 3 Treatment Groups

Sphericity
Sphericity assumed P = .006

Group 1 baseline 4.7 0.8 3.1-6.3
Group 1 4th visit 5.8 0.8 4.1-7.5
Group 2 4th visit 5.1 0.9 3.3-7.0
Group 3 4th visit 8.0 3.8 0.2-15.7
Group 1 1wFU 6.2 0.9 4.4-8.0
Group 2 1wFU 5.2 0.8 3.5-6.9
Group 3 1wFU 9.0 4.2 0.2-17.7

Group 1
Baseline–4th visit − 1.1 0.3 .044 − 2.2 to 0.0
4th visit–1wFU − 0.4 0.2 1.0 − 1.3 to 0.5
Baseline–1wFU − 1.5 0.4 .033 − 2.9 to − 0.1
Group 2
4th visit–1wFU − 0.1 0.3 1.0 − 1.3 to 1.0
Baseline–1wFU − 0.7 0.3 1.0 − 1.9 to 0.5
Group 3
4th visit–1wFU − 1.0 0.5 1.0 − 3.0 to 0.9
Baseline–1wFU − 5.4 4.5 1.0 − 21.8 to 11.0
Group 1–Group 2
Baseline 0.2 0.5 1.0 − 1.6 to 2.0
4th visit 0.7 0.5 1.0 − 1.1 to 2.6
1wFU 1.0 0.6 1.0 − 1.1 to 3.1
Group 2–Group 3
Baseline 0.9 0.5 1.0 − 1.0 to 2.8
4th visit − 2.8 3.9 1.0 − 17.0 to 11.4
1wFU − 3.8 4.5 1.0 − 20.1 to 12.5
Group 1–Group 3
Baseline 1.1 0.6 1.0 − 1.0 to 3.1
4th visit − 2.1 4.1 1.0 − 16.8 to 12.6
1wFU − 2.8 4.6 1.0 − 19.4 to 13.9
a
respectively, based on participant diaries. The actual Data Collection and Patient Retention. The WOMAC and the
treatment doses, based on the actual number of treatments OTE surveys are easily accessible using an online search
and exercise sessions undertaken in groups 1, 2, and 3, were engine. Of the original 83 randomly allocated participants,
120, 240, and 360 minutes, respectively (Table 1). The there was a 6% dropout (5/83). Usually, a sample size for a
average participant was a 62-years-old woman, was not proposed trial is increased by 20% to account for dropouts,
working, was overweight, took very little exercise, and had so a 6% dropout rate was considered acceptable by the
mild-moderate OA of the knee. authors in this trial. Although the authors speculate that the
Participants were recruited over a 6-month period, from dropout rate in a larger trial would be higher, it would be
September 2010 to February 2011, delivering a patient prudent to expand on a required sample size by 20% and
screening rate of 20 potential patients per month (5/week) account for this by extending the recruitment period. The
and a screening exclusion rate of 18% (3 per month). number of eligible participants recruited was 81, being 75%
Monthly assessment/examination rate was 15 patients with of the 111 patients first presenting for screening and a
an 8% exclusion rate (8/month). recruitment rate of around 14 participants per month.
Table 5. Comparison of OTE Data of the 3 Treatment Groups the potential for significant type II error in this pilot trial.
Friedman P ≤ .01 Using the average effect size across all 4 domains (pain,
Minimum required difference of mean rank: 1.7572 disability, stiffness, and cumulative) of the WOMAC of
0.1, the sample size required for a confirmatory trial with
Summary Statistics Mean Rank Median SE 95% CI
an individual-randomization design would be 962 total,
Group 1 Section A 4th visit 4.6 4 0.3 3-5
or 323/group over 3 groups (power ≥ 80%; ANCOVA
Group 1 Section B 4th visit 7.5 5 0.3 4-6
Group 2 Section A 4th visit 4.3 4 0.3 3-5
statistical test for 3 groups and 3 covariates; 2-tailed test;
Group 2 Section B 4th visit 6.3 5 0.3 4-5 α = .05) 48 . For a given effect size of 0.2 and 0.3 (as
Group 3 Section A 4th visit 5.4 4.5 0.5 3-5 reported or calculated from similar trials), the total
Group 3 Section B 4th visit 8.4 5 0.3 5-6 sample size required would be 244 (82/group) and 111
Group 1 Section A 1wFU 6.0 4 0.4 4-5 (37/group), respectively. 12,49,50 If the recommendations
Group 1 Section B 1wFU 8.1 5 0.2 5-6
Group 2 Section A 1wFU 6.1 4.5 0.4 4-5 proposed later in this article are implemented to improve
Group 2 Section B 1wFU 7.3 5 0.3 4-6 on trial design, then an effect size of 0.2 would be
Group 3 Section A 1wFU 6.0 4.5 0.5 3-5 reasonable. Therefore, a recommended sample size for an
Group 3 Section B 1wFU 8.2 5.5 0.3 5-6 individual-randomized trial would be ≥ 82/group (total
≥ 244; Table 9).
Between-Group Comparison However, this sample size does not fully account for
sample differences (cluster effects) if there are ≥ 2 study
Mean Rank Difference SE P 95% CI
sites. Although individual-randomization is possible at each
Group 1–Group 2 Section A study site, as in this pilot trial, the variance between sites
4th visit 0.3 0.4 1.0 − 2 to 2
needs to be considered when estimating a sample size for a
1wFU − 0.1 0.6 1.0 − 2 to 2
Group 1–Group 2 Section B confirmatory trial, as with a cluster-randomized design. 51,52
4th visit 1.2 0.5 1.0 − 1 to 2 The sample size requirement for a multisite or cluster-
1wFU 0.8 0.4 1.0 − 1 to 2 randomized trial would need to be inflated by a variance
Group 2–Group 3 Section A inflation factor (VIF) to account for the loss of power due to
4th visit −1.1 0.4 1.0 − 2 to 2
the clustering effect. Determining summaries of sample size
1wFU 0.1 0.5 1.0 − 2 to 2
Group 2–Group 3 Section B estimation for cluster-randomized trials has been well
4th visit − 2.1 0.3 b .05 − 2 to 1 described in the literature. 52,53 The VIF for a confirmatory
1wFU − 0.9 0.4 1.0000 − 2 to 1 trial, based on the WOMAC data of this trial, is 45.5 (rounded
Group 1–Group 3 Section A to 46), where VIF = 1 + (n − 1)p, where n = sample size;
4th visit −0.8 0.7 1.0 − 3 to 3
p = intraclass correlation coefficient (0.55). 54,55 Therefore,
1wFU −0.1 0.7 1.0 − 2 to 3
Group 1–Group 3 Section B the required sample size per group for a multisite or cluster-
4th visit 0 0.5 1.0 − 2 to 2 randomized trial would be 82 + 46 + 26 = 154/group (sample
1wFU −0.1 0.5 1.0 − 2 to 2 estimate for an individually-randomized trial + VIF + dropout),
P values less than 0.05 are statistically significant. or a total of 462 for 3 treatment groups. With sample
1wkFU, 1-week follow-up; CI, confidence interval; SE, standard error. sizes of this number it would be important to have a
numerous clinician assessors, treating clinicians and
research assistants to be able to manage the sample and
Acceptability of Interventions. No complaints or feedback from the data collection, and careful consideration on this matter
participants indicated a reluctance or objection to treatment is required for future trials. The fundamental costing for a
provided. Participants were informed that they had the right to confirmatory trial, at ≈ US$240.00 per participant, would
withdraw from the study at any time, without a need to be in the region of ≈ US$110 000.00)—this excludes
provide a reason, and without prejudice. No adverse events or patient compensation costs.
complications were reported (such as persistent, severe
nonresolving pain, stiffness, or disability), and no patients
were known to have left the trial because of side effects, but Secondary Outcome: Clinical Outcomes
rather appeared to drop out by choice. Although there were Within-group analyses (Tables 2, 6, 7, and 8) demon-
isolated cases of transient, benign symptoms of stiffness, or strated statistically significant (P ≤ .004) and clinically
pain reported, these benign side effects subsequently resolved meaningful changes in scores for the WOMAC from
in all cases and were not reported as adverse effects. baseline to week 5 across all 3 groups and all 3 domains
(pain, stiffness, and disability).There were no statistically
significant changes in scores for knee flexion/extension
Sample Size Calculation for a Confirmatory Trial (P ≥ .08; Tables 3 and 4). Within-group post hoc power
Post hoc average effect sizes and power were ≤ 0.17 across all groups was ≥ 0.94. Treatment effectiveness was
and ≤ 0.24, for WOMAC, respectively (Table 9), implying not explored further in this pilot trial, and the study did not
Potential Patients Responding to

Advertising/word of mouth
N = 111
Potential patients excluded after

interview/screening n = 20
Patients who underwent

assessment after being
screened
N = 91
Potential patients
excluded after
assessment
n=8
Eligible patients that were randomly allocated to a treatment group

N = 83
Group 1 MMT only Group 2 Exercise only Group 3 M MT + Exercise

n = 27 n = 28 n = 28
Drop outs Drop outs Drop outs

n=1 n=2 n=2
Number of participants Number of participants Number of participants

from whom data was from whom data was from whom data was
available available available
n = 26 n = 26 n = 26
Fig 2. Flow diagram of participant recruitment and retention (CONSORT diagram). MMT, manual and manipulative therapy.
include a control group (no-treatment or placebo treatment). patient satisfaction and improvement, with no group demon-
Figure 2 (WOMAC), Figure 3 (knee flexion and extension strating significantly higher scores over another (Table 5). Post
ROM), and Figure 4 (the OTE) bar charts give an overview hoc effect sizes and power were ≤ 0.17 and ≤ 0.24,
of change in scores (Figs 2, 3, and 4). respectively (Table 5). Although the patient satisfaction
Between-group analysis of week 5 (final consultation) data scale used in this study (OTE) cannot be directly compared
did not reveal any significant differences in scores (P ≥ .46) (for short-term outcomes only), it is interesting to look at
across any of the treatment groups for any of the outcome the long-term 1-year follow-up patient satisfaction scales in
measures (Table 9). The mean difference in scores between 2 other knee OA MMT (with and without exercise and/or
groups at week 5 was ≤80/2400 points (≤ 3%) for WOMAC usual, or medical practitioner, care) clinical trials. 22,56 The
and ≤ 4° (≤ 3%) for knee flexion/extension. However, the first delivered 8 treatments for 4 weeks and the next more
overall percent change in the WOMAC in group 1 or MMT recent study 9 total treatments for about 2 months. 22,56
alone (50%) in group 2 (37%) and group 3 combined MMT Patients were trained to and continued home exercise for
plus rehabilitation (51%) with similar percentage-like scores knee OA after release. 22,56 The first study listed patient
for the domains of pain, stiffness, and disability are notable satisfaction at 1 year using a Likert scale, with the MMT +
and suggest at minimum that further research is justified exercise group reporting 52% “very much satisfied” compared
(Tables 6, 7, 8, and 10). The median OTE score at week 5 with the exercise-only group reporting 25% “very much
across the groups was ≥ 5/7 (≥ 72%; range, 72%-79%), with satisfied.” 22 Another recently published Knee OA study using
the percentage score for groups 1, 2, and 3 being 79%, 75%, a 0-10 scale (10 worst) demonstrated overall pain intensity
and 72%, respectively. This shows that participants in all 3 decreased by − 1.1 points (for MMT + usual care) on a
groups experienced relatively high levels of self-perceived 0–10 scale vs exercise (+ usual care) of − 0.45 and combined
Table 6. Comparison of Pain Data (WOMAC) of the 3 Treatment Groups

Sphericity

Group 1 baseline 227.3 17.2 191.8-262.8
Group 2 baseline 205.8 15.2 174.5-237.1
Group 3 baseline 216.8 17.0 181.9-251.8
Group 1 4th visit 150.4 21.3 106.5-194.2
Group 2 4th visit 127.7 12.2 102.6-152.8
Group 3 4th visit 133.5 14.5 103.7-163.3
Group 1 1wFU 102.3 17.1 67.0-137.5
Group 2 1wFU 129.2 12.9 102.5-155.8
Group 3 1wFU 97.7 16.4 64.0-131.5

Group 1
Baseline–4th visit 76.9 17.8 b .0077 12.9 to 140.8
4th visit–1wFU 48.1 11.2 b .0085 7.8 to 88.5
Baseline–1wFU 125.0 17.6 b .0001 61.6 to 188.4
Group 2
4th visit–1wFU − 1.4 13.8 1.0000 − 50.9 to 48.0
Baseline–1wFU 76.7 17.0 b .0048 15.5 to 137.8
Group 3
4th visit–1wFU 35.7 9.3 b .0276 2.2 to 69.3
Baseline–1wFU 119.1 15.5 b .0001 63.6 to 174.7
Group 1–Group 2
Baseline 21.5 23.1 1.0 − 61.7 to 104.7
4th visit 22.7 24.0 1.0 − 63.7 to 109.0
1wFU − 26.9 18.6 1.0 − 93.7 to 40.0
Group 2–Group 3
Baseline − 11.0 25.4 1.0 − 102.4 to 80.3
4th visit − 5.7 20.6 1.0 − 79.9 to 68.0
1wFU 31.4 21.5 1.0 − 45.9 to 108.7
Group 1–Group 2
Baseline 10.4 24.6 1.0 − 77.9 to 98.7
4th visit 16.9 26.0 1.0 − 76.4 to 110.3
1wFU 4.5 25.0 1.0 − 85.4 to 94.4
a
MMT + exercise (+ usual care) of − 0.84. 56 (Tables 5, 6, 7, 8, may well increase recruitments rates to over double those
and 10; Fig 5). rates in this pilot trial. The authors recommend 3 or more
clinic sites, with referral from local medical and orthopedic
clinics, to achieve the estimated sample size for a fully
DISCUSSION powered confirmatory study. Referral may be encouraged
Primary Outcome: Evaluation of the Research Integrity and by providing continuing medical education workshops for
Methodological Rigor physicians with a view to facilitate patient referral and
Patient Recruitment, Enrollment, and Allocation. This trial had a lectures for family physicians, where presentations on
successful recruitment rate that could be improved in a research may be offered and may enhance referrals and
confirmatory trial by having multiple study sites, 2 or more understanding of these research activities.
clinicians conducting the screening and examination at each The screening criteria were sufficiently broad to allow
site, and cooperation from local medical, physiotherapy, the assessment of patients with knee pain, yet were likely to
and orthopedic clinics to advertise or refer patients. This focus on those who probably had knee OA. Screening of
Table 7. Comparison of Stiffness Data (WOMAC) of the 3 Treatment Groups

Sphericity

Group 1 baseline 96.5 9.6 76.9-116.2
Group 2 baseline 96.5 9.6 76.9-116.2
Group 3 baseline 119.3 8.7 101.4-137.3
Group 1 4th visit 70.5 9.3 51.3-89.6
Group2 4th visit 63.0 6.2 50.1-75.8
Group 3 4th visit 65.9 8.0 49.5-82.3
Group 1 1wFU 46.6 6.4 33.5-59.7
Group 2 1wFU 48.5 7.1 33.9-63.2
Group 3 1wFU 41.1 7.7 25.4-56.9

Group 1
4th visit–1wFU 23.8 7.1 .0909 − 1.7 to 49.4
Baseline–1wFU 49.9 9.6 .0008 15.4 to 84.5
Group 2
4th visit–1wFU 14.4 4.6 .1560 − 2.1 to 31.0
Baseline–1wFU 47.4 9.3 .0011 13.9 to 80.8
Group 3
Baseline–4th visit 53.5 8.1 b.0001 24.5 to 82.5
4th visit–1wFU 24.8 6.2 .0188 2.4 to 47.1
Baseline–1wFU 78.2 8.4 b.0001 48.2 to 108.3
Group 1–Group 2
Baseline 0.6 11.1 1.0 − 39.2 to 40.5
4th visit 7.5 10.1 1.0 − 28.7 to 43.7
1wFU − 1.9 8.3 1.0 − 31.9 to 28.0
Group 2–Group 3
Baseline − 23.4 11.9 1.0 − 66.0 to 19.2
4th visit − 2.9 8.6 1.0 − 34.0 to 28.2
1wFU 7.4 11.1 1.0 − 32.6 to 47.5
Group 1–Group 3
Baseline − 22.8 13.9 1.0 − 72.6 to 27.0
4th visit 4.6 13.6 1.0 − 44.2 to 53.4
1wFU 5.5 10.9 1.0 − 33.7 to 44.7
a
patients by the clinical lead at each study site and the for future trial. The descriptive statistics indicates that most
consequent scheduling of appointments for further assess- participants in this trial were grade 1 knee OA, some with
ment of potential participants were logistically successful. grade 0, and very few with other grades. A recommendation
The subsequent assessment and examinations of potential is that all grades of knee OA be represented (grades 1-4),
participants by the same clinical lead allowed for continuity excluding grade 0, and by having a large enough sample
of assessment and uniformity of participant selection. The size to allow the representation of these grades. This
inclusion criteria were thorough and facilitated the selection approach would allow subgroup analysis based on knee OA
of participants with genuine knee OA. The diagnosis was grades, to explore which grade(s) the intervention(s) may be
reached after assessment and review of radiographs and the of benefit. Worth considering for a confirmatory trial are
report by the primary treating clinician. However, the broader diagnostic criteria developed for knee OA through
validity of the diagnosis would be bolstered by using 2 systematic review and Delphi panel analysis to take into
assessors to confirm the diagnosis, and this is recommended account a variety of presentations: symptoms include
Table 8. Comparison of Disability Data (WOMAC) of the 3 Treatment Groups

Sphericity

Group 1 baseline 759.0 47.6 660.9-857.2
Group 2 baseline 731.7 50.8 627.0-836.3
Group 3 baseline 411.7 52.0 304.5-518.9
Group 1 4th visit 573.8 56.4 457.7-689.9
Group2 4th visit 521.1 39.5 439.8-602.4
Group 3 4th visit 514.4 61.6 387.6-641.2
Group 1 1wFU 389.7 49.4 288.0-491.4
Group 2 1wFU 411.7 52.0 304.5-518.9
Group 3 1wFU 378.9 62.0 251.1-506.6

Group 1
4th visit–1wFU 184.1 35.0 .0007 58.4 to 309.8
Baseline–1wFU 369.3 42.0 b.0001 218.5 to 520.2
Group 2
4th visit–1wFU 109.4 32.2 .0820 − 6.3 to 225.2
Baseline–1wFU 320.0 60.0 .0006 104.2 to 535.7
Group 3
4th visit–1wFU 135.5 31.3 .0076 23.0 to 248.0
Baseline–1wFU 453.0 63.2 b.0001 225.6 to 680.4
Group 1–Group 2
Baseline 27.4 57.2 1.0000 − 178.3 to 233.1
4th visit 52.7 63.3 1.0000 − 174.9 to 280.3
1wFU − 22.0 61.5 1.0000 − 243.0 to 199.0
Group 2–Group 3
Baseline − 100.2 81.9 1.0000 − 394.8 to 194.3
4th visit 6.7 68.9 1.0000 − 241.0 to 254.5
1wFU 32.8 69.1 1.0000 − 215.6 to 281.2
Group 1–Group 3
Baseline − 72.8 84.2 1.0000 − 375.5 to 229.8
4th visit 59.4 93.5 1.0000 − 277.0 to 395.7
1wFU 10.8 89.0 1.0000 − 309.4 to 331.0
a
persistent knee pain, limited knee stiffness (b 30 minutes), included a cooling off period of up to 3 days to afford each
and reduced function, and signs include crepitus, restricted eligible patient to reflect on their decision and change their
movement, and bony enlargement (the more symptoms and mind if they so wished. The 3-day cooling off period also
signs the more likely the diagnosis of knee OA (all 6 acted as a brief quantification period to ensure the patient's
denoting a 99% confidence interval [CI]). 8,57 knee pain was not transient but a persistent knee pain in line
The patient information sheet provided to eligible with the diagnosis of knee OA.
participants, as approved by the respective ethics committee Data Collection and Patient Retention. In a trial testing manual
and internal review board, was deemed satisfactory. The therapy or exercise, neither participant nor therapist/
format of the information sheet was similar to that of those clinician blinding is practical or possible, respectively.
found in clinical trials. It contained all the necessary However, to reduce the chance of treatment contamination
information to enable eligible participants to make an and clinician bias, a blind assessor collected the data from
informed choice about volunteering for the study and each participant at the appropriate time-points in this pilot
Table 9. Comparison of the Data at Week 5 for All Outcome Measures

Analysis Homogeneity Of
Group 1 a Group 2 b Group 3 c (ANCOVA d) Regressions Post hoc Power
Mean (SEM) Mean (SEM) Mean (SEM) Power
Outcome Measure [95% CI] [95% CI] [95% CI] P Value (r) P value (Effect Size)
WOMAC Cumulative 553.0 (80.7) [387-719] 633.5 (63.4) [503-764] 570.3 (86.7) [392-749] .78 (− 0.01) .87 0.10 (0.09)
WOMAC Pain 102.3 (17.1) [67-138] 129.2 (12.9) [103-156] 97.7 (16.4) [64-132] .34 (− 0.04) .64 0.24 (0.17)
WOMAC Stiffness 46.6 (6.4) [34-60] 48.5 (7.1) [34-63] 41.1 (7.7) [25-57] .75 (− 0.07) .97 0.10 (0.09)
WOMAC Disability 389.7 (49.4) [288-491] 411.7 (52.0) [305-519] 378.9 (62.0) [251-507] .95 (− 0.04) .57 0.06 (0.05)
Knee flexion 106.1 (3.6) [99-114] 105.5 (3.5) [98-113] 109.7 (3.0) [104-116] .67 (0.02) .46 0.16 (0.13)
Knee extension 6.2 (0.9) [4-8] 5.2 (0.8) [4-7] 9.0 (4.2) [0.2-18] .61 (0.04) .87 0.22 (0.16)
OTE Part A (median) 4 (0.4) [4-5] 4.5 (0.4) [4-5] 4.5 (0.5) [3-5] .97 (− 0.01) .93 0.06 (0.04)
OTE Part B (median) 5 (0.2) [5-6] 5 (0.3) [4-6] 5.5 (0.3) [5-6] .58 (− 0.02) .80 0.11 (0.10)
ANCOVA, analysis of covariance; CI, confidence interval; OTE, McMaster Overall Therapy Effectiveness; WOMAC, a 24-question survey used to
measure pain, joint stiffness, and function (disability).
a
b
Exercise prescription alone.
c
Manipulative therapy plus exercise.
d
With mean scores adjusted for the covariates of age, body mass index, and duration of symptoms.
trial. The data were collected by an independent research and, for studies of 1 year or longer, joint imaging. 58 In a
assistant who was not involved in the study otherwise. As systematic review, the most common outcome measures
with other staff, the research assistant was provided training encountered in published trials for knee OA are the
on the outcome measures and how to administer them. No WOMAC, visual analog scale, the Arthritis Impact Measure-
problems were encountered in this trial in administering ment Scales, and the Knee injury and Osteoarthritis Outcome
these outcome measures post training. Logistically, it was Score (KOOS). 12 In addition, Health-related quality of
more practical to book appointments for participants on life assessment is receiving increased attention as an
specific days of the week so to coordinate with availability outcome measure in OA. 59 The RAND-36 Measure of
of the clinician(s) and research assistant, for treatment and Health-Related Quality of Life, as a well-known and
data collection, respectively. tested questionnaire, could offer meaningful data in this
The outcome measures, being the WOMAC, OTE, and regard. The overall impression of the authors is that the
knee ROMs, were straightforward to administer by the primary outcome measures for a knee OA trial should
research assistant at both study sites. Clearly, the WOMAC is comprise the widely used tools that cover the domains
the preferred clinical outcome measure, being well-known, now commonly stipulated for knee OA to include quality
valid, reliable, and easy to administer. The WOMAC is of life measures, amenable to meta-analysis in future
recommended as a key clinical outcome measure for future systematic review. Therefore, the authors recommend the
trials because of its utility, ease of use, and the ability for WOMAC and the RAND-36 Measure of Health-Related
researchers to amalgamate data from various trials using the Quality of Life plus 1 other, either the Arthritis Impact
WOMAC for meta-analysis, for example, systematic reviews Measurement Scales 2 or the KOOS, with the exclusion
and in clinical guideline development. of the OTE and knee ROM. 60–63
In addition, the WOMAC collects data across 4 domains Patient tracking occurred through appointment schedul-
(pain, stiffness, disability, and cumulative), allowing for ing and follow-up. Clinic managers and clinical leads for
individual domain analysis and amenable to being used as a this trial did not report any major issues with patient
single outcome measure if a study is constrained by time/ tracking, record keeping, or follow-up. However, for a
practical issues. larger trial, the following should be considered:
The utility and appropriateness of both the OTE and knee
ROMs are uncertain. Manual goniometric measurement in a. A clear indication in the participant consent form that the
the clinical setting is prone to measurement error, and as an agreement to participate implies that an appointment and
outcome measure, the relationship between knee ROM and instruction would be followed to the best of the
functional disability is questionable, particularly with only participant's ability.
relatively small reductions in ROM in lower grades of knee b. The study should have a written flowchart indicating
OA. The OTE is encountered sporadically in the health care patient scheduling and time-points of follow-up, with
literature and may well be a useful participant self-report of a view to ensure appropriate timing of appointments,
the effectiveness of care, but it has been suggested that participant tracking, and follow-up.
outcome measures for OA trials should include 4 key c. Ensure clinical and administrative record keeping in
domains: pain, physical function, patient global assessment, line with required standards of practice.
Fig 3. Changes in the WOMAC for cumulative, pain, disability, and stiffness scores from baseline, to the fourth visit and for the final or
fifth visit, or 1-week follow-up for group 1 (manual therapy alone), group 2 (exercise only), and group 3 (manual therapy and exercise).
Fig 4. Changes in knee ROM in flexion and extension from baseline, to the fourth visit and for the final or fifth visit, or 1-week follow-up
for group 1 (manual therapy alone), group 2 (exercise only), and group 3 (manual therapy and exercise).
To ensure participant compliance, scheduling of appoint- a. Education about exercise and the benefits of exercise
ments occurred early in the treatment period, usually at b. Use of a graded progressive exercise or physical
baseline. Participants were followed up telephonically to activity program that ensures that pain and discomfort
remind them of appointments, or to reschedule, as necessary. are not excessive during or after exercise
Participants were reminded verbally, by the treating clinician c. Initiate exercise under instruction and supervise
at the respective appointments, of the treatment and the exercise sessions if possible
importance of compliance. d. Supplement face to face instruction with other materials;
For those participants undertaking home exercise, they e. Increase self-efficacy by incorporating goal setting,
were required to maintain a diary to encourage engagement positive reinforcement, use of an exercise contract,
with the exercise routine and compliance. Adherence to and self-monitoring using a diary 63,64
home exercise is often difficult to maintain, and lack of
adherence limits the long-term effectiveness of exercise. Based on these recommendations, a trial requires a clear
Strategies to improve compliance include the following 64: written protocol and explanation about knee and knee OA
Table 10. Change in Score From Baseline to Week 5 for WOMAC 9

Overal Therapy Effectiveness
a d e 8
Group 1 Group 2 Group 3
(n b= 26) (n = 26) (n = 26)
Score at Week 5
7
Outcome Change in % c Change in % Change in % 6
Measure (Mean Difference) (Mean Difference) (Mean Difference) 5
WOMAC 50 (560) 37 (364) 51 (595) 4
Cumulative 3
WOMAC 55 (125) 37 (77) 55 (119) 2
Pain
1
WOMAC 52 (50) 49 (47) 66 (78)
Stiffness 0
Grp1 PartA Grp2 PartA Grp3 PartA Grp1 PartB Grp2 PartB Grp3 PartB
WOMAC 47 (369) 44 (320) 54 (453) Groups
Disability
WOMAC, a 24-question survey used to measure pain, joint stiffness, and
function (disability).
Fig 5. Scores at week 5 (final consultation, after the 4-week
a
treatment period) for both Part A and Part B of the OTE index.
b
Sample size.
c
Change in scores from baseline to week 5 presented as % change and
mean differences score.
Design Alternative. Because of the complex nature of treatment
d
Exercise prescription alone. and care delivery in community-based care, a design
e
Manipulative therapy plus exercise. alternative is the cluster-randomized approach. This method-
ology is thoroughly discussed in the literature and is thought to
so that the participants understand that the increased activity be very useful for the testing of complex interventions. 51,55,59
of the exercises to treat their knee OA are similar to simple However, this approach usually requires sample size inflation,
activities such as increased walking and will not further hurt as demonstrated in the sample size calculation previously,
their knee if carried out cautiously as taught—and how to adding to the project cost and duration. 13
modify, reduce, or expand on these exercises (thus, a diary
is required) based on participant response. 63,64
Clinical Outcomes
Acceptability of Interventions. No complaints or feedback from The impression generated from the results of statistical
participants indicated a reluctance or objection to treatment analysis suggest that all 3 treatment approaches had a
provided. As indicated previously, benign side effects were beneficial effect in the short term (4 weeks and 1-week
transient and no adverse events were reported. Patients also follow-up) based on WOMAC scores (Table 10). The
were required to read instructions (Appendix A available results of this trial correlate with those reported by another
online), which details possible adverse effects from all of study that demonstrated significant short-term benefits of
the 3 treatments offered, and it was made clear that the most manual therapy and supervised exercise, also based on
common side effect for any of the treatments was temporary WOMAC scores. 30 Therefore, a reasonable inference is that
stiffness and soreness. They were also informed that in any of the treatments tested in this study could improve
Appendix A, per each protocol, they were to report to the symptoms over a 4-week treatment period. Broadly, the
treating chiropractor immediately if they felt any side outcomes of this trial are also consistent with the positive
effects, or injury from treatment, which then would have WOMAC outcomes reported with the use of MMT for knee
been dealt with as a serious adverse reaction. There were OA in other published (Table 10) trials. 22,23,56
only mild, transient side effects of soreness and stiffness The greatest change in WOMAC scores in this trial was in
noted (in all 3 groups), but in retrospect, although data groups 1 and 3 (Table 2), where treatment was provided
around adverse events were to be noted in patient files with a directly by a clinician (on 6 treatment occasions), as opposed to
view to identify dropouts, the minimal side effects seen were group 2, where direct supervision was provided on only 3
not comprehensively reported (such as a percentage or mean) occasions. There was also a “hands-on” manual therapy
and, therefore, not fully explored in the data analysis. This component of treatment in groups 1 and 3, which was not
oversight is described later as a limitation of the study. offered in group 2. So, there may be a potential dose-response
Acceptability of interventions was considered through synthe- association related to the frequency of direct treatment or
sis of (a) the number of dropouts and the reasons for such, (b) supervision. Although this association was not statistically
frequency and type of adverse events, and (c) feedback from explored in this study, it does bear similarity to the conclusions
the participants, treating clinicians, and patient records related drawn by others where the greater the level/frequency of
to treatment. There was no formal outcome measure or survey supervision, the better the clinical outcomes, particularly when
of acceptability, but rather a cumulative measure. A more exercise prescription is an intervention. 12,22,30 Plausibly, the
formal feedback system, as part of reporting adverse events, higher levels of direct supervision or hands-on treatment, as
should be considered in future trials. offered in groups 1 and 3, resulted in better participant
compliance, particularly with self-directed home exercise, and short term. 22,56 This hypothesis should be tested in a
therefore improved clinical outcome. future fully powered confirmatory trial because definitive
The matter of attention bias will always be present in inferences cannot be drawn from the results of this
studies that test physical therapies where 1 treatment may external pilot trial.
be offered more frequently, for longer or have a more
intense treatment “dose.” It is possible therefore that if the
participants in group 2 (rehabilitation alone) received more Limitations
direct supervision, the outcomes may have been better. The limitation of this trial is that there is no control
Arguably, the rehabilitation group (group 2) should receive group featuring a “wait-and-see” approach or a “minimum-
the same dose and level of supervision as the other groups in a treatment” group, so conclusions regarding the effective-
confirmatory trial. Also, rehabilitation should perhaps be more ness of treatment in each group cannot be drawn.
comprehensive and consensus led (by a panel of clinical Furthermore, the natural history of knee OA, which is
experts) with a view to create an intervention that is of often characterized by fluctuating signs and symptoms,
equivalent in dose to other intervention groups being tested. alongside the potential effect of the Hawthorne phenom-
Manual and manipulative therapy alone appeared to enon, may account for some of the improvement seen in
have a positive effect on outcomes, based on WOMAC each treatment group. Also, as a pilot trial, this study also
scores (Table 2), possibly even better than the rehabil- does not permit definitive conclusions regarding clinical
itation program as delivered in this pilot trial. Although outcomes due to its inherent low power.
there were no statistically significant differences between Adverse events and treatment side effects were not
the groups (Tables 2 and 10), the positive effect of MMT comprehensively reported in this trial and (only mild side
corroborates with those reported in a systematic review effects were noted, but neither were they given as a
of treatments for knee OA, where the authors recommend percentage per group or descriptively described), therefore,
manual mobilization in addition to supervised exercise to not fully explored in the data analysis. Treatment safety and
gain better pain relief (over exercise alone). 12 Under- adverse events are important components to a pilot trial
standably then, one could speculate that the “right” because these data inform the design and treatment
combination of MMT plus exercise delivered in a better protocols for a definitive trial. In future trials, there should
or best way may yield better clinical outcomes than either be a protocol of noting, reporting, and analysis of adverse
MMT or exercise alone. events and side effects per group either (at minimum)
A potential confounding factor is the overlap of descriptively or, better, statistically in future trials.
manual therapy in both the rehabilitation and MMT Practical and financial constraints limited this trial to the
groups, specifically soft tissue therapy and passive outcome measures described previously and excluded the
stretching, which are arguably also manual therapies. initially planned neuromuscular outcomes such as balance and
With these 2 treatments included in the rehabilitation coordination. Insights into these proprioceptive outcomes
group, it is difficult to explain which of the treatment would be valuable in future trials related to the potential
components in that group may have had an effect. In neuromuscular component of the disorder, because balance
future trials, there should be clearer treatment “bound- and coordination are directly related to falls—falls being a
aries” for each group. major concern causing further injury and disability. Also, this
Recent high-quality studies found significant and clinically trial did not include performance-based (such as the timed get
important benefits with exercise and manual therapy for knee up and go test, the 30-second sit to stand test, or the 40-m self-
OA, but treatment was provided over a longer period in these paced walk test) or other patient-reported outcomes previously
trials, as opposed to the 4 weeks in this trial. 22,56 The noted above, the former offering insight into outcomes related
implication is that conservative treatments, such as MMT and to patients that regularly participate in sport and, the latter,
exercise, need to be offered at regular intervals over an providing deeper insight into patient-perceived effect of
extended period to obtain the best possible outcomes. For treatment. 30,56 Both these types of outcomes warrant consid-
example, the first study provided treatment for 4 weeks eration in future trials.
(8 treatments) and the second for 2½ months (9 treatments), In retrospect, the overlap of manual therapy in both the
respectively, with long-term follow-up. rehabilitation and MMT groups (not boney manipulation and
However, based on the trends in outcomes in this trial, mobilization) but specifically, soft tissue therapy and passive
the authors speculate that the addition of MMT to a stretching, considered by some (also) manual therapies, may
rehabilitation or exercise program (with a recent have produced better outcomes in the rehabilitation group than
recommendation that initially, manual therapy and the components of exercise and self-stretching alone would
exercise be delivered—in a clinic—on opposite days) have accomplished. 30,56 As the authors of a recently completed
may indeed be more beneficial than either MMT or trial put it in describing the use of exercise alone or exercise
rehabilitation alone, but possibly only clinically demon- physiotherapy, they were adamant in stating that those who
strable over a longer treatment period rather than in the were to receive the “exercise therapy protocol” were strictly
(otherwise) not allowed therapist-applied manual forces. 56 In WOMAC is an obvious primary clinical outcome
future trials, clear treatment boundaries should be defined for measure for a confirmatory trial, but also an HRQoL
each group. measure (eg, RAND-36) and the KOOS (or AMS2).
Data on precisely how many clinicians provided f. In addition, balance and coordination measures should
treatment or the frequency of treatment were not available be considered with a view to measure neuromuscular
and were difficult to retrieve post hoc. Not all patients were and proprioceptive functional changes with treatment,
treated by the same clinicians. Treating clinician demo- alongside patient-reported outcomes.
graphics/data should be reported in future trials. g. Sufficiently large sample size to achieve more
A further limitation of this pilot trial was that participant than 80% power, which is estimated at ≥ 154/group
recruitment was arguably slow, with essentially only 1 for a multicenter or cluster-randomized trial for 3
clinician performing the assessment of patients and 1 to 2 treatment groups.
clinicians delivering the treatment. A larger confirmatory h. The short-, medium-, and long-term outcomes should be
trial would benefit from a greater number of clinicians analyzed with data collection points at baseline, 2 weeks,
performing assessment and treatment, although this would 1 month, 3 months, 6 months, and 1 year—(a) these
potentially increase the study's costs. timescales are often reported in the literature for trials,
As in this pilot trial, there are inherent difficulties and and (b) the timescales enable analysis of the data at short-,
confounding factors in testing of complex nonpharmacologic medium, and long-term end-points and, possibly, allow
interventions, for example, characteristics of treatment such as for subgroup analysis and treatment dose-response.
timing and frequency of treatment and patient compliance. i. Cost analysis and dose-response assessment would be
very useful adjuncts to data collection and analysis.
Recommendations for Future Studies
Development of treatment approaches for each inter-
CONCLUSIONS
vention based on the best-available research evidence,
including statements on the timing and frequency of This pilot trial suggests that a confirmatory trial is
treatment, is recommended. feasible. There were significant changes in scores from
Each group should have distinct treatment boundaries so baseline to week 5 across all groups, suggesting that all 3
that the treatments are not too similar. For example, the treatment approaches may be of benefit to patients with
rehabilitation group should only include exercise and active mild-to-moderate knee OA, justifying a confirmatory trial
(self) stretching, but no soft tissue or passive stretching. to compare these interventions.
Broader inclusion criteria include grades 1 to 4 of knee
OA, excluding grade 0, allowing for subgroup data
analysis. Recommendations include: FUNDING SOURCES AND POTENTIAL CONFLICTS OF INTEREST
We thank the NCMIC Foundation for the support in the
a. Have 2 or more assessors, arguably at least 3 per site, development of this manuscript. No conflicts of interest
to confirm the diagnosis for each eligible participant as were reported for this study.
this would improve on diagnosis/selection validity.
b. There should be a number of treating clinicians at each
site, at least 3 to 4 per site if a sample of more than 200
CONTRIBUTORSHIP INFORMATION
per site is expected, all of whom having had training in
the study's assessment and treatment protocols, with a Concept development (provided idea for the research):
view to standardize care. L.D., G.F.P-S., J.W.B., C.K., T.K.C.
c. Treating clinician demographics/data, in terms of the Design (planned the methods to generate the results): L.D.,
number of clinicians and the frequency of treatment, G.F.P-S., J.W.B., C.K., T.K.C.
should be reported in a confirmatory trial. Supervision (provided oversight, responsible for orga-
d. There should be a protocol to report adverse events. nization and implementation, writing of the manuscript):
Although not essential, inclusion of a control group L.D., J.W.B., C.K.
to explore treatment effectiveness, that is, a wait-and- Data collection/processing (responsible for experiments,
see or a minimum treatment group, is strongly patient management, organization, or reporting data): L.D.,
recommended. J.W.B., C.K., T.K.C.
e. Selection of the outcome measures that measure Analysis/interpretation (responsible for statistical analysis,
various domains, such as pain, disability, and so evaluation, and presentation of the results): L.D., G.F.P-S.,
forth. The best-available outcomes are those that are J.W.B., C.K., T.K.C., G.G., D.B., V.T.
valid, reliable, and believed to be the most appropriate Literature search (performed the literature search): L.D.,
by the researchers to achieve the research objectives. G.F.P-S., J.W.B., C.K., T.K.C.
Writing (responsible for writing a substantive part of the knee pain: a meta-analysis of randomised placebo-controlled
manuscript): L.D., G.F.P-S., J.W.B., C.K. trials. Eur J Pain 2007;11:125-38.
11. Bronfort G, Haas M, Evans R, Leiniger B, Triano J.
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RA. Strength training alone, exercise therapy alone, and
Rehabilitation consultation and overview and radiologic exercise therapy with passive manual mobilization each
interpretation: D.B., V.T. reduce pain and disability in people with knee osteoarthritis:
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45. Browne RH. On the use of a pilot sample for sample size 63. Grime J, Richardson JC, Ong BN. Perceptions of joint pain
determination. Stat Med 1995;14:1933-40. and feeling well in older people who reported being healthy: a
46. Donders A, van der Heijden G, Stijnen T, Moons K. Review: a qualitative study. Br J Gen Pract 2010;60:597-603.
gentle introduction to imputation of missing values. J Clin 64. Bellamy N, Kirwan J, Boers M, et al. Recommendations for
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Journal of Manipulative and Physiological Therapeutics Dwyer et al 21.e1
APPENDIX A. PATIENT INFORMATION & WRITTEN CONSENT follow up on your progress and/or for general communi-
cation. At 6 months you will receive a questionnaire with a
Manual and Manipulative Therapy in Addition
pre-paid and stamped return envelope with 2 questionnaires
to Rehabilitation for Osteoarthritis of the
to complete and return to us (please see below).
Knee: Assessor-blind Randomized Pilot Trial.
We invite you to take part in a study at (XXX) clinic.
Our purpose is to study the effect of manipulative therapy Treatments
and rehabilitation on knee osteoarthritis (knee OA). The
Group A will receive manual and manipulative therapy
principal investigator of the study is (blinded).
alone, in the form of chiropractic care. Chiropractic care
To join this study - you must not have not received
in this case consists of adjustive or manipulative therapy
chiropractic care or other manual treatment (massage or
of the knee, spine, hip, ankle and foot, and any other
physical therapy) for your Knee OA, in the last month. You
indicated joints and soft tissue treatment and exercise.
also cannot have started in the last month other types of care
You will also receive advice and regular communication
or treatment for your knee OA such as acupuncture,
on exercise and health habits from licensed, experienced
prescribed non-steroidal anti-inflammatory drugs, or med-
chiropractor(s). This will take up to 1 hour each visit.
ical care, etc. You must be able to stand and walk most of
Group B will receive a rehabilitation program. In this
the time without constant dependency on canes, walkers or
case treatment consists initially of exercise therapy
braces. Occasionally using a cane or other support is
performed under supervision in the clinic for the knee
acceptable. Serious knee deformity such as “severe knock-
OA. It also consists of training, education, advice and as
knees or bowed-legs” or instability (usually manifesting as
needed communication about how to carry out home
a knee that “gives way” or “buckles”) may exclude you
exercises for you knee OA and on health habits from
from this trial.
licensed, experienced chiropractor(s). This will take up
to 1 hour each visit.
Procedures Group C will be treated with manual & manipulative
If you are eligible and agree to join the study, you will therapy combined with rehabilitation.
first undergo an interview, a physical exam and knee
We will also ask you (whichever group you are assigned
radiographs, unless you already have recent radiographs.
too) to keep a diary and record medication use. There is a 6
Radiographs of the knee(s) are required for this study to rule
month by mail only follow up in which we ask you to fill
our severe knee OA and other pathology that could
out 2 forms and send them back to (blinded). These will
contraindicate treatment. We will also ask you to perform
have a self-addressed pre-postage paid stamped envelope.
activity tests (such as bending the knees or hips, standing
on1leg, etc.). This visit will take about 2-2½ hours.
You will then be randomly assigned to1of 3 different Benefits
treatment groups. The treatments being compared in this You may benefit by getting the results of your exams.
study have been shown to be effective for knee OA, which The treatment may also benefit your knee osteoarthritis. All
means that whichever group you are allocated to, the exams, treatment and informational materials are free of
treatment would be beneficial. This study is designed to find charge. Future patients with knee OA may also benefit as
out if1treatment is better than the other. Your participation the results of this study may inform clinical practice so that
may help us find out which has the most benefit. patients get the best available treatment for their problem.
The 3 treatments are not exactly the same and vary from
each other. If you are in Groups A or C you will need to
receive treatment around twice per week for a total of 6 visits. Risks/Discomforts
If you are in Group B, you will need to come in for a total of 3 All tests and treatments used in this study are commonly
visits over 3 weeks for education, as exercise mostly can be used by chiropractors. These treatments are believed to
done at home. Both groups are examined at the end of the 3 involve little risk. Serious side effects are rare. Some people
weeks of visits. You must be examined at or just after 3 weeks experience mild and temporary discomfort (soreness and or
from when you started and finished your care. stiffness) after a chiropractic adjustment. Some rehabilita-
tion procedures will require mild to moderate exertion.
Some people may experience fatigue, muscle soreness and
Follow Up or stiffness after the rehabilitation procedures.
After the last in clinic visit there is a 1 week follow up We will make every effort to prevent injury during this
and a 3 month follow up at the (blinded) clinic you will study. No compensation (such as medical expenses, lost
receive a follow-up exam and complete questionnaires. You wages, or payments for emotional distress) is offered by
will then be asked to continue your exercise protocol at (blinded), (as all treatments in this research have been
home. We will contact some of you by phone if necessary to independently or together long and commonly employed
21.e2 Dwyer et al Journal of Manipulative and Physiological Therapeutics
and are considered within the standard of care and safely without prejudice at any time For further information,
delivered by chiropractors) although compulsory insurance concerns, complaints or withdrawal from the study, please
covers matters of malpractice. (blinded) do not pay for contact (blinded).
medical treatment needed due to injury. It does not pay for
non-related medical problems or financial losses due to
injury. If an injury occurs, you do not give up any legal Confidentiality of Records
rights as a research participant by signing this consent form. All records with your name in them will be kept private.
If you think you have suffered a research-related injury, Your name will only be available to people conducting the
let the study physician or doctor know right away. study. In any report we publish or present, we will not include
Chiropractors will check you carefully at the beginning information that will make it possible to identify you.
of the study. We will not allow you to take part in the study Questions regarding this Study: Please ask the research
if we believe that you are at risk for serious injury from any assistant or doctor any questions you have now. If you have
of the study treatments. If you are in the study and the questions later, please contact (blinded). We will give you a
investigators feel that it is harmful for you to continue, they copy of this form to keep for your records.
will remove you from the study.
Alternatives to Participation Statement of Consent

Your regular medical doctor can give you a similar exam I, have read the above information and all
and prescribe treatment. Many local chiropractors or some Print Name Here
physical therapists can give you similar treatment. Many my questions have been addressed. I freely and
local exercise programs are also available. voluntarily consent to participate in this study.
Voluntary Participation: You are free to take part or not Signature:____________________________________
take part in this study. You may withdraw for any reason Date_________________

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ORIGINAL ARTICLES

MANUAL AND MANIPULATIVE THERAPY IN

O chronic arthritis, with radiologic evidence of joint

The participant was reassured that knee OA is not an Outcome Measures

Table 2. Comparison of Cumulative or Total WOMAC Data of the 3 Treatment Groups

Summary Statistics Mean SE 95% CI

Mean Difference SE Pa 95% CI a

Table 3. Comparison of Knee Flexion ROM Data of the 3 Treatment Groups

Summary Statistics Mean SE 95% CI

Mean Difference SE Pa 95% CI a

Table 4. Comparison of Knee Extension ROM Data of the 3 Treatment Groups

Summary Statistics Mean SE 95% CI

Mean Difference SE Pa 95% CI a

Potential Patients Responding to

Potential patients excluded after

Patients who underwent

Eligible patients that were randomly allocated to a treatment group

Group 1 MMT only Group 2 Exercise only Group 3 M MT + Exercise

Drop outs Drop outs Drop outs

Number of participants Number of participants Number of participants

Table 6. Comparison of Pain Data (WOMAC) of the 3 Treatment Groups

Summary Statistics Mean SE 95% CI

Mean Difference SE Pa 95% CI a

Table 7. Comparison of Stiffness Data (WOMAC) of the 3 Treatment Groups

Summary Statistics Mean SE 95% CI

Mean Difference SE Pa 95% CI a

Table 8. Comparison of Disability Data (WOMAC) of the 3 Treatment Groups

Summary Statistics Mean SE 95% CI

Mean Difference SE Pa 95% CI a

Table 9. Comparison of the Data at Week 5 for All Outcome Measures

Table 10. Change in Score From Baseline to Week 5 for WOMAC 9

Alternatives to Participation Statement of Consent

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