Collagenase Injection versus Limited Fasciectomy for Dupuytren's Contracture.
Dias J, Tharmanathan P, Arundel C, Welch C, Wu Q, Leighton P, Armaou M, Johnson N, James S, Cooke J, Bainbridge L, Craigen M, Warwick D, Brady S, Flett LG, Jones J, Knowlson CN, Watson M, Keding A, Hewitt CE, Torgerson D
- DOI
- 10.1056/NEJMoa2312631
- Record issued
- 2026-08-16
- Engine
- 7.39.0
- Exported
- 2026-09-22
Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/f67765cd-58d4-4ab5-a6b2-f34ca1235e99 is authoritative.
How this rating was calculated
- StatisticsImpossible or misreported statistic ×4−4★
- IntegrityIntegrity concern−0.5★
- StatisticsPrinted percentage does not match its own count (capped) ×4−0.25★
- ReportingData & code availability partially met−0.25★
- CitationsUnresolved reference−0.25★
A demonstrable critical failure caps the rating at the minimum, regardless of the deductions above.
- The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 14 reported means were read, and their group size is not stated where the values are printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.
- No data or code availability links were detected to verify.
- 01Printed percentage does not match its own countdemonstrable
8% does not match the reported count 26/178
“26/178 (8.0%)”
- 02Printed percentage does not match its own countdemonstrable
1.7% does not match the reported count 5/149
“5/149 (1.7%)”
- 03Printed percentage does not match its own countdemonstrable
8% does not match the reported count 26/178
“26/178 (8.0%) patients in the collagenase group”
ResultsFind in source - 04Printed percentage does not match its own countdemonstrable
1.7% does not match the reported count 5/149
“5/149 (1.7%) participants in the limited fasciectomy group”
ResultsFind in source - 05Printed percentage does not match its own count
82.6% does not match the reported count 196/237
“Limited fasciectomy n=237 82.6%”
ResultsFind in source - 06Printed percentage does not match its own count
96.5% does not match the reported count 285/295
“96.5% of limited fasciectomy participants”
ResultsFind in source
2 further findings of this severity or below — every one is in the sections below, filed under its error type.
This Kaimen Rigor review uses Kaimen Rigor reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.
This is a well-conducted and well-reported randomized non-inferiority trial with rigorous design, clear ethical approvals, and appropriate statistical methods. The main weakness is the vague data availability statement, which lacks a concrete access mechanism, and a few minor reporting inconsistencies.
Both reviewers independently scored all eight dimensions and agreed on all statuses, so no divergence needed reconciliation. The statistics verification component could not recompute any of the 8 checked tests because they are model-based estimates or threshold p-values, which is expected and not a deficiency. The citation check found one reference not found in any registry, which is flagged as a potential fabrication signal.
Numerical inconsistencies
3 findings · worst criticalValues that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.
- Summary statistic impossible for the stated N (GRIM/GRIMMER)Recomputed
- Printed percentage does not match its own countRecomputed
- Internal contradictions in the reported numbersAssessed
4 reported summary statistics mathematically impossible for the stated N (PERCENT). 4 printed percentages that do not match their own count.
- PERCENT8% does not match the reported count 26/178
“26/178 (8.0%)”
- PERCENT1.7% does not match the reported count 5/149
“5/149 (1.7%)”
- PERCENT82.6% does not match the reported count 196/237
“Limited fasciectomy n=237 82.6%”
ResultsFind in source - PERCENT96.5% does not match the reported count 285/295
“96.5% of limited fasciectomy participants”
ResultsFind in source - PERCENT68.6% does not match the reported count 224/326
“compared to 68.6% of participants treated with collagenase”
ResultsFind in source - PERCENT2% does not match the reported count 7/326
“2% vs 5%”
Results - PERCENT8% does not match the reported count 26/178
“26/178 (8.0%) patients in the collagenase group”
ResultsFind in source - PERCENT1.7% does not match the reported count 5/149
“5/149 (1.7%) participants in the limited fasciectomy group”
ResultsFind in source
- lowinternal contradictionThe abstract reports 2-year difference as 7.2 (95%CI 4.2 to 10.9) with n=229 and n=197, but the results section reports 2-year difference as 7.5 (4.2 to 10.9) in Figure 2 legend. The point estimate differs (7.2 vs 7.5).
At 2 years (n = 229 and n = 197 in collagenase and limited fasciectomy groups, respectively), the between group difference was 7.2 (95%CI: 4.2 to 10.9). ... 2 years = 7.5 (4.2 to 10.9).
Figure 2reviewer’s wording
Overstated conclusions
1 finding · worst lowConclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.
- Conclusions only partially backed by the presented evidenceAssessed
6 major claims checked against the paper's own evidence: 2 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.
- partialReviewer 1Collagenase injection may be preferred by patients who prioritize avoiding the higher risk of moderate to severe complications and longer time to improvement associated with surgery.The claim is speculative and not directly tested, but is a reasonable interpretation of the complication data.Evidence: Complication rates are lower in the collagenase group, but patient preference was not directly assessed.
“Despite our findings favoring limited fasciectomy, collagenase injection may be preferred by patients who prioritize avoiding the higher risk of moderate to severe complications and longer time to improvement associated with surgery.”
DiscussionFind in source - partialReviewer 2Results appeared similar between groups for other patient reported outcomes and for finger joint contracture at 1 year.The paper reports differences favoring limited fasciectomy for joint contracture, but the claim of 'similar' is vague; the data show increasing differences over time.Evidence: Joint measurements show differences favoring LF at 1 year (e.g., passive extension deficit difference 10.1°).
“Results appeared similar between groups for other patient reported outcomes and for finger joint contracture at 1 year.”
Discussion ¶1Find in source - supportedReviewers 1, 2Collagenase was not non-inferior to limited fasciectomy with respect to the Patient Evaluation Measure hand health questionnaire score at 1-year post-treatment.The primary outcome difference and CI exceed the non-inferiority margin, supporting the claim.Evidence: Primary outcome difference 5.9 (95%CI 3.1 to 8.8) with non-inferiority margin of 6 points.
“Collagenase was not non-inferior to limited fasciectomy with respect to the Patient Evaluation Measure hand health questionnaire score at 1-year post-treatment.”
ConclusionFind in source - supportedReviewers 1, 2The percentage of persons with moderate to severe complications was 2% in the collagenase group and 5% in the limited fasciectomy group.The complication rates are directly reported in the results and table.Evidence: Table 2 shows moderate/severe complication rates of 2% vs 5%.
“The percentage of persons with moderate to severe complications was 2% in the collagenase group and 5% in the limited fasciectomy group.”
AbstractFind in source - supportedReviewers 1, 2Recurrent contracture requiring re-intervention occurred in 8% after collagenase versus 1.7% after limited fasciectomy.The re-intervention rates are reported in the results section.Evidence: Results section reports 26/178 (8.0%) vs 5/149 (1.7%) re-interventions.
“Recurrent contracture requiring re-intervention occurred in 8% after collagenase versus 1.7% after limited fasciectomy.”
AbstractFind in source - supportedReviewer 2Moderate or severe adverse events were uncommon but more frequent in the limited fasciectomy group.The complication severity data support this claim.Evidence: Table 2: Moderate+Severe rates 5% vs 2%.
“Moderate or severe adverse events were uncommon but more frequent in the limited fasciectomy group.”
DiscussionFind in source
Efficacy claim is anchored to an adequate endpoint and a meaningful effect.
- ADEQUATESurrogate endpointThe primary outcome is the Patient Evaluation Measure Hand Health Questionnaire score, a validated patient-reported outcome measure for hand health, which is a clinical outcome directly relevant to the condition. The trial also includes hard clinical outcomes such as re-intervention rates and complications. The non-inferiority margin was anchored to a minimal clinically important difference derived from anchor-based methods.
“The primary outcome was the score on the Patient Evaluation Measure Hand Health Questionnaire (range 0 to 100, higher scores indicating worse outcome) 1-year post-treatment.”
- ADEQUATEEffect sizeThe primary analysis shows a between-group difference of 5.9 points (95% CI 3.1 to 8.8) at 1 year, which exceeds the pre-specified non-inferiority margin of 6 points, leading to the conclusion that collagenase is not non-inferior. The effect size is anchored to a clinically meaningful threshold (the non-inferiority margin) and is statistically supported.
“At 1-year, the mean score on the Hand Health questionnaire was 17.8 in the collagenase group (n = 284) and 11.9 in the limited fasciectomy group (n = 250); between group difference = 5.9 (95%CI: 3.1 to 8.8, one sided p value for non-inferiority 0.49).”
Data authenticity concerns
None foundAn adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.
Checked — nothing surfaced.
Reporting gaps
1 finding · worst mediumRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
- Data/code availability incompleteAssessed
The introduction cites prior studies on collagenase versus placebo and notes the lack of direct comparative evidence. The rationale for the trial is logically derived from this gap, and the non-inferiority design is justified by the potential benefits of collagenase (clinic administration, cost savings, quicker recovery). Limitations of prior research are implicitly addressed by the trial's design, though not explicitly discussed.
“Collagenase was shown to be better than placebo in correcting the contracture to 0-5 degrees at 30 days.”
“Evidence comparing these treatments is limited.”
“The benefits of collagenase treatment include its administration in a clinic instead of an operating room, potential cost savings – and a quicker recovery time compared to limited fasciectomy.”
“Collagenase was shown to be better than placebo in correcting the contracture to 0-5 degrees at 30 days.”
“Evidence comparing these treatments is limited.”
“We assumed that this difference in score (6 points) represents the minimum threshold at which changes in hand function become appreciated by patients.”
Randomization used random varying block sizes with stratification, and allocation was concealed via a central online service. Blinding was not feasible due to the nature of interventions, but this is stated. A priori sample size calculation with 90% power and a non-inferiority margin of 6 points is provided. Inclusion/exclusion criteria are clearly defined. The analysis population (all participants with at least one post-treatment measurement) and missing data handling (multiple imputation) are pre-specified. No independent replication is applicable for a single pivotal trial.
“Participants were randomized 1:1 to receive collagenase injection or limited fasciectomy, using randomly varying block sizes (Sizes 4 and 6) and stratification by the reference joint (metacarpophalangeal or proximal interphalangeal joint).”
“Clinicians and participants could not be blinded due to the nature of trial interventions.”
“Using these parameters, a sample size of 568 participants (284 per arm) was required to obtain 90% power to test H 0 : δ ≥ 6 vs H 1 : δ < 6 with one sided p < 0.025.”
“Participants were randomized 1:1 to receive collagenase injection or limited fasciectomy, using randomly varying block sizes (Sizes 4 and 6) and stratification by the reference joint (metacarpophalangeal or proximal interphalangeal joint).”
“Clinicians and participants could not be blinded due to the nature of trial interventions.”
“a sample size of 568 participants (284 per arm) was required to obtain 90% power to test H 0 : δ ≥ 6 vs H 1 : δ < 6 with one sided p < 0.025.”
The paper reports age, sex, ethnicity, and various clinical characteristics in Table 1. Since both sexes are enrolled, sex justification is not applicable. Age and health status are reported. Species/strain and housing conditions are not applicable for a human trial. Demographics are adequately reported, though the study population is predominantly White, which is acknowledged as a limitation.
“Age (years) | 66.5 (9.2) | 66.4 (8.8) | | Male, n (%) | 263 (78.3) | 270 (80.4)”
“White | 333 (99.1) | 332 (98.8)”
“Active extension deficit of ref. joint (°) | 52.3 (15.4) | 51.5 (16.7)”
“Male, n (%) | 263 (78.3) | 270 (80.4)”
“White | 333 (99.1) | 332 (98.8)”
“Active extension deficit of ref. joint (°) | 52.3 (15.4) | 51.5 (16.7)”
The study was approved by the Leeds West Research Ethics Committee, UK Health Research Authority, and UK Medicines and Healthcare products Regulatory Authority. Written informed consent was obtained from all participants. Regulatory compliance is implied by the approvals, though not explicitly named as a framework.
“The study and amendments were approved by the Leeds West Research Ethics Committee, UK Health Research Authority and UK Medicines and Healthcare products Regulatory Authority.”
“Participants provided written informed consent prior to randomization.”
“The study and amendments were approved by the Leeds West Research Ethics Committee, UK Health Research Authority and UK Medicines and Healthcare products Regulatory Authority.”
“Participants provided written informed consent prior to randomization.”
Collagenase is identified as 'Collagenase clostridium histolyticum' and its administration is described. The comparator (limited fasciectomy) is a surgical procedure, not a drug. Statistical software (Stata/SE-v17.0) is identified. No other key biological or chemical resources are used.
“Collagenase was injected as three aliquots at set points following the current approved Summary of Product Characteristics.”
“All analyses were undertaken at the end of the follow-up period using Stata/SE-v17.0.”
“Another treatment involves injection of an enzyme, Collagenase clostridium histolyticum (Collagenase), into the cord”
“All analyses were undertaken at the end of the follow-up period using Stata/SE-v17.0.”
The primary analysis uses a longitudinal mixed model, and the non-inferiority test is based on the upper bound of the 95% CI. Effect sizes with 95% CIs are reported for primary and secondary outcomes. Exact p-values are reported for the primary outcome (p=0.49) and for some secondary analyses. Statistical software is identified. Data presentation includes figures with confidence intervals and per-group n. Mathematical plausibility checks were not performed due to continuous outcomes and model-based estimates.
“For the primary analysis, a longitudinal model, incorporating all available post-treatment Patient Evaluation Measure scores, was used to estimate differences in scores at each timepoint.”
“between group difference = 5.9 (95%CI: 3.1 to 8.8, one sided p value for non-inferiority 0.49)”
“All analyses were undertaken at the end of the follow-up period using Stata/SE-v17.0.”
“For the primary analysis, a longitudinal model, incorporating all available post-treatment Patient Evaluation Measure scores, was used to estimate differences in scores at each timepoint.”
“between group difference = 5.9 (95%CI: 3.1 to 8.8, one sided p value for non-inferiority 0.49)”
“All analyses were undertaken at the end of the follow-up period using Stata/SE-v17.0.”
The paper mentions supplementary materials but does not provide a clear data availability statement. It states that data are available in the supplementary material, but no repository or accession numbers are given. Since this is a clinical trial with patient-level data, managed access would be acceptable, but the statement is not explicit. Code sharing is not applicable as no custom code is mentioned.
“Supplementary Material Supplement”
“Supplementary Material Supplement”
The trial is registered (ISRCTN18254597). Methods are detailed enough for replication. A CONSORT diagram is referenced. All pre-specified outcomes are reported, including secondary outcomes. Limitations are discussed, including the impact of COVID-19 and generalizability. Conclusions are proportional to the results. Funding and conflicts of interest are disclosed.
“Trial registration: ISRCTN18254597”
“A Consolidated Standards of Reporting Trials (CONSORT) diagram summarized participant flow and data completeness.”
“Limitations of our study should be noted. Substantive changes to provision of care for patients with Dupuytren’s Contracture impacted treatment delivery at different points during the trial”
“Trial registration: ISRCTN18254597”
“A Consolidated Standards of Reporting Trials (CONSORT) diagram summarized participant flow and data completeness.”
“Limitations of our study should be noted. Substantive changes to provision of care for patients with Dupuytren’s Contracture impacted treatment delivery at different points during the trial”
Registered (1 ID: ISRCTN). Reporting guideline cited: CONSORT.
Broken references and links
1 finding · worst lowReferences checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.
- References not resolvable to a published paperRecomputed
Checked 23 references by DOI: 18 verified — 1 DOI unresolved, 4 no DOI (shown, not verified).
- UNRESOLVED10.1016/s0895-4356(99DISC: Dupuytren’s Interventions Surgery vs., CollagenaseCited DOI does not resolve to any Crossref record.
- NO DOIXiapex: Summary of Product CharacteristicsNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIPatient-Rated Outcome Measures and Dupuytren ContractureNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIDupuytren’s interventions surgery vs collagenaseNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOICausal Inference: Efficacy and Mechanism EvaluationNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
Copyediting
6 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 6 minor suggestions below.
6 copyedit issues flagged: mostly consistency, punctuation, typo.
- MINORtypoTable 2 footnote“considerered possibly related to treatmen’”→ Change to 'considered possibly related to treatment'Typographical error in footnote.
- MINORconsistencyResults, Complications and Re-intervention“26/178 (8.0%) patients in the collagenase group and 5/149 (1.7%) participants in the limited fasciectomy group”→ Ensure consistent use of 'patients' vs 'participants'.Minor inconsistency in terminology.
- MINORpunctuationDiscussion“Dupuytren’s Disease has been reported to predominantly affect Causasian persons”→ Change 'Causasian' to 'Caucasian'Spelling error.
- MINORpunctuationTable 2 footnote“treatmen’”→ Change to 'treatment'Apostrophe used incorrectly.
- MINORconsistencyResults, Complications and Re-intervention“26/178 (8.0%) patients in the collagenase group and 5/149 (1.7%) participants”→ Use consistent terminology (patients vs participants) throughout.Inconsistent use of 'patients' and 'participants' in the same sentence.
- MINORclarityMethods, Outcomes“overall hand assessment and and complications”→ Remove duplicate 'and'Duplicate word.
The published work is robust and generally trustworthy, but an informed reader should weigh the vague data availability statement and the minor internal contradiction in the 2-year effect estimate. A correction or erratum to reconcile the 7.2 vs 7.5 discrepancy and to clarify data access would strengthen the paper's transparency.
- 1.CRITICALstatisticsCorrect or explain the statistically impossible value: PERCENT: 8% does not match the reported count 26/178Demonstrable critical failure — blocks the verdict from passing.
- 2.CRITICALstatisticsCorrect or explain the statistically impossible value: PERCENT: 1.7% does not match the reported count 5/149Demonstrable critical failure — blocks the verdict from passing.
- 3.HIGHdata codeAdd a detailed data availability statement in the Methods or a dedicated section, specifying a concrete access route such as a named data access committee or repository (e.g., YODA, Vivli) with conditions and timeframe.The current statement is vague and does not meet transparency standards for a clinical trial, which reviewers will flag.
- 4.HIGHreportingReconcile the 2-year difference reported in the abstract (7.2, 95%CI 4.2 to 10.9) with the results section/Figure 2 legend (7.5, 4.2 to 10.9) and correct the discrepancy.An internal contradiction in a primary outcome estimate undermines trust and may warrant an erratum.
- 5.HIGHotherVerify or correct the reference 'DISC: Dupuytren’s Interventions Surgery vs., Collagenase' (DOI 10.1016/s0895-4356(99) which was not found in any registry.A reference that cannot be located in Crossref/OpenAlex may be fabricated or contain an incorrect DOI, which is an integrity concern.
- 6.MEDIUMotherSpecify the manufacturer and formulation of collagenase used in the trial in the Methods, Treatments section.Providing the exact product details improves reproducibility and was flagged as inadequate by one reviewer.
- 7.MEDIUMcopyeditFix the typo in Table 2 footnote: change 'considerered possibly related to treatmen’' to 'considered possibly related to treatment'.Typographical errors in footnotes can confuse readers and reflect poorly on the manuscript's quality.
- 8.MEDIUMcopyeditCorrect the spelling of 'Causasian' to 'Caucasian' in the Discussion.Spelling errors are easily fixed and improve professionalism.
- 9.MEDIUMcopyeditRemove the duplicate 'and' in Methods, Outcomes: 'overall hand assessment and and complications'.Duplicate words are a clear copyedit issue that should be corrected.
- 10.MEDIUMcopyeditEnsure consistent use of 'patients' vs 'participants' throughout the Results, Complications and Re-intervention section.Inconsistent terminology in the same sentence is a minor but noticeable inconsistency.
- 11.LOWreportingExplicitly state compliance with the Declaration of Helsinki or ICH-GCP guidelines in the ethics section.While regulatory approvals are mentioned, explicit compliance statements are standard for clinical trials and strengthen the ethics reporting.
- 12.LOWreportingAdd a note on the generalizability of the predominantly White study population in the limitations section.The study population is >98% White, and acknowledging this limitation is important for interpreting the results.
- 13.LOWdata codeIf any bespoke analysis code was used, provide it in a public repository (e.g., GitHub) with a version and DOI, and reference it in the methods.Sharing analysis code enhances reproducibility, though it is not mandatory for this trial.
The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”
- Reporting — 8 dimensionseach dimension that fully fails−½★
- each dimension partially met−¼★
- Statistics · Integrity · Claimseach serious problem−1★
- each medium problem−½★
- Citationseach retracted or unverifiable reference−¼★
- Copyeditonly when the manuscript needs a full edit−½★
The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.
The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.
Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.
This Kaimen Rigor review is model-assisted and is not a substitute for formal expert review. It complements human evaluation by surfacing potential methodological concerns — verify each finding against the source.