The CeCORD-J study is a prospective, multicenter, non-randomized controlled, observational study with two parallel groups. This study provides the utmost respect for the treatment choices of patients.
Study setting
After the ethics committee approval of Nagoya University Hospital (2017-0506-4), the CeCORD-J study was approved by the academic research project committee of the Japanese Society for Surgery of the Hand (JSSH) as an official project in 2017. We invited participation from all major referral centers of hand surgery in Japan with at least one hand surgery specialist. A final total of 28 hand surgery centers accepted and joined this study. Patients were recruited from those centers. Investigators had to have specialist certification in hand surgery because CCH injection can only be performed by hand surgery specialists in Japan. All participating investigators had previously performed both CCH injection and fasciectomy before initiation of the study. Hand surgeons participating in this study held three meetings before starting this study to confirm the protocol.
Ethics and dissemination
Both treatment options are standard procedures for patients with DC in Japan. This study was not a randomized controlled study for intervention selection. We have the utmost respect for patient preferences in terms of treatment selection. This study was therefore not interventional but observational in nature. This policy offers substantial benefits for patient recruitment. Our major concern was bias in the number of cases in each group. One solution to this issue is propensity score adjustment after study completion.
Information on the trial and patient approval
Written information was used to explain the study to patients. Because this study was observational in nature, patients were able to select their preferred treatment after explanation of both treatments by hand surgery specialists. Hand surgery specialists obtained informed consent for participation from each patient after the decision-making process.
Participants
The inclusion criteria were: 1) patients with passive extension deficit in either only PIP joints or both PIP and MP joints; 2) flexion contractures in at least two fingers of one hand; 3) age >20 years; and 4) the ability to answer questionnaires in Japanese.
Exclusion criteria were: 1) recurrent contracture in the finger to be treated; 2) contraindications for CCH injection; 3) pregnancy or planning to become pregnant; 4) need for continued anticoagulation; 5) participation in another clinical study; 6) judgement that study participation would be inappropriate by the enrolling investigator.
Baseline assessment
Baseline demographics of patients included age, sex, family history of DC, duration of symptoms, medical history, histories of smoking and drinking, involved fingers and joints, and PROMs for the hand (Hand10), EQ-5D-5L, and satisfaction (a 5-point scale).
Interventions
Patients requesting CCH injection were included in the Collagenase group. In this group, 0.58 mg of CCH was injected into the cord of the affected finger. One day after injection, the affected finger was manipulated under local anesthesia or wrist block. Patients could receive additional CCH injections up to 3 times in total if necessary, at intervals of >30 days.
Patients hoping to undergo fasciectomy were included in the Surgery group. In this group, aponeurectomy was performed under general anesthesia or axillary block.
Patients in both groups received hand therapy including splinting based on the judgement of the surgeon. An attending hand surgery specialist decided whether inpatient or outpatient treatment was warranted. Generally, patients in the Surgery group required inpatient treatment, and those in the Collagenase group could be treated using either outpatient or inpatient treatment.
Study outcomes
Primary outcome
The primary outcome was the PROM score for the Hand10 before and 1, 2, 4, 8, and 26 weeks after intervention. The Hand10 is a valid instrument for patients with upper limb disorder, even in elderly individuals, as the questionnaire includes illustrations that provide favorable effects on reproducibility14. The Hand10 questionnaire consists of 10 self-reported questions designed to measure upper extremity disability and symptoms. Scores for the Hand10 range from 0 to 100, with lower numbers indicating lower levels of disability.
Secondary outcomes
We set the following secondary outcomes: 1) EQ-5D-5L (QOL) score; 2) patient satisfaction; 3) degrees of extension deficit and flexion of the treated joint, and 4) direct medical costs. We also investigated: 1) complications; and 2) recurrences as other outcomes. Recurrences were assessed 1 year after treatment, and all other secondary outcomes were evaluated up to 26 weeks after interventions.
Recurrence was considered to have occurred if the degree of extension deficit worsened by more than 30° after treatment. We classified complications as: grade I, minor complications without needing any unexpected surgery or anesthesia; or grade II, major complications needing unexpected surgery under anesthesia or inpatient treatment. Each outcome was compared with baseline data.
Discontinuation criteria
Discontinuation criteria were: 1) when the patient requested to withdraw from the study; 2) when the patient was found not to satisfy eligibility criteria after registration; 3) when continuation of the study was difficult because symptoms or complications worsened; or 4) when the hand surgery specialist decided on discontinuation for any other reason. When discontinuation occurred, data collection was stopped, but data collected up to the time of discontinuation were retained for use in the study.
Power analysis
Setting values of α=0.05 and β=0.8, sample size “n” was calculated as n=16s2/d2, where “s” is the standard deviation and “d” is the difference between two groups. According to previous papers, mean DASH score at 1 year postoperatively was 12.7 (standard deviation, 3.6)8, and mean DASH score at 1 year after CCH injection was 7 (standard deviation, 9)16. We did not use DASH score, but Hand10 was expected to show similar results. We therefore used “s” as 9, and “d” as 5.7 for sample size calculations. If both groups were to include the same number of patients, a sample size of 40 per group was required.
Statistical analysis
We compared baseline patient demographics between groups using the unpaired t-test or chi-square test. Baseline patient demographics included age, sex, number of involved fingers and joints, degree of extension deficit, Hand10 score, EQ-5D-5L (QOL) score, and satisfaction.
As the primary outcome, Hand10 scores were compared between groups using the unpaired t-test.
EQ-5D-5L (QOL) score, satisfaction, and degree of extension deficit were compared between groups as secondary outcomes using the unpaired t-test. Satisfaction was compared between groups using the Mann-Whitney U test. We compared mean direct medical costs between groups.
Prevalence and severity of complications were summarized and compared between groups using the chi-square test.
Propensity score adjustment was used to balance differences in patient characteristics between Collagenase and Surgery groups. In a logistic regression model with treatment assignment variables (Collagenase group = 0, Surgery group = 1) as the dependent variables, the following independent variables were introduced to obtain the propensity score (= probability of undergoing surgery) for each patient: age, sex, total number of affected joints per patient, total number of affected fingers per patient, family history of DC, duration of symptoms, smoking, drinking, past or present history of diabetes mellitus, epilepsy, history of hand trauma, malignant tumor, baseline Hand10 score, baseline degree of extension defect of the primary PIP joint, degree of extension of the primary MP joint, and baseline EQ-5D-5L (QOL) score.
Outcomes were then compared between treatment groups after adjusting for propensity scores. Specifically, a generalized linear model with treatment assignment variables (Collagenase group = 0; Surgery group = 1) and propensity scores as independent variables and outcomes as dependent variables was used to determine differences in outcomes and associated 95% confidence intervals and p-values in the collagenase-controlled Surgery group.
The outcome variables examined were: Hand10 score (weeks 1, 2, 4, 8, and 26), EQ-5D-5L (QOL) score (weeks 1, 2, 4, 8, and 26), direct cost, degree of extension deficit of the PIP (weeks 4 and 26), degree of extension deficit of the MP (weeks 4 and 26), degree of PIP flexion (weeks 4 and 26), and degree of MP flexion (weeks 4 and 26).
Statistical analysis was performed using STATA version 16 software.
Data management
We used a central monitoring system in the data center. Each hand surgery center registered anonymized patient information to the data center. Hand surgery specialists noted patient data at each time point and those data were stored at each hand surgery center. Anonymized patient data were collected at the data center by mail after finishing the follow-up period. This study was monitored by an independent assessor during patient recruitment and after completion of the study.
This study followed and respected the Declaration of Helsinki and the principles of good clinical practice.