Clinical trial NCT02725528
Conditions: Dupuytren's Disease
Sponsor: McMaster University
Start date: 2017-07-08; Completion date: 2021-12-17
Enrollment: 22 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a prospective, multi-centre, pragmatic randomized controlled trial to compare both the clinical effectiveness and cost-effectiveness of collagenase injections (CI) versus limited palmar fasciectomy (LPF) to determine if collagenase is a superior treatment in terms of improved quality of life and reducing recurrence of the disease without serious complications. Since collagenase injections are costly it is also important to know if this novel intervention is cost-effective from the patient, Ministry of Health and societal perspectives.

Detailed description:
Limited palmar fasciectomy (LPF) and collagenase injection (CI) are the most common procedures to manage symptoms of Dupuytren's Disease. This randomized controlled trial (RCT) aimed to directly compare patient outcomes 12 months following CI and LPF. Twenty-two patients with Dupuytren's Disease were randomized to either LPF or CI. The primary outcome was health state measured by the Michigan Hand Questionnaire. Secondary outcomes were health status (The Health Utility Index-3), function (The Unité Rhumatologique des Affections de la Main and The Southampton Dupuytren's Scoring Scheme), and range of motion (ROM) of treated digits. Measurements were collected at baseline and 1-, 3-, 6-, and 12-months post-procedure.

Arms: arm 1: This procedure will be performed either in a minor procedure room or the hand clinic as per surgeon's routine practice. Collagenase will be administered with or without local anesthesia. As this is a pragmatic study there may be more than one digit injected at a time just as surgery occurs on more than one digit at a time. A recently published study by Gaston et al confirmed that two concurrent injections of collagenase to 2 affected joints in the same hand are generally well tolerated and the frequency of most adverse events (AEs) is similar to those reported in studies that use single sequential injections. arm 2: The Dupuytren's cord will be excised under local anesthesia in a minor procedure room setting or main operating room under local or general anesthetic depending on the complexity of the disease and the surgeon's routine. As this is a pragmatic study comparison of collagenase injections (novel intervention) to limited palmar fasciectomy as it is actually presently performed in all settings academic or community (local in minor room or general/local anesthetic in the main operating room) will be examined. Surgery will be performed according to the operating surgeon's preferred technique i.e. zig-zag Brunner incision or straight incision with z-plasty closure of the skin.
Interventions: intervention 1: collagenase injection intervention 2: limited palmar fasciectomy
Intervention descriptions: intervention 1: injection intervention 2: surgery

Protocol documents:
Prot_SAP_000.pdf: 
A MULTI-CENTER, RANDOMIZED CONTROLLED TRIAL 
COMPARING THE CLINICAL EFFECTIVENESS AND COST-
EFFECTIVENESS OF COLLAGENASE INJECTION (XIAFLEX) AND 
PALMAR FASCIECTOMY IN THE MANAGEMENT OF 
DUPUYTREN’S DISEASE 
EVALUATION OF XIAFLEX: TRIAL OF EFFECTIVENESS iN DUPUYTREN’S 
(EXTEND) 
 
Principal Investigator: 
Dr. Achilles Thoma 
Co- Investigators:  
 
Dr. Feng Xie 
Dr. Gary Foster 
Dr. Lehana Thabane 
Dr. Bimpe Ayeni 
Dr. Rodger Shortt 
 
Protocol/version #: 
Current Version Date: 
2.0 
2022-03-29 


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TABLE OF CONTENTS 
PAGE 
TABLE OF CONTENTS ...................................................................................................................2 
1 
INTRODUCTION: BACKGROUND AND SCIENTIFIC RATIONALE ....................................4 
1.1 
Background Information ..............................................................................................4 
1.2 
Rationale .....................................................................................................................5 
2 
STUDY OBJECTIVES ............................................................................................................6 
2.1 
Primary Objective ........................................................................................................6 
2.2 
Secondary Objectives .................................................................................................6 
3 
STUDY DESIGN .....................................................................................................................6 
3.1 
General Design ...........................................................................................................6 
3.2 
Primary Outcome Measure .........................................................................................6 
3.3 
Secondary Outcome Measures ..................................................................................6 
4 
STUDY ENROLLMENT AND WITHDRAWAL .......................................................................7 
4.1 
Inclusion Criteria .........................................................................................................7 
4.2 
Exclusion Criteria ........................................................................................................7 
4.3 
Patient Screening Log ................................................................................................8 
4.4 
Strategies for Recruitment and Retention ..................................................................8 
4.5 
Treatment Assignment Procedures ............................................................................9 
4.5.1 
Randomization Procedures ............................................................................9 
4.5.2 
Masking Procedures .......................................................................................9 
4.6 
Subject Withdrawal .................................................................................................. 10 
5 
STUDY INTERVENTIONS .................................................................................................. 10 
5.1 
Collagenase Injection (CI) Group ............................................................................ 10 
5.2 
Limited Palmar Fasciectomy (LPF) Group .............................................................. 11 
5.3 
Concomitant Medications/Treatments ..................................................................... 11 
5.4 
Procedures for Training of Clinicians on the Interventions ..................................... 12 
6 
STUDY PROCEDURES /EVALUATIONS........................................................................... 13 
6.1 
Schedule of Study Procedures ................................................................................ 13 
6.2 
Baseline Assessment .............................................................................................. 14 
6.3 
Follow-up Assessment ............................................................................................. 14 
6.4 
Health-related Quality of Life (HRQL) ..................................................................... 14 
6.4.1 
Michigan Hand Questionnaire (MHQ) ......................................................... 14 
6.4.2 
Health Utilities Index Mark 3 (HUI3) ............................................................ 15 
6.4.3 
Unité Rhumatologique des Affections de la Main (URAM) ......................... 15 
6.4.4 
Southampton Dupuytren’s Scoring Scheme (SDSS) .................................. 15 
6.5 
Healthcare Resource Utilization .............................................................................. 15 
7 
ASSESSMENT OF SAFETY ............................................................................................... 17 
7.1 
Adverse Events ........................................................................................................ 17 
7.2 
Reporting of Adverse Events ................................................................................... 18 
7.3 
Serious Adverse Events .......................................................................................... 18 
7.4 
Reporting of Serious Adverse Events ..................................................................... 18 


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STATISTICAL CONSIDERATIONS .................................................................................... 18 
8.1 
General .................................................................................................................... 18 
8.2 
Sample Size Determination ..................................................................................... 19 
8.3 
Clinical Effectiveness Analysis ................................................................................ 19 
8.4 
Cost-Utility Analysis (CUA) ...................................................................................... 20 
9 
ETHICS/PROTECTION OF HUMAN SUBJECTS .............................................................. 20 
9.1 
Ethical Standard ....................................................................................................... 20 
9.2 
Research Ethics Board (REB) ................................................................................. 20 
9.3 
Informed Consent Process ...................................................................................... 21 
10 
DATA HANDLING AND RECORD KEEPING ..................................................................... 21 
10.1 
Case Report Forms (CRFs) ..................................................................................... 21 
10.2 
Data Management Responsibilities ......................................................................... 22 
10.3 
Archiving of Study Documents ................................................................................ 22 
11 
PUBLICATION PLAN .......................................................................................................... 22 
12 
KEY ROLES AND CONTACT INFORMATION................................................................... 23 
13 
LITERATURE REFERENCES ............................................................................................. 24 
14 
APPENDIX.  SCHEDULE OF ENROLMENT, INTERVENTIONS, AND ASSESSMENTS. 27 
 
 
 


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1 INTRODUCTION: BACKGROUND AND SCIENTIFIC RATIONALE  
1.1 
Background Information 
Dupuytren’s Disease (DD) is a benign fibroproliferative condition, which although 
generally painless, it gradually causes flexion contractures to the digits and causes 
functional problems to those who have it.  Although multiple etiologies have been 
implicated in this condition, it is thought to be mostly transmitted through autosomal 
dominant gene with variable penetrance affecting primarily patients with Northern 
European ancestry[1]. A recent systematic review and meta-analysis has shown that 
prevalence of DD in Western countries varies from 0.6% to 31.6% and increases 
steadily with increasing age [2]. Another recent review of prevalence and incidence in 
the United States found that prevalence ranged from 0.5% to 11% consistent with the 4-
6% prevalence rates found in previous studies of general populations and concluded 
that there are a number of unmet medical needs particularly for better understanding, 
recognition and treatment of DD [3]. Many surgical approaches have been introduced 
over the years to deal with DD including percutaneous needle aponeurotomy, open 
fasciotomy, and commonly limited open palmar fasciectomy[4,5]. Non-surgical 
management options such as injections with steroids or verapamil have been previously 
proven ineffective and rejected clinically[6]. Limited palmar fasciectomy (LPF) has been 
the most common and widely accepted treatment for this condition.  In the last 6 years 
however, collagenase injection (CI) has been making inroads as a legitimate treatment 
for DD.  A multicentre double-blind RCT in 2009 (CORD I study) comparing collagenase 
to placebo has demonstrated its clinical safety and efficacy[7]. A second multicentre 
double-blind study also comparing collagenase to placebo (CORD II study) in 2010 
confirmed that collagenase is effective and well tolerated in DD[8].  A number of 
adverse effects have been associated with collagenase injections but these are mostly 
well tolerated by patients. The most severe complication is tendon rupture which is rare, 
with an overall incidence at around 0.5% in previous randomized, double-blind, placebo-
controlled studies[7–9].  Technical tips have been provided by a number of authors to 
avoid this complication[6–8].  A more recent study (CORDLESS study) in 2013 
evaluated the long term efficacy and safety of collagenase treated patients in 5 previous 
clinical studies (which included both CORD RCTs in addition to 3 open-label trials) over 
a 3 year period and found that the recurrence rate was comparable to the surgical 
approaches to DD. Furthermore, they found no long term adverse effects[10]. This 
study has subsequently published 5 year follow-up results for the same cohort and has 
concluded that collagenase is an effective and safe treatment for DD with comparable 
recurrence rates after surgical treatments[11]. 
 
The two previous RCTs (CORD I and CORD II) have greatly influenced the adoption of 
collagenase, which now stands as a legitimate contender to palmar fasciectomy for DD.  


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The main methodological weakness of the CORD I and CORD II trials is that the 
comparative intervention was placebo. Many trial methodologists would be concerned 
with using a placebo when existing surgical techniques exist such as the commonly 
performed palmar fasciectomy. We believe that presently, we are uncertain if 
collagenase, a non-surgical treatment is superior to palmar fasciectomy, a surgical 
treatment.  An RCT is warranted for a head-to-head comparison.  Zhou et al. directly 
compared CI to LPF in a propensity score matched study and found that CI was not 
significantly different from LPF in reducing metacarpophalangeal joint contractures.  CI 
was also inferior to LPF in correcting proximal interphalangeal joint contractures. On the 
positive side, CI provided a more rapid recovery of hand function than LPF and was 
associated with fewer serious adverse events [12]. However, their study evaluated only 
short-term clinical results at 12 weeks after surgery and included a minimal number of 
recurrent cases in their sample. They also acknowledge the limitation of propensity 
matching in terms of confounding and that a well-designed randomized trial would help 
eliminate some confounding factors. Their overall conclusion stated that long-term 
effectiveness trials are still needed in head-to-head comparison studies. Based on the 
available evidence we believe that there presently exists a state of equipoise, which is a 
precondition for an RCT comparing the effectiveness of these two approaches. 
 
A previous cost-effectiveness study  by Baltzer and Binhammer found that the 
collagenase injection was cost-effective from the societal perspective[5]. Our appraisal 
of the study however, identified some methodological weaknesses. That study used a 
decision analysis model which was not an ideal study design as it relies on secondary 
data. A trial-based cost-effectiveness analysis would be greatly strengthened by its 
access to individual patient level data collected directly from the trial cohort. In addition, 
Brazzelli et al has published a systematic review and economic evaluation in October 
2015 [13] concluding that there is no evidence that CI is clinically better or worse than 
surgical treatments and that LPF appears to be the most cost-effective choice for 
moderate to severe contractures. However, the results of their cost-utility analysis were 
based on an indirect comparison of clinical effectiveness.  The Markov model they used 
for the CUA was fraught with considerable uncertainty about the appropriateness of 
many assumptions and parameters used in the model.  They conclude that a RCT is 
required to confirm or refute these findings. 
1.2 
Rationale 
No study to-date has compared both the clinical effectiveness and cost-effectiveness of 
collagenase injection versus limited palmar fasciectomy with patient derived data in a 
prospective RCT study. Therefore, we do not know for certain if collagenase is, indeed, 
a superior treatment for DD as previous studies imply.  Furthermore, the collagenase 


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injections are costly and therefore, we need to know if this novel medical intervention is 
cost-effective from the patient, Ministry of Health (MOH), and societal perspectives.  
2 STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to compare the clinical effectiveness of 
collagenase injections (CI) versus limited palmar fasciectomy (LPF) as measured by the 
12 month post-randomization Michigan Hand Questionnaire (MHQ) after adjusting for 
the pre-randomization MHQ score. 
2.2 
Secondary Objectives 
Secondary objectives include the cost-effectiveness of CI versus LPF from the 
consumer (patient), payer (Ministry of Health) and societal perspectives and additional 
measures of clinical effectiveness.  
 
3 STUDY DESIGN 
3.1 
General Design 
This trial is a prospective, randomized, multicentre, parallel, pragmatic clinical trial to 
investigate the clinical effectiveness and cost-effectiveness of collagenase injection (CI) 
versus limited palmar fasciectomy (LPF) in the treatment of Dupuytren’s disease.  
3.2 
Primary Outcome Measure 
The primary outcome is  Health-Related Quality of Life (HRQL) measured with the 
Michigan Hand Outcomes Questionnaire (MHQ), a hand-specific outcomes instrument 
[14], at one year post-treatment. 
3.3 
Secondary Outcome Measures 
Secondary outcomes include: 
(a) HRQL measured with the Health Utility Index Mark 3 (HUI3), a generic multi-attribute 
health-status classification instrument [15].  
(b) HRQL measured with the Unité Rhumatologique des Affections de la Main (URAM),  
a disease-specific HRQL measure developed for Dupuytren’s contracture [16]. 
(c) HRQL measured with the Southampton Dupuytren’s Scoring Scheme (SDSS), a 
disease-specific scoring system developed for Dupuytren’s contracture [17]. 
(d) Quality Adjusted Life Years (QALY) measured with the HUI3. QALY is an important 
component of Cost-Utility Analysis (CUA), a variant of Cost-Effectiveness Analysis 


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(CEA); therefore, we will be able to calculate incremental cost per QALY gained 
between the two treatments. Utility scores of HRQL derived from responses to the 
HUI3 questionnaire have the required measurement properties for calculating 
QALYs[18].   
(e) Self-reported healthcare utilization (e.g. visits to hand surgeons, family physician, 
parking costs, etc.) and productivity loss (e.g. time lost from work and leisure 
activities by patient and caregiver). 
(f) Range of motion (ROM) of hand joints measured with goniometry 
(g) Recurrence rates defined as an increase in joint contracture in any treated joint of at 
least 20 degrees at one year post-treatment. 
(h) Necessary Dupuytren’s Disease treatments applied to the previously affected digit(s) 
(the digit(s) treated in the EXTEND trial) up to 4 years following their original 
(EXTEND trial) treatment.  
4 STUDY ENROLLMENT AND WITHDRAWAL 
Following receipt of verbal and written information about the study, the patient must 
provide signed and dated informed consent before any study related activity is 
carried out. Patients will be recruited from the practices of plastic hand surgeons in 
Ontario. Patients will be eligible for entry into this study if they meet all of the inclusion 
criteria and have no exclusion criteria present. 
4.1 
Inclusion Criteria 
1. 18 years of age or older 
2. Dupuytren’s contracture of the metacarpophalangeal (MCP) joint or of the 
proximal interphalangeal (PIP) joint with a fixed flexion contracture of 20º 
or greater in at least 1 finger (not the thumb) 
3. Demonstrated inability to simultaneously place the affected finger and 
palm flat on a table  
4. Able to understand and communicate in English 
4.2 
Exclusion Criteria 
1. Previous treatment of the primary joint within 90 days of study inclusion 
2. Patients undergoing any concomitant procedure on the same hand (e.g. 
carpal tunnel release, stenosing tenosynovitis release) 
3. Persistent extension deficit from a previous surgery of the same digit 
4. Any chronic muscular or neuromuscular disorder affecting wrist or hand 
5. Patient generally unfit for surgery 
6. Patient with specific treatment preference 
7. Bleeding disorder or recent stroke 
8. Allergy to collagenase 
9. Collagenase treatment or treatment with any investigational drug within 
30 days of study inclusion 


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10. Use of a tetracycline derivative within 14 days of first dose of study drug 
(because tetracycline derivatives may inhibit the collagenolytic activity of 
mammalian collagenase homologs [i.e., matrix metalloproteinases]) 
11. Pregnant or breast feeding patients 
12. Patients who do not have insurance coverage for collagenase injections 
13. Patients who are unable to provide informed consent or are unable to 
complete quality of life questionnaires due to mental capacity or neuro-
psychological problems. 
 
4.3 
Patient Screening Log 
A Patient Screening Log will be used in this study to document all patients who have 
provided written informed consent and have been screened, including those who cannot 
be randomized.  
 
4.4 
Strategies for Recruitment and Retention 
For the successful conduct and timely completion of the study, it is important that the 
collaborating surgeons see a high volume of patients with DD. We chose the 
participating surgeons as we know these practicing surgeons and their willingness to 
participate in the study. These practices in various cities represent the diversity of the 
general population in Ontario. 
 
The surgeons involved in our study each perform LPF on an average of 60 patients per 
year. It is assumed that 50% of potential patients will either be ineligible or not enrolled 
due to refusal of consent. It is therefore anticipated that 50% of eligible patients will be 
recruited.  
 
Assuming that at least 10 surgeons screen a total of 600 patients and 50% of patients 
screened will be enrolled it is likely that approximately 300 patients can be recruited 
over a 12 month period. Using the estimated sample size of 128, it is estimated that all 
the patients could be recruited over approximately a 6-month year period. If the actual 
rate of enrollment is better than predicted, the duration of patient recruitment will be 
shortened accordingly. If the actual rate of enrollment is worse than predicted, additional 
surgeons will be invited to participate in this trial.  
 
Every reasonable effort will be made to follow all participants for the entire duration of 
the trial. We will collect contact information for a family member, name & address of 
workplace/business, email address, and any social media account details to make it 
easier to locate the participant. Patients will be contacted via telephone the week before 
each follow-up appointment as a reminder. We will try to coordinate the study-related 


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follow up visit with the regular clinical visit to avoid extra trips to the clinic. If this is not 
possible, we will provide the participants with a gift card and/or parking vouchers. 
Compromises will be made for participants who are unable or unwilling to come for a 
follow-up such as completing questionnaires via mail or email.  
 
For the research staff, quarterly meetings or teleconferences will be organized to 
discuss the recruitment & retention issues and their troubleshooting options. A standard 
operations manual will be developed at the beginning of the trial, and this will be 
updated and circulated at regular intervals as necessary. We will try to hire study 
coordinators who can commit to the duration of the study. In any case, the coordinators 
will be required to maintain a log of all the participants and note any scheduling issues.  
4.5 
Treatment Assignment Procedures 
4.5.1 
Randomization Procedures 
Eligible, consenting patients will be randomly allocated (1:1) to receive either CI or LPF 
using block randomization to ensure equal group sizes. Allocation will be determined in 
advance using a computer-based random number generator and stratified by primary 
joint type (MCP or PIP).  We will use central randomization via a web-based system 
generated by the Biostatistics Unit at St Joseph’s Healthcare—Hamilton. The 
randomization will be blocked within strata using randomly permuted blocks of various 
sizes. Approximately 2-3 months prior to their procedure, eligible, consenting patients 
will be randomized to one of the 2 treatments.  
4.5.2 
Masking Procedures 
Blinding of patient and surgeon will not be possible. No or very minor scar is expected 
from collagenase injections. For palmar fasciectomy however, a noticeable scar is 
expected. As such, the patients will know which procedure they received. Outcome 
assessors will be hand occupational therapists or physiotherapists who will perform the 
goniometric measurements. Although they cannot be blinded for the same reason, they 
nevertheless work independent of the surgeon and therefore the risk of bias in the 
measurements will be mitigated. The statistician for the study however, can be blinded 
as he will be unaware of group allocation (Study A vs Study B). 
 
As the palmar fasciectomy can be performed some weeks later there is a risk of cross-
over but this can be avoided by obtaining the consent for palmar fasciectomy in the 
same clinic visit as the randomization. 


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4.6 
Subject Withdrawal 
Participants will be able to withdraw from the study at any point and for any reason, and 
without stating a reason. A ‘consent to withdraw’ with the permission to use/not use 
patient information will be signed by the patient. The reason for withdrawal will be 
documented and may include any of the following reasons: voluntary withdrawal, non-
compliant patient, unable to contact patient⁯ (lost-to-follow-up), medical contraindication, 
adverse event(s), patient deceased, etc.  In case of written withdrawal of consent for 
follow-up visits, and unless otherwise stated by the patient in the informed consent form, 
investigators will be encouraged to get information from the general practitioner, any 
other physician, or other medical-care provider, in order to follow the medical status of 
the patients (especially if they withdraw their consent after having experienced an 
AE/SAE). Investigators will also be expected to try as much as possible to re-contact 
those patients at the end of the trial, in order to obtain at least their vital status (dead or 
alive), as well as their health status (recurrence), and thus avoid lost to follow-up. For 
patients considered lost to follow-up, the CRF must be completed up to the last visit 
performed.  
 
5 STUDY INTERVENTIONS 
5.1 
Collagenase Injection (CI) Group 
This procedure will be performed either in a minor procedure room or the hand clinic as 
per surgeon’s routine practice.  Collagenase will be administered with or without local 
anesthesia. As this is a pragmatic study we may inject more than one digit at a time just 
as we operate on more than one digit at a time. A recently published study by Gaston et 
al confirmed that two concurrent injections of CI to 2 affected joints in the same hand 
are generally well tolerated and the frequency of most AEs is similar to those reported in 
studies that use single sequential injections [19].  
 
The patient’s affected hand will be prepped with antiseptic solution. Using a hubless 
syringe with 0.01 mL graduations and a permanently fixed 26- or 27-gauge ½ inch 
needle the required amount of reconstituted collagenase clostridium histolyticum will be 
withdrawn as follows: a) Cord affecting an MP joint, withdraw 0.25 mL of the 
reconstituted solution; b) Cord affecting a PIP joint: withdraw 0.20 mL of the 
reconstituted solution per published guidelines.  
 
While applying tension to the cord in the hand to be treated, the needle will be placed 
into the cord while carefully ensuring that the tip stays within the cord and does not pass 
through the cord. After confirming the needle is placed correctly in the cord, 


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approximately one-third of the dose is injected. The needle tip is then withdrawn from 
the cord and repositioned in a slightly more distal location to the initial injection in the 
cord (approximately 2 to 3 mm) and another one-third of the dose is injected.  Again, the 
needle tip is withdrawn from the cord and repositioned proximal to the initial injection 
(approximately 2 to 3 mm) and the final portion of the dose injected into the cord. When 
injecting a cord affecting the PIP joint of the fifth finger, the needle insertion should not 
be more than 2 to 3 mm in depth and injecting more than 4 mm distal to the palmar 
digital crease should be avoided. 
 
After the injections are completed, the patient’s treated hand will be wrapped with a soft, 
bulky gauze dressing and kept elevated for the remainder of the day. The patient will 
return to the surgeon’s office/clinic 1-7 days post-injection to assess if the contracture 
has resolved. If a contracture remains, a passive finger extension procedure, with or 
without local anesthesia as determined by the surgeon, will be undertaken in an attempt 
to disrupt the cord. If residual contracture remains the patient will return for a 30-day 
follow-up when the cord may be reinjected and the finger extension procedure repeated.  
 
5.2 
Limited Palmar Fasciectomy (LPF) Group 
The Dupuytren’s cord will be excised under local anesthesia in a minor procedure room 
setting or main operating room under local or general anesthetic depending on the 
complexity of the disease and the surgeon’s routine. As this is a pragmatic study we will 
be comparing CI (novel intervention) to LPF as it is actually presently performed in all 
settings academic or community (local in minor room or general/local anesthetic in the 
main operating room).  The procedure will be performed according to the operating 
surgeon’s preferred technique i.e. zig-zag Brunner incision or straight incision with z-
plasty closure of the skin. Loupe magnification will be used in surgery to identify and 
protect the digital neurovascular bundles. The diseased Dupuytren’s fascia (cords) 
causing the contracture will be excised. Contracted ligaments at the PIP joints may be 
released by passive stretching or with knife intraoperatively. A plaster splint will be 
applied at the discretion of the surgeon. Patients will be discharged home the same day 
as their surgery and will return within 1 week for assessment. 
5.3 
Concomitant Medications/Treatments 
Medicines for pain control will be prescribed at the discretion of the operating surgeon. 
 


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5.4 
Procedures for Training of Clinicians on the Interventions 
As CI is the “novel” intervention in this RCT, we need to consider the learning curve. 
Participating surgeons will be expected to review the detailed description of the 
technique, by viewing the provided learning video 
(http://www.xiaflexrems.com/video/dupuytren/Xiaflex_REMS.html ) and have performed 
at least 10 CI injections with successful correction of the extension deficit (less than 5°) 
without serious complication before they begin the enrollment in the study.  
 
 
 
 


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6 STUDY PROCEDURES /EVALUATIONS 
6.1 
Schedule of Study Procedures 
Patients referred to the recruiting surgeons will be screened for eligibility during their 
initial consultation.  Patients who meet the inclusion criteria with no exclusion criteria 
present will be invited to join the trial and asked to provide written informed consent. 
Patients will be randomized after eligibility has been confirmed; it is expected that their 
procedure will occur 2-3 months after randomization. For the CI group, collagenase will 
be ordered and the procedure scheduled for as soon as possible following 
randomization. For the LPF group, the procedure will be done sometime in the ensuing 
weeks, as the procedure needs to be booked by the participating surgeon’s office with 
the OR of the appropriate hospital. Approximately 1 week prior to their scheduled 
procedure, eligible, consenting patients will have their baseline data collected.  
Surgeons may maintain their standard care for follow-up to patients. All patients will be 
seen for their study-specific follow-up visits at 1, 3, 6, and 12 months after their 
procedure. Best efforts will be made to coordinate routine patient care with study follow-
up visits. Patients will be encouraged to contact their surgeon’s office if they have any 
complications, questions, or concerns. If they are experiencing difficulties outside of 
regular hours, they will return to the emergency room of their surgeon’s hospital. 
Patients will be asked at their follow-up visits if they have seen a physician not 
associated with the trial regarding their affected hand, and if so, the record will be 
obtained. If a patient is unable to return for follow up, copies of the quality of life 
questionnaires will be mailed to the patients. Reminder telephone calls will also be 
made to help ensure complete follow up. 
If any unscheduled visits occur, the number of visits will be recorded in the patient’s 
study diary. If occupational or physiotherapists are required to administer treatment, this 
information will also be recorded in the patient’s study chart and in the study diary. 
Additional visits for each of the study groups may occur as follows: 
Collagenase Injection Group: 
Patients in the CI group will return to the surgeon’s office within 1-7 days after receiving 
their injection to determine if the contracture has resolved. If a contracture remains, a 
passive finger extension procedure will be undertaken in an attempt to disrupt the cord. 
If residual contracture remains the patient will return for a 30-day follow-up when the 
cord may be reinjected and finger extension procedure repeated. 
Limited Palmar Fasciectomy Group: 


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Patients in the LPF group will return to the surgeon’s office 1 week following their 
procedure.  
The schedule of study procedures is presented in the Appendix. 
6.2 
Baseline Assessment 
Baseline demographic information will be collected approximately 1 week prior to the 
patient’s procedure and will include age, height, weight, marital and employment status, 
income and education level, medical history and level of co-morbidities. ROM will also 
be collected. 
In addition, 4 HRQL questionnaires will be administered at the baseline visit: MHQ, 
HUI3, URAM, and SDSS (see Health-related Quality of Life section below for further 
details). These questionnaires will be completed in the office/clinic and will take 
approximately 20-30 minutes to complete. The patient will also be given a diary to keep 
track of hospital and doctor visits, blood work, medications, and other health services 
related to their procedure as well as personal expenses incurred and time off from work.  
6.3 
Follow-up Assessment 
All patients will be seen for their study-specific follow-up visits at 1, 3, 6, and 12 months 
after their procedure. This will involve repeat administration of the same 4 
questionnaires as at the baseline assessment (MHQ, HUI3, URAM and SDSS) along 
with ROM assessment. Adverse events and recurrence will be monitored and 
documented throughout the follow-up period. 
6.4 
Health-related Quality of Life (HRQL) 
HRQL will be assessed using the MHQ, a hand-specific outcomes instrument, at 
baseline and 12 months as the primary outcome measure. Secondary measures of 
HRQL include the HUI3, URAM and SDSS. All questionnaires will be scored using 
algorithms provided by the individual developers[14–17]. 
6.4.1 
Michigan Hand Questionnaire (MHQ) 
The MHQ is a thoroughly developed and sensitive hand-specific outcomes instrument 
which measures the health outcomes of patients with chronic hand conditions [14,20]. 
The MHQ contains six distinct scales: 1) overall hand function, 2) activities of daily 
living, 3) pain, 4) work performance, 5) aesthetics, and 6) patient satisfaction with hand 
function with scores ranging from 0 (poorest function) to 100 (best function). The MHQ 
takes approximately 15 minutes to complete and is self-administered. It can assess a 
patient’s general hand function or if administered several times (i.e., pre- and post-
operatively), it can be used to assess changes in hand function.  The raw scale score 


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for each of the six scales is the sum of the responses of each scale item, which is 
converted to a score ranging from 0-100. For the pain scale, a higher score indicates 
more pain. For the other five scales, higher scores indicate better hand performance. 
6.4.2 
Health Utilities Index Mark 3 (HUI3) 
The HUI3 is a generic multi-attribute health-status classification instrument composed of 
eight attributes or dimensions: vision, hearing, speech, ambulation, dexterity, emotion, 
cognition, and pain with five or six levels per attribute [15,21,22]. The HUI3 produces 
health utilities anchored at 0 for equal to being dead and 1 for perfect health. Negative 
scores represent states of health considered worse than being dead. The HUI3 takes 
approximately 10 minutes to complete and is self-administered. 
6.4.3 
Unité Rhumatologique des Affections de la Main (URAM) 
The URAM is a relatively new disease-specific HRQL measure developed for DD [16] 
and is composed of a 9-item patient-reported questionnaire. Each item is scored 
between 0 and 5 depending on the difficulty in performing that particular function with 
total scores for DD–associated disability ranging from 0 (best) to 45 (worst). High scores 
suggest high levels of disability and disturbance. The URAM scale is a 1-domain 
outcome measure postulated to be related to disability associated with DD. The 
questionnaire takes approximately 1 minute to complete and is self-administered.  
6.4.4 
Southampton Dupuytren’s Scoring Scheme (SDSS) 
The SDSS is also a new disease-specific scoring system developed for DD with 5 
domains, each relevant to DD[17] and scored on a five-point scale (no problem, mild 
inconvenience, modest inconvenience, definitely troublesome, severe problem). The 
minimum score is 0 and maximum score is 20 with higher scores suggesting higher 
levels of disability. The SDSS takes approximately 1 minute to complete and is self-
administered.  
6.5 
Healthcare Resource Utilization 
We will identify and tabulate the costs for the two procedures under the purview of the 
patient, Ministry of Health and society. We will further classify these costs into two 
categories: surgery-related costs and costs incurred by the patient. These valuations 
will be calculated for the financial year of 2015 and in Canadian dollars. The 
methodology used for the economic evaluation will be as per Drummond et al.[23], A 
methodological guide to performing cost-utility study comparing surgical techniques Can 
J Plast Surg 2004;12:179-187[18] and Thoma et al. Cost-Effectiveness Analysis Parallel 


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to a  Randomized Controlled Trial Comparing Vertical Scar Reduction and Inverted T-
Shaped Reduction Mammaplasty PRS 134:1093, 2014[24].  
Procedural-related costs: 
Pre-operative and Operative costs 
The plastic surgeon’s fees will be obtained from the Ministry of Health Schedule for 
Benefits for Physician Services (http://www.health.gov.on.ca/en/pro/). The 
anaesthesiologist’s fees will be calculated based on an arithmetic sum of the costs of 
preoperative consultation and time in the operating room (i.e., Basic and time units used 
in the operating room.  The time units are calculated as: time × fee per time unit). 
According to the Ontario Health Insurance Plan fee code, one time unit corresponds to 
15 minutes of anesthesiologist time. The operating room time units for the two 
procedures will be obtained from the surgeon case report form respectively.  The costs 
for the nursing staff will be based on time required in the operating room and for 
inpatient services.  
For palmar fasciectomy the services of 2 full-time nurses are required in the operating 
room or 1 nurse for the Minor Procedure Room (MPR). Direct costs for the surgery, 
including costs for the medications, bandages, haematological investigations, etc., will 
be obtained from the Finance Department at St. Joseph's HealthCare, Hamilton or from 
other participating hospitals. The amount and type of medication required by the patient 
during the procedure will be obtained from each patient’s anaesthesia record, and the 
medication costs will be determined based on the Ministry of Health’s Ontario Drug 
Benefit Formulary/Comparative Drug Index (Available online:  
https://www.healthinfo.moh.gov.on.ca/formulary/). 
Post-operative costs 
Postoperative costs (post-discharge from the hospital) and costs related to 
complications will include the costs to visit plastic surgeon and/or other health 
professional (family physician), walk-in clinics and emergency room visits and will be 
obtained from the Ministry of Health Schedule of Benefits for Physician Services. Costs 
pertaining to any kind of investigation (including pathology/haematological or 
radiographic) and/or overnight stay at the hospital will be obtained from the Finance 
Department of St. Joseph’s Healthcare, Hamilton or from other participating hospitals. 
The costs for medications will be calculated in the manner similar to that given above 
and will be based on each patient’s post-operative note and orders. If the patient 
requires a visit(s) from community nurse post-surgery, the costs will be obtained from a 
local community nursing program. 


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Lost productivity costs: 
The information related to the time lost from work by the patient and care-giver will be 
obtained from the individual patient diaries. To estimate the costs, we will use the 
Human Capital method (i.e. obtain average market wages for skilled workers (2015) 
from Statistics Canada) [23]. This statistic is equal to $x/day and $y on a weekly basis. 
We will use unskilled labour wage rates to calculate the costs related to time lost from 
usual or volunteering activities by the patient and the caregiver.  
Costs incurred by the patient: 
These expenses will include transportation-related cost (fuel and/or parking expenses, 
public transportation, taxi services etc. for their physician visits) and costs to hire a 
babysitter, housekeeper, or other services as a result of being away from home during 
these visits. The cost to buy hand /finger splints and out of hospital physiotherapy 
treatments, etc. that are not reimbursed as a part of OHIP will be included in this 
category. These out of pocket expenditures will be obtained from the patient diary. 
7 ASSESSMENT OF SAFETY 
7.1 
Adverse Events 
An Adverse Event (AE) is broadly defined as any untoward medical occurrence in a 
patient or clinical investigation occurring after the patient has signed the study consent 
form. The AE does not necessarily have a causal relationship with the study treatment 
or study procedures. Consequently, AEs include adverse drug reactions, significant 
abnormal laboratory values and intercurrent diseases.  
 
AEs are expected when their nature, severity or outcome are consistent with the latest 
version of the Investigator’s Brochure for XIAFLEX®. At each patient visit, from the date 
the patient provides written informed consent until the end of the study, each patient will 
be asked non-leading questions regarding their well-being since the last visit. Any 
unintended and unfavourable sign (e.g. a clinically significant abnormal laboratory 
finding), symptom or disease described by the patient or noted by the site staff will be 
recorded as an AE in the source documents, on the study CRF and followed up with 
more specific questions or actions as required. 
 
If a change in the patient’s health status was noted prior to drug administration, it will be 
recorded in the patient’s source documents and in the medical, surgical or physical 
screening CRF pages. Only medically qualified personnel must assess AEs. For the 
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through 12 months of the study period are to be recorded on the CRF by the study site. 
This requirement includes AEs recorded from unscheduled visits as well as scheduled 
visits. 
7.2 
Reporting of Adverse Events 
All AEs must be recorded on the study CRF and described using appropriate medical 
terminology. If a sign or symptom is one component of a diagnosis or syndrome, then 
only the diagnosis or syndrome should be recorded on the AE page of the CRF. Each 
event is to be evaluated for duration, severity, relationship to the investigational 
product/procedure and any action taken. 
A pre-existing condition should not be reported as an AE at baseline but must be 
reported in the appropriate section of the baseline CRF. Medical conditions/diseases 
present at baseline before the study procedure are to be considered as an AE only in 
cases where they worsen after starting the study.  
7.3 
Serious Adverse Events 
We define serious adverse events (SAEs) as any untoward medical occurrence that 
results in death, is life threatening, requires inpatient hospitalization or prolongation of 
existing hospitalization or events that are believed with a reasonable level of certainty to 
be associated with participation in the trial . For such events research personnel will 
complete an SAE CRF and immediately fax or email it to the PI’s office, who will then 
inform the necessary authorities. 
7.4 
Reporting of Serious Adverse Events 
Any SAE, regardless of causal relationship, must be reported to the principal 
investigator’s office immediately (i.e. within 24 hours of knowledge of the event) on the 
SAE CRF and should be accompanied by any relevant documents. All SAEs that have 
not resolved upon discontinuation of the patient’s participation in the study must be 
followed until either the event resolves, stabilizes, or returns to baseline.  Investigators 
are responsible for reporting SAEs to their local ethics committee according to local 
regulations.  
 
8 STATISTICAL CONSIDERATIONS 
8.1 
General 
Analysis of baseline characteristics will be performed using descriptive statistics 
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quartile) for continuous variables and count (percent) for categorical variables. All 
analyses of primary and secondary outcomes will follow the intention-to-treat principles. 
We will use multiple imputation to handle missing data [25]. The results for comparisons 
between groups will be presented as mean difference (for continuous outcomes) and 
relative risk (for binary outcomes), corresponding 95% confidence intervals and 
associated p-values. P-values will be reported to four decimal places with p-values less 
than 0.001 reported as p < 0.001. All analyses will be performed using SAS software 
version 9.4 (Cary, NC, USA).  
8.2 
Sample Size Determination 
The sample size will be based on the 12 month post-randomization MHQ score 
adjusted for baseline MHQ score. According to the paper by London, Stepan and Calfee 
[26] the MCID for the total MHQ score from an ROC analysis of patients from a 
population with multiple hand and forearm diagnoses is 8.7.  The MCID for the total 
MHQ score falls between 8-13 points (depending on the method used to obtain an 
MCID) with a mean equal to 10.8.  If we adopt an MCID of 8.7 it will be in the lower end 
of the range of estimates which will require a larger sample size than if the MCID were 
larger.  For an estimate of the SD of the total MHQ score for patients with DD we obtain 
a value of 15.0 from the one week pre-operative assessment and 16.0 for the 12 month 
post-operative assessment based on the papers by Thoma et al [27,28].  The midpoint 
of these two estimates is 15.5.      
 
If we use α=0.05, β = 0.80, MCID=8.7 and SD=15.5 for the sample size calculation, 
assuming a correlation value of 0.0 between baseline and 12-month post-randomization 
MHQ scores, based on the method outlined in Borm et al[29] the required total sample 
is 102 patients, or 51 per group.  If we account for a 20% loss to follow-up rate the 
required sample increases to 128 (64 per group). These calculations assume that the 
relationship between the baseline and 12 month post-randomization MHQ scores is 
linear and that the slopes of the best fit lines of the two groups are parallel.  
 
8.3 
Clinical Effectiveness Analysis 
The clinical effectiveness of the collagenase will be assessed using the following HRQL 
instruments: MHQ, HUI3, URAM and SDSS (see section 6.4 for details). Objective 
measures of ROM will also be conducted and used to evaluate improvement and 
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8.4 
Cost-Utility Analysis (CUA) 
Quality Adjusted Life Years (QALY) will be measured with the HUI3. QALY is an 
important component of Cost-Utility Analysis (CUA), a variant of Cost-Effectiveness 
Analysis (CEA); therefore, we will be able to calculate incremental cost per QALY 
gained between the two treatments. Of the available utility scales, the HUI3 is the most 
powerful as it can discriminate among close to one million different health states.  Utility 
scores of HRQL derived from responses to the HUI3 questionnaire have the required 
measurement properties for calculating QALYs[18].   
 
The methodology used for data analysis will be as per Drummond et al. Methods for the 
economic evaluation of health care programs, Oxford University Press, 2005 [23] and  
Thoma et al. A methodological guide to performing cost-utility study comparing surgical 
techniques, Can J Plast Surg 2004;12:179-187[18] and Thoma et al. Cost-Effectiveness 
Analysis Parallel to a  Randomized Controlled Trial Comparing Vertical Scar Reduction 
and Inverted T-Shaped  Reduction Mammaplasty PRS 134:1093, 2014[24]. 
 
Probabilistic sensitivity analysis will be undertaken to assess stochastic uncertainty 
using nonparametric bootstrapping to quantify the joined effect of uncertainty around the 
costs and the QALYs. Nonparametric bootstrapping will be used to estimate the 
confidence interval around the mean treatment effects and the incremental cost-
effectiveness ratio[30]. This technique randomly draws with replacement samples of the 
original cost and quality-adjusted life-year data over a large number of times (1000 
replications) [23]. These bootstrapped cost-QALY pairs are graphically represented on 
an incremental cost-effectiveness plane. The bootstrapped estimates will be further 
used to construct the cost-effectiveness acceptability curves.  These will show the 
probability that collagenase injection is cost-effective compared to limited palmar 
fasciectomy across a selected set of cost-effectiveness threshold values when taking 
into consideration the uncertainty inherent in the estimates[31]. 
9 ETHICS/PROTECTION OF HUMAN SUBJECTS 
9.1 
Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with the 
principles set forth in Tri-Council Policy Statement-2: Ethical Conduct for Research 
Involving Humans (2010).  
9.2 
Research Ethics Board (REB) 
The protocol, informed consent form(s), recruitment materials, and all subject materials 
will be submitted to the Research Ethics Board (REB) for review and approval.  


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Approval of both the protocol and the consent form must be obtained before any subject 
is enrolled.  Any amendment to the protocol will require review and approval by the REB 
before the changes are implemented in the study.   
9.3 
Informed Consent Process 
Informed consent is a process that is initiated prior to the individual agreeing to 
participate in the study and continues throughout study participation.  Extensive 
discussion of risks and possible benefits of study participation will be provided to 
subjects and their families, if applicable.  A consent form describing in detail the study 
procedures and risks will be given to the subject.  Consent forms will be REB-approved, 
and the subject is required to read and review the document or have the document read 
to him or her.  The investigator or designee will explain the research study to the subject 
and answer any questions that may arise.  The subject will sign the informed consent 
document prior to any study-related assessments or procedures.  Subjects will be given 
the opportunity to discuss the study with their surrogates or think about it prior to 
agreeing to participate.  They may withdraw consent at any time throughout the course 
of the study.  A copy of the signed informed consent document will be given to subjects 
for their records.  The rights and welfare of the subjects will be protected by 
emphasizing to them that the quality of their clinical care will not be adversely affected if 
they decline to participate in this study. 
The consent process will be documented in the clinical or research record.  
 
Consent for the follow-up portion of the EXTEND trial will take the form of verbal 
consent over the telephone. The principal investigator’s office administrator or the study 
coordinator will contact the patients to obtain consent using the script uploaded to the 
HiREB portal. The date that the patient was contacted, their consent decision and who 
obtained consent will be recorded on the form also uploaded to the HiREB portal.   
 
10 DATA HANDLING AND RECORD KEEPING 
10.1 
Case Report Forms (CRFs) 
Data will be recorded on study-specific paper-based CRFs by the site investigator or by 
designated staff authorized by the investigator and sent to the office of the principal 
investigator for central review and entry into the study database by the research 
assistant. The CRFs must be completed as soon as possible during or after any patient 
visit. Access to CRF data will be limited to personnel directly participating in the study. 
Data should be recorded on the CRF completely by the site investigator or by staff 


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authorized by the investigator. Completed CRFs will be shipped to the office of the PI by 
courier service. 
10.2 
Data Management Responsibilities 
Paper-based CRFs and patient diary/quality of life questionnaires will be used for this 
study and managed centrally in the office of the principal investigator. Data collected will 
be reviewed and entered into the study database by the research assistant. Entered 
data will be statistically checked for coherency and outliers. Data from the patient 
diaries will be extracted and recorded on study CRFs by the research assistant. All CRF 
data and questionnaires will be stored in a locked cabinet in a locked office at each site. 
Personal data shall be handled and processed in accordance with national legislation 
regulating privacy and data protection. When the database has been declared to be 
complete and accurate, the database will be locked. Any changes to the database after 
that time can only be made by written agreement between the PI and the study site 
investigator. 
10.3 
Archiving of Study Documents 
The investigator at each study site must make arrangements to store the essential study 
documents, (as defined in Essential Documents for the Conduct of a Clinical Trial [ICH 
E6, Guideline for GCP]). 
In addition, the investigator is responsible for archiving of all relevant source documents 
so that the study data can be compared against source data after completion of the 
study (e.g. in case of inspection from regulatory authorities). 
The investigator is required to ensure the continued storage of the documents, even if 
the investigator, for example, leaves the clinic/practice or retires before the end of 
required storage period. 
 
11 PUBLICATION PLAN 
Findings will be shared and discussed with all of the investigators for the study. An 
estimated timeline for creation of an abstract/manuscript will be defined at that time. The 
publication or presentation of any study results shall comply with all applicable privacy 
laws. 
 


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12 KEY ROLES AND CONTACT INFORMATION 
Principal 
Investigator:   
Dr. Achilles Thoma, Hamilton 
Clinical Site 
Investigators: 
Dr. Bimpe Ayeni, Newmarket 
Dr. Rodger Shortt,  Oakville 
Dr. Nancy De Kleer, Oakville  
Dr. Yasser El-Sheikh, Toronto 
Dr. Tara Lynn Teshima, Toronto  
Dr. Carolyn Levis, Hamilton 
Dr. James Bain, Hamilton 
Dr. Bing Siang Gan, London 
Dr. Murray Allen, Ottawa 
Other Key 
Personnel: 
Jessica Murphy, Research Assistant 
Lorrie Costantini, Research Assistant 
Dr. Feng Xie, Health Economist 
Dr. Gary Foster, Biostatistician 
Dr. Lehana Thabane, Biostatistician 
 
 
 


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Boyle M. Multiattribute and single-attribute utility functions for the health utilities 
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22.  Horsman J, Furlong W, Feeny D, Torrance G. The Health Utilities Index (HUI): 
concepts, measurement properties and applications. Health Qual Life Outcomes. 
England; 2003;1:54.  
23.  Drummond M, Sculpher M, Torrance G. Methods for the economic evaluation of 
health care programs. 3rd ed. Oxford, UK: Oxford University Press; 2005.  
24.  Thoma A, Kaur MN, Tsoi B, Ziolkowski N, Duku E, Goldsmith CH. Cost-
effectiveness analysis parallel to a randomized controlled trial comparing vertical 
scar reduction and inverted T-shaped reduction mammaplasty. Plast Reconstr 


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EVALUATION OF XIAFLEX: TRIAL OF EFFECTIVENESS iN DUPUYTREN’S (EXTEND) 
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14 APPENDIX.  SCHEDULE OF ENROLMENT, INTERVENTIONS, AND 
ASSESSMENTS. 
 
 
STUDY PERIOD 
 
Screening 
Enrolment 
Procedure 
Post-allocation 
Unscheduled 
visits 
TIMEPOINT 
 
-1wk 
0 
1mo 
3mo 
6mo 
12mo 
 
ENROLMENT: 
 
 
 
 
 
 
 
 
Eligibility screen 
X 
 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
INTERVENTIONS: 
 
 
 
 
 
 
 
 
Collagenase Injection 
(CI) 
 
 
X 
 
 
 
 
 
Limited Palmar 
Fasciectomy (LPF) 
 
 
X 
 
 
 
 
 
ASSESSMENTS: 
 
 
 
 
 
 
 
 
In-hospital utilization 
 
 
X 
 
 
 
 
 
Baseline demographics 
 
X 
 
 
 
 
 
 
HRQL questionnaires 
 
X 
 
X 
X 
X 
X 
 
Range of Motion 
 
X 
 
X 
X 
X 
X 
 
Resource utilization 
 
 
 
X 
X 
X 
X 
X 
AE/SAE monitoring 
 
 
 
X 
X 
X 
X 
X 
Recurrence 
 
 
 
X 
X 
X 
X 
X 
Study completion 
 
 
 
 
 
 
X 
X