Journal of Plastic Surgery and Hand Surgery

ISSN: 2000-656X (Print) 2000-6764 (Online) Journal homepage: https://www.tandfonline.com/loi/iphs20

A post hoc analysis of Dupuytren contracture

treated with collagenase Clostridium histolyticum
across disease stages

Gary M. Pess, Maj Sundbom, Koo Wilson, Daniel Lindqvist & Lars B. Dahlin

To cite this article: Gary M. Pess, Maj Sundbom, Koo Wilson, Daniel Lindqvist & Lars B. Dahlin
(2018) A post�hoc analysis of Dupuytren contracture treated with collagenase Clostridium
histolyticum across disease stages, Journal of Plastic Surgery and Hand Surgery, 52:5, 301-306,
DOI: 10.1080/2000656X.2018.1484753

To link to this article: https://doi.org/10.1080/2000656X.2018.1484753

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JOURNAL OF PLASTIC SURGERY AND HAND SURGERY
2018, VOL. 52, NO. 5, 301–306
https://doi.org/10.1080/2000656X.2018.1484753

ARTICLE

A post hoc analysis of Dupuytren contracture treated with collagenase

Clostridium histolyticum across disease stages
Gary M. Pessa,b, Maj Sundbomc, Koo Wilsonc, Daniel Lindqvistc and Lars B. Dahlind,e
a
Central Jersey Hand Surgery, Eatontown, NJ, USA; bDrexel University School of Medicine, Philadelphia, PA, USA; cSwedish Orphan Biovitrum
(Sobi), Stockholm, Sweden; dDepartment of Translational Medicine, Division of Hand Surgery, Lund University, Jan Waldenstr€oms gata 5,
Malm€o, Sweden;; eDepartment of Hand Surgery, Skåne University Hospital, Malm€ o, Sweden

ABSTRACT ARTICLE HISTORY

This post hoc analysis from a multicenter study (NCT01674634) was designed to evaluate the efficacy of Received 7 February 2018
collagenase Clostridium histolyticum (CCH) treatment in patients with different stages of Dupuytren con- Revised 22 May 2018
tracture. Previously untreated patients who received two concurrent injections of CCH in two affected Accepted 31 May 2018
joints in the same finger were assessed by disease severity (Tubiana stage). The mean (SD) improvement
KEYWORDS
in total fixed flexion contraction (FFC) 31 days post-CCH treatment in 181 patients was: 71.1 (36.5)% for Collagenase Clostridium
Tubiana I, 77.0 (21.0)% for Tubiana II, 72.0 (20.4)% for Tubiana III and 66.4 (22.2)% for Tubiana IV. histolyticum; Dupuytren
Treatment of metacarpophalangeal and proximal interphalangeal joints in the same finger resulted in a contracture; fasciectomy;
mean (SD) improvement of 82.5 (24.8)% and 66.4 (27.9)%, respectively. In conclusion, CCH is an effective fixed flexion contracture;
treatment alternative for all stages of Dupuytren contracture and it provides a less invasive treatment percutaneous
alternative to surgery with similar short-term efficacy in patients with more severe disease. needle fasciotomy

Introduction Factors, such as patient’s preference, age, disease severity, finan-

Dupuytren disease (OMIM 126900) is a benign fibroproliferative
progressive disorder, affecting the palmar fascia of the hands and
fingers, and is characterized by flexion contracture within the
joints of the fingers. The prevalence varies between populations
and age groups and the disease is more common among men
and in people of Northern European descent [1–3]. The disease is
heterogeneous involving both genetic and environmental factors
[4,5]. The onset and progression varies and occasionally other
fibroproliferative conditions, such as Peyronie disease (OMIM
171000) and plantar fibromatosis (or Ledderhose disease), are
associated with Dupuytren contracture.
Although there is no curative treatment for Dupuytren dis-
ease, there are several treatment options of which limited fas-
ciectomy (LF) is the most frequently used and considered the
gold standard for treatment [5–7]. Disadvantages of this proced-
ure are the risk of surgical complications [8] and the long post-
operative recovery period [9]. Percutaneous needle fasciotomy
(PNF) is less invasive and uses a needle to puncture the cord
until it can be disrupted by mechanical force. This is completed
during one visit and has relatively low complication rates [10].
One drawback with this technique is a tendency for early recur-
rence [6,11,12]. The affected cords can also be disrupted enzy-
matically by collagenase Clostridium histolyticum (CCH), the first-
in-class biologic treatment of Dupuytren disease, which is
injected into the cord followed by a finger extension procedure
1 to 3 days postinjection to break the cord [13]. Both PNF and
CCH provide an outpatient treatment option with shorter recov-
ery compared to LF [14].
cial considerations and the physician’s personal preference and
experience with the available techniques, are determinants for the
treatment option chosen for an individual patient. The fact that
there are no randomized controlled studies comparing all three
available treatment modalities complicates decision making, and
results from separate studies are used as guidance to provide the
best treatment option. However, the comparison of such study
results is hampered by the different patient populations, the com-
plexity of the disease, possible co-morbidities, the number of joints
and fingers involved and the lack of uniform definitions of efficacy
and the way recurrence is determined [15]. For example PNF treat-
ment appears less effective than LF in more severe cases with dis-
ease classified as Tubiana III or IV [16], emphasizing the need to
take disease stage into account when comparing different study
results. Treatment outcome is also affected by the type of joints
studied, for example, metacarpophalangeal (MP) joints typically
have better treatment outcome than proximal interphalangeal (PIP)
joints [9], which may further complicate study comparisons.
This paper describes a post hoc analysis from a large open-label
phase 3 b study on CCH that evaluated the efficacy and safety of
two concurrent injections of CCH in two joints [13]. This analysis
evaluates CCH treatment efficacy by disease severity (Tubiana stage)
on short-term treatment outcomes. The CCH results are compared
descriptively with results from the only randomized clinical trial
with LF and PNF. Therefore, the patient population had to match
with regards of baseline characteristics, hence only previously
untreated patients with both MP and PIP joints affected in the
same finger were selected for this post hoc analysis [16].

CONTACT Maj Sundbom maj.sundbom@sobi.com Swedish Orphan Biovitrum (Sobi), SE-112 76 Stockholm, Sweden
Supplemental data for this article can be accessed here.
ß 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
302 G. M. PESS ET AL.

Methods Efficacy assessment

Study design The primary outcome measure of this post hoc analysis was the
change in total FFC 31 days after CCH treatment. The total FFC
This is a post hoc analysis of a previously published multicenter,
was calculated as the sum of the passive extension deficit (meas-
open-label, phase 3 b study that investigated the safety and effi-
ured in degrees) of affected MP and PIP joints located in the
cacy of two concurrent CCH injections (0.58 mg/injection) for two
same finger. Assessment of distal interphalangeal (DIP) joints was
joint contractures (MP and/or PIP) caused by palpable cords in the
not included since such data were not collected in the original
same hand (www.clinicaltrials.gov identifier: NCT01674634) [13].
study. The total FFC, including MP and PIP joints in the same fin-
The objective of this post hoc analysis was to assess the improve-
ger, was used as an approximation for total passive extension def-
ment of the total fixed flexion contractures (FFC), 31 days after
icit (TPED) in the whole finger. Total FFC is presented according
CCH treatment, by Tubiana stage.
to Tubiana stage [17], which represents a generally accepted clas-
The original study was conducted according to ICH GCP guide-
sification measuring total flexion deformity for a single affected
lines and the Declaration of Helsinki and it was approved by the
digit; Stage I; TPED of 1–45
, stage II; TPED 46–90
, stage III; TPED
relevant Ethics Committees [13].
of 91–135
, stage IV; TPED >135
[17,18].

Patient population Statistical analysis

The original study enrolled 715 patients who had at least two FFC
of 20 degrees or greater on the same hand in MP and/or PIP
joints (not thumbs) that were caused by palpable cords and who
had a positive tabletop test [13]. This post hoc analysis comprises
a subpopulation of previously untreated patients enrolled in the
original study who received two injections and had at least one
follow-up efficacy assessment. We present the analysis of two
populations, one population including previously untreated
patients with two injections in the same finger (181 patients:
181 MP joints and 181 PIP joints) that was used for the analysis of
FFC by Tubiana and as well for joint specific analyses, and one
population including all previously untreated patients (346
patients: 461 MP joints and 231 PIP joints) that was used for the
joint specific analysis only. Previously untreated patients were
included to better match patients in previous studies on LF and
PNF [16] to allow for indirect comparisons.
Raw data for the statistical analyses were available from the trial
‘Safety and Efficacy of Two Concurrent Injections of AA4500 in
Adult Subjects With Multiple Dupuytren’s Contractures’
(NCT01674634, [13]) by kind permission of Endo Pharmaceuticals.
The change in the total FFC after treatment was calculated and
presented for previously untreated patients. Results are presented
for patients with two treated joints in the same finger by Tubiana
stage (Tubiana I to IV) and by joint type (MP, PIP). An ANOVA was
performed to test for any significant differences in treatment out-
come in the different Tubiana stages.
Results
Demographics
Previously untreated patients who received two concurrent injec-
tions of CCH in cords affecting MP and PIP joints in the same finger

Table 1. Demographics and baseline characteristics of previously untreated patients with

Dupuytren disease.
Previously untreated patients [13]
All Two treated joints in one finger
Characteristic n ¼ 346a,b n ¼ 181
Age (years)
Mean (SD) 63.8 (9.8) 64.1 (9.9)
Median (range) 65.0 (20–86) 65.0 (27–86)
Gender, n (%)
Male 295 (85.3%) 154 (85.1%)
Female 51 (14.7%) 27 (14.9%)
Race, n (%)
White 340 (98.3%) 177 (97.8%)
Black or African American 5 (1.4%) 3 (1.7%)
American Indian or Alaska Native 1 (0.3%) 1 (0.6%)
Alcohol, n (%)
Never 41 (11.8%) 24 (13.3%)
Current 275 (79.5%) 143 (79.0%)
Former 30 (8.7%) 14 (7.7%)
Smoking, n (%)
Never 149 (43.1%) 70 (38.7%)
Current 57 (16.5%) 39 (21.5%)
Former 140 (40.5%) 72 (39.8%)
Diabetes, n (%)
No diabetes 305 (88.2%) 161 (89.0%)
Diabetes 41 (11.8%) 20 (11.0%)
CCH: collagenase Clostridium histolyticum; SD: standard deviation.
a
The original study [13] reports n ¼ 338 previously untreated patients but this analysis comprise 8
additional patients since they had valid fixed flexion contracture measurements and could therefore
be included.
b
n here refers to the number of untreated patients from the original study [13]. In this group, there
were 461 treated MP joints and 231 treated PIP joints.
 JOURNAL OF PLASTIC SURGERY AND HAND SURGERY 303

Table 2. Change in total FFC following two concurrent injections of collagenase Clostridium histolyticum (one injection per joint;
1MP:1PIP) in the same finger in previously untreated patients with Dupuytren disease divided by Tubiana stage.
Baseline total FFC (0) Day 31 total FFC (0) Change in total FFC (0) Change in total FFC (%)
Tubiana I (n ¼ 5)
Mean (SD) 44.0 (2.2) 13.0 (16.4) 31.0 (15.6) 71.1 (36.5)
Tubiana II (n ¼ 65)
Mean (SD) 76.0 (11.5) 17.9 (16.7) 58.1 (17.2) 77.0 (21.0)
Tubiana III (n ¼ 83)
Mean (SD) 111.6 (11.6) 31.4 (23.0) 80.2 (23.6) 72.0 (20.4)
Tubiana IV (n ¼ 28)
Mean (SD) 157.2 (13.8) 52.6 (34.7) 104.5 (36.7) 66.4 (22.2)
All (n ¼ 181)
Mean (SD) 104.0 (31.4) 29.3 (25.9) 74.6 (29.5) 72.9 (21.5)
Fingers with two treated joints in the same finger were used to calculate total FFC in order to provide the best approximation of the total
passive extension deficit used for Tubiana classification. An ANOVA analysis showed no statistically significant differences in the treatment
outcome between the different Tubiana groups (p ¼ .17).
FFC: fixed flexion contractures; SD: standard deviation.

Table 3. Change in total FFC following collagenase Clostridium histolyticum
treatment of MP and PIP joints in previously untreated patients with
Dupuytren disease.
Change in FFC (%)
Metacarpophalangeal (MP) Proximal interphalangeal (PIP)
Same finger
n 181 181
Mean (SD) 82.5 (24.8) 66.4 (27.9)
All
n 461 231
Mean (SD) 85.9 (23.7) 64.5 (30.4)
Distal interphalangeal joints were not assessed (Gaston et al. [13]).
n refers to the number of treated joints.
FFC: fixed flexion contractures; SD: standard deviation.
were subject of this post hoc analysis (n ¼ 181). The demographics
and baseline characteristics were similar to that of all previously
untreated patients and to the total population, which has been
published previously [13]. Most subjects were male (85%), white
(98%) and the mean (SD) age was 64.1 (9.9) years (Table 1).
Improvement in total FFC by Tubiana stage after
CCH treatment
To investigate if CCH treatment efficacy is similar independent of
disease advancement, previously untreated patients who received
two concurrent injections in two affected joints in the same finger
(one injection per joint, 1MP:1PIP) were assessed by Tubiana stage
(Table 2). The mean (SD) improvement in FFC, 31 days after treat-
ment, was in the same range for all Tubiana stages: 71.1 (36.5)%
for Tubiana I, 77.0 (21.0)% for Tubiana II, 72.0 (20.4)% for Tubiana
III and 66.4 (22.2)% for Tubiana IV, indicating similar treatment
outcome independent on disease severity. An ANOVA analysis
showed no statistically significant differences in the treatment out-
come between the different Tubiana groups (p ¼ .17). The overall
mean (SD) improvement in FFC independent of Tubiana stage
was 72.9 (21.5)% (Table 2), which is in the same range as the
improvement among previously treated patients, 70.6 (23.1)%
(n ¼ 169) (Supplementary Table 1). It is also in the same range as
the total population in the original publication who had two
treated joints in the same finger, 72 (22)% (n ¼ 350), and included
both previously treated and untreated patients [13].
Treatment efficacy in different joints
MP joints generally have greater treatment success than PIP joints,
therefore individual joint analyses were performed [9]. The mean
(SD) improvement in total FFC, 31 days after CCH treatment of MP
and PIP joints in the same finger, was 82.5 (24.8)% for MP joints
(n ¼ 181) and 66.4 (27.9)% for PIP joints (n ¼ 181). A similar level
of improvement was observed when including all MP and PIP
joints in the analysis, independent on if MP and PIP were located
in the same finger or not (N ¼ 346, MP [n ¼ 461], PIP [n ¼ 231])
(Table 3).
Discussion
In this post hoc analysis, we present data indicating that CCH is
effective in all severities of Dupuytren disease. Due to the absence
of any clinical trial comparing the different treatment options for
this disease, we have selected subgroups to closely match that of
a previously published randomized prospective study on LF and
PNF, using similar definitions, in order to evaluate the short-term
treatment outcome of available treatments.
In the PNF and LF study that included previously untreated
patients with Dupuytren disease, the majority of the fingers (PNF:
75% and LF: 80%) were in Tubiana I or II, while the previously
untreated population in the CCH study included patients with
more severe disease stages (only 39% in Tubiana I or II). To take
this difference in disease stage into consideration, we analyzed
the total FFC by Tubiana stage. The average improvement in total
FFC after CCH treatment in the population of fingers with two
treated joints ranged from 66% to 77% between Tubiana stages.
This is similar, or slightly lower, than the average improvement
previously reported after LF treatment that ranged from 75% to
82% (Figure 1(A)). This new information reveals that some patients
traditionally considered suitable for surgery might also be well
suited for CCH treatment.
Our post hoc analysis strived to be as similar as possible to the
randomized controlled trial of LF and PNF is one way of reanalyz-
ing data to optimize the use of available patient level data.
However, there are other means of indirectly comparing treatment
options where patient level data cannot be accessed. The conclu-
sion of this post hoc analysis is confirmed by the results from a
meta-analysis of 10 studies comparing the same three treatment
options concluding an equivalent clinical efficacy in the short and
medium term for CCH and fasciectomy [19].
PNF is generally more favorable for fingers in Tubiana I and
Tubiana II (Figure 1(A)) [16]. The comparable outcome of CCH and
PNF treatment in lower Tubiana stages is in line with other studies
focusing on less severe cases of Dupuytren disease [14,20,21]. A
limitation of the post hoc analysis presented here is the lack of data
for DIP joints; instead the total FFC for MP and PIP was used as an
approximation of TPED. A consequence of this approach of
304 G. M. PESS ET AL.

Figure 1. Comparison of CCH, LF and PNF treatment efficacy. (A) Mean change in total FFC (%) 31 days after CCH treatment (previously untreated patients, 1MP:1PIP
in the same finger) or 6 weeks after LF and PNF treatment (previously untreated patients, overall joint distribution of 3MP:2PIP), by Tubiana grade. LF and PNF meas-
ures include DIP joint assessment and therefore represent TPED values. (B) Mean change in FFC (%) in MP and PIP joints 31 days after CCH treatment or 6 weeks after
LF and PNF treatment. CCH: collagenase Clostridium histolyticum; FFC: fixed flexion contracture; LF: limited fasciectomy; MP: metacarpophalangeal; PIP: proximal inter-
phalangeal; PNF: percutaneous needle fasciotomy; TPED: total passive extension deficit.

approximating TPED, where the population was selected for having
both MP and PIP joints treated in the same finger, is the relatively
high disease severity in such group. The milder forms of the
Dupuytren disease typically involve only one joint, explaining the
low number of patients in Tubiana 1 (n ¼ 5) in this post hoc ana-
lysis, which possibly makes the data in this group less representa-
tive of the actual patient population. However, the successful
treatment of CCH in a population with mild disease severity and
with a representative joint distribution has been confirmed in ear-
lier studies [22,23].
Joint distribution can be a factor to consider when interpreting
results from different studies. Tubiana I usually involves only one
joint, and since MP joints typically have better treatment out-
comes than PIP joints, it is important to consider the study popu-
lation in detail when comparing data from different studies. The
more severe stages of Dupuytren disease typically span several
adjacent joints with varying degree of flexion extension deficit. To
take this in consideration a joint-specific comparison of the avail-
able treatment options was performed. The improvement of MP
joints was similar between the different treatment options, rang-
ing from 75% to 87%, while the improvement of PIP joints was
lower and varied more, ranging from 33% to 66% (Figure 1(B)).
This post hoc analysis is limited to an indirect comparison of
short-term outcome. The long-term outcome is also of interest.
However, this is even more complicated to compare. The study on
LF and PNF included evaluation of long-term efficacy showing 21%
overall recurrence rate for LF and 85% for PNF within five years. The
retreatment rates were 10% for LF, 63% for PNF and 33% of the
PNF patients needed a third medical intervention during the five
years [12,24]. The recurrence rate for CCH is studied in 644 patients
and the rate of recurrence was 47% within five years in previously
successfully treated joints and the retreatment rate was 16% for suc-
cessfully treated joints and 18% for all treated joints (196 of 1081).
There are currently two randomized clinical trials published with one
year follow-up data and one with two year follow-up data for PNF
versus CCH, showing similar outcome between the groups.
However, due to relatively small populations, low disease severity
and mainly MP joints [14,20,25], data may not be representative for
the normal distribution of patients with Dupuytren disease. The defi-
nitions of recurrence may also not be equal between studies. Some
study-specific joints, others study whole fingers and some studies
do not take retreatments in consideration [16].
Local treatment strategies, previous training, treatment safety
profile, funding situation and the experience of the treating

physician are factors influencing the choice of treatment in
Dupuytren disease. Patient-related considerations include age, dis-
ease severity, the presence of diathesis [26], concomitant diseases
and the risk of recurrence and wound infection [5,27,28], time of
recovery and ultimately the patient’s preference. Elderly patients,
who have slow progression of contracture and concomitant dis-
eases, might benefit from one of the less invasive treatment
options. In addition, the underlying status of the affected joints,
skin condition, cord location, cord size, cord thickness, potential
nerve involvement and scarring from previous treatments all influ-
ence the decision.
All of these factors, and the potential risks and complications of
each procedure, are important to consider when choosing the opti-
mal treatment for an individual patient. However, the lack of
randomized controlled clinical trials evaluating the relative effective-
ness of the different treatments in different disease stages makes it
difficult to evaluate therapy alternatives. While the results of our
analysis are restricted to the limits of the methodology, this is a
post hoc analysis of a large, prospective open-label trial, controlled
to support the label expansion of two instead of only one injection
of CCH in the same hand [13]. Raw data were stratified into rele-
vant populations allowing for comparison to the study on LF and
PNF [16]. Our data suggest that CCH is a valid treatment option for
all Tubiana stages, including patients with more advanced disease.
Ethical approval
Informed consent was provided by the patients in the original
study. Since this is a post hoc analysis, any further details on this
is not provided here.
Acknowledgements
We thank Tine Weis (Gentofte Hospital, Hellerup, Denmark),
Frederik Verstreken (Ortopedisch Centrum Antwerpen, Belgium)
and Zsolt Szabo (BAZ University County Teaching Hospital,
Miskolc, Hungary) for valuable discussions and participation in an
advisory board meeting regarding treatment of Dupuytren dis-
ease. We also thank Hans Olivecrona (Sobi, Sweden) for continu-
ous intellectual contribution and support during this project and
Kristina Lindsten (Sobi, Sweden) for medical writing support in
accordance with good publication practice (GPP3) guidelines
(http://www.ismpp.org/gpp3).
Disclosures statement
GM Pess: Advisory Board for Sobi, Speaker Bureau for Endo
Pharmaceuticals and royalties from Biomet, Inc.
L Dahlin: investigator in the trial of the post hoc analysis pre-
sented in this manuscript and in a trial sponsored by Polyganics,
Netherlands.
M Sundbom, K Wilson and D Lindqvist: employees of Sobi and
holders of equity interest in Sobi.
Funding
This post hoc analysis was fully funded by Sobi that is responsible
for the commercialization of collagenase clostridium histolyticum
(XiapexV) in Europe.
R
JOURNAL OF PLASTIC SURGERY AND HAND SURGERY 305
ORCID
Lars B. Dahlin http://orcid.org/0000-0003-1334-3099
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