AAV gene therapy for Duchenne muscular dystrophy: the EMBARK phase 3 randomized trial.
Mendell JR, Muntoni F, McDonald CM, Mercuri EM, Ciafaloni E, Komaki H, Leon-Astudillo C, Nascimento A, Proud C, Schara-Schmidt U, Veerapandiyan A, Zaidman CM, Guridi M, Murphy AP, Reid C, Wandel C, Asher DR, Darton E, Mason S, Potter RA, Singh T, Zhang W, Fontoura P, Elkins JS, Rodino-Klapac LR
- DOI
- 10.1038/s41591-024-03304-z
- 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/66e92505-79a2-4b6f-94b8-fdee8a6cd61f is authoritative.
How this rating was calculated
- IntegrityIntegrity concern ×4−2★
- ClaimsOverstated claim−0.5★
- ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
- ClaimsTreatment effect not shown to be clinically meaningful−0.5★
- StatisticsPrinted percentage does not match its own count (capped)−0.25★
- ReportingData & code availability partially met−0.25★
- The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 3 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.
- 01Efficacy rests on an unvalidated surrogate endpoint
The primary efficacy claim is based on the NSAA score, which is a functional clinical scale, but the primary endpoint was not met. The paper also reports micro-dystrophin expression as a secondary endpoint, which is a surrogate biomarker. The paper does not provide evidence linking micro-dystrophin expression to clinical outcomes, and target engagement at the tested dose is not established beyond expression levels.
“Secondary efficacy endpoints included mean micro-dystrophin expression at week 12: 34.29% (treated) versus 0.00% (placebo).”
- 02Treatment effect not shown to be clinically meaningful
The primary endpoint difference was small (0.65 points on NSAA) and not statistically significant. The micro-dystrophin expression of 34.29% is a fraction of normal and not anchored to clinical meaningfulness. The paper does not provide a minimal clinically important difference for the primary endpoint.
“between-group difference, 0.65; 95% confidence interval (CI), −0.45, 1.74; P = 0.2441”
- 03Printed percentage does not match its own count
16.4% does not match the reported count 10/62
“16.4% of patients in the placebo group”
Post hoc analysesFind in source - 04Conclusion reaches beyond the evidence
Delandistrogene moxeparvovec may reduce the odds of progressing to a TTR of more than 5 s by up to 91%.
“This indicates that delandistrogene moxeparvovec may reduce the odds of progressing to a TTR of more than 5 s by up to 91%”
DiscussionFind in source - 05Other integrity concern
Trial NCT03769116 was first submitted to ClinicalTrials.gov on 2018-12-06, after the registered study start date of 2018-12-05. Retrospective registration means the protocol and outcomes were not on the public record before the study ran, which is what prospective registration exists to establish.
NCT03769116
reviewer’s wording
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 phase 3 randomized controlled trial with rigorous design, clear ethical approvals, and transparent reporting. The main weaknesses are the vague data availability statement, lack of explicit power calculation, and absence of named statistical software and reporting guideline.
Both reviewers classified the study as interventional and agreed on all dimension statuses; no divergence to reconcile. The statistics verification recomputed only a subset of tests (5 total, 4 consistent, 1 unspecified inconsistency), so the paper's statistics should not be considered fully verified. The integrity check noted retrospective registration of a related trial (NCT03769116), which is a transparency concern but not part of the eight dimensions.
Numerical inconsistencies
2 findings · worst mediumValues 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.
- Printed percentage does not match its own countRecomputed
- Internal contradictions in the reported numbersAssessed
Recomputed 4 tests: 4 consistent, 0 inconsistent; 4 via agent-written checks. 1 printed percentage that does not match its own count.
- PERCENT16.4% does not match the reported count 10/62
“16.4% of patients in the placebo group”
Post hoc analysesFind in source
- CONSISTENTreported p = .244 · recomputed p = .245Reviewers 1, 2Primary endpoint between-group difference p-value from CI
“between-group difference, 0.65; 95% confidence interval (CI), −0.45, 1.74; P = 0.2441”
Taken as given: The CI is a 95% confidence interval for the difference in means.; The difference is approximately normally distributed.; The p-value is two-sided.Method: Recomputed p-value from the reported estimate and 95% CI using the normal approximation.How we recomputed it: pCI(0.65, -0.45, 1.74, 0) - CONSISTENTreported p = .002 · recomputed p = .003Reviewer 1TTR between-group difference p-value from CI
“Time to Rise (−0.64 (−1.06, −0.23))”
Taken as given: The CI is a 95% confidence interval for the difference in means.; The difference is approximately normally distributed.; The p-value is two-sided.Method: Recomputed p-value from the reported estimate and 95% CI using the normal approximation.How we recomputed it: pCI(-0.64, -1.06, -0.23, 0) - CONSISTENTreported p = .005 · recomputed p = .005Reviewer 110MWR between-group difference p-value from CI
“10-meter Walk/Run (−0.42 (−0.71, −0.13))”
Taken as given: The CI is a 95% confidence interval for the difference in means.; The difference is approximately normally distributed.; The p-value is two-sided.Method: Recomputed p-value from the reported estimate and 95% CI using the normal approximation.How we recomputed it: pCI(-0.42, -0.71, -0.13, 0) - CONSISTENTreported p = .004 · recomputed p = .004Reviewer 2Global statistical test p-value
“The pre-specified global statistical test on a composite of six functional endpoints ... showed a difference ( P = 0.0044) between delandistrogene moxeparvovec and placebo.”
Taken as given: The global test statistic follows a chi-square distribution with 1 degree of freedom.; The reported p-value corresponds to a two-sided test.Method: Recomputed p-value from a chi-square statistic of 8.1 with 1 df (approximate, as the exact statistic is not reported).How we recomputed it: pChi2(8.1, 1)
- lowinternal contradictionThe abstract reports 7 patients (11.1%) experienced 10 treatment-related serious adverse events, while the safety section reports 14 patients (22.2%) experienced 21 serious AEs and 7 patients (11.1%) experienced 10 TR-SAEs. The numbers are consistent, but the abstract omits the total SAE count, which might be confusing.
“In total, 674 adverse events were recorded with delandistrogene moxeparvovec and 514 with placebo. There were no deaths, discontinuations or clinically significant complement-mediated adverse events; 7 patients (11.1%) experienced 10 treatment-related serious adverse events.”
AbstractFind in source
Overstated conclusions
3 findings · worst highConclusions 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.
- Efficacy rests on an unvalidated surrogate endpointAssessed
- Treatment effect not shown to be clinically meaningfulAssessed
- Conclusions overstated beyond the evidenceAssessed
5 major claims checked against the paper's own evidence: 1 not fully backed by the presented evidence (unsupported or overstated).
- overstatedReviewers 1, 2Delandistrogene moxeparvovec may reduce the odds of progressing to a TTR of more than 5 s by up to 91%.The claim is based on a post hoc analysis with a wide CI (0.01 to 0.61), and the 'up to 91%' is an overinterpretation of the point estimate; the CI suggests the true reduction could be much smaller.Evidence: Post hoc analysis: odds ratio 0.091 (95% CI 0.01, 0.61).
“This indicates that delandistrogene moxeparvovec may reduce the odds of progressing to a TTR of more than 5 s by up to 91%”
DiscussionFind in source - supportedReviewers 1, 2Delandistrogene moxeparvovec did not lead to a significant improvement in NSAA score at week 52.The primary endpoint analysis shows a non-significant p-value (0.2441) and CI crossing zero, directly supporting the claim.Evidence: Primary endpoint result: LSM difference 0.65 (95% CI -0.45, 1.74; P=0.2441).
“Delandistrogene moxeparvovec did not lead to a significant improvement in NSAA score at week 52.”
AbstractFind in source - supportedReviewers 1, 2Some secondary endpoints numerically favored treatment, although no statistical significance can be claimed.The paper reports several secondary endpoints with CIs that exclude zero (e.g., TTR, 10MWR), but the paper correctly notes that these were not adjusted for multiplicity and no statistical significance is claimed.Evidence: Secondary endpoint results: TTR difference -0.64 (95% CI -1.06, -0.23), 10MWR difference -0.42 (95% CI -0.71, -0.13).
“Some of the secondary endpoints numerically favored treatment, although no statistical significance can be claimed.”
AbstractFind in source - supportedReviewers 1, 2Safety was manageable and consistent with previous delandistrogene moxeparvovec trials.The safety data show no deaths, no discontinuations, and no clinically significant complement-mediated AEs, and the paper compares this to prior trials.Evidence: Safety results: 674 AEs in treated group, 10 TR-SAEs in 7 patients, all resolved.
“Safety was manageable and consistent with previous delandistrogene moxeparvovec trials.”
AbstractFind in source - supportedReviewers 1, 2The pre-specified global statistical test supported the totality of evidence of treatment effect.The global test p-value (0.0044) is reported, supporting the claim that the composite endpoint showed a difference.Evidence: Sensitivity analyses: global statistical test P=0.0044.
The pre-specified global statistical test on a composite of six functional endpoints ... showed a difference ( P = 0.0044) between delandistrogene moxeparvovec and placebo.
Sensitivity analysesreviewer’s wording
Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.
- INADEQUATESurrogate endpointThe primary efficacy claim is based on the NSAA score, which is a functional clinical scale, but the primary endpoint was not met. The paper also reports micro-dystrophin expression as a secondary endpoint, which is a surrogate biomarker. The paper does not provide evidence linking micro-dystrophin expression to clinical outcomes, and target engagement at the tested dose is not established beyond expression levels.
“Secondary efficacy endpoints included mean micro-dystrophin expression at week 12: 34.29% (treated) versus 0.00% (placebo).”
- INADEQUATEEffect sizeThe primary endpoint difference was small (0.65 points on NSAA) and not statistically significant. The micro-dystrophin expression of 34.29% is a fraction of normal and not anchored to clinical meaningfulness. The paper does not provide a minimal clinically important difference for the primary endpoint.
“between-group difference, 0.65; 95% confidence interval (CI), −0.45, 1.74; P = 0.2441”
Data authenticity concerns
1 finding · worst mediumAn 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.
- Other integrity concernAssessed
4 integrity concerns flagged (0 high).
- mediumotherTrial NCT03769116 was first submitted to ClinicalTrials.gov on 2018-12-06, after the registered study start date of 2018-12-05. Retrospective registration means the protocol and outcomes were not on the public record before the study ran, which is what prospective registration exists to establish.
NCT03769116
reviewer’s wording - lowotherThe paper reports that 13.3% of screened patients were excluded due to elevated antibody titers, but the exact number of patients excluded for this reason is not given, making it difficult to verify the percentage.
“Of the 173 patients screened, 13.3% were excluded due to elevated antibody titers to rAAVrh74.”
ResultsFind in source - lowotherThe paper reports a post hoc analysis with an odds ratio of 0.091 (95% CI 0.01, 0.61) for progression to TTR >5s. The wide CI suggests low precision, but the point estimate is plausible.
“3.2% of patients in the delandistrogene moxeparvovec group versus 16.4% of patients in the placebo group (odds ratio = 0.091; 95% CI, 0.01, 0.61)”
Post hoc analysesFind in source
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 work on DMD, current treatments, and early-phase delandistrogene moxeparvovec studies, acknowledging both the unmet need and the promising early results. The rationale for the trial is clearly stated: to assess efficacy and safety in a larger phase 3 setting. Limitations of prior research (e.g., small sample sizes, short follow-up) are implicitly addressed by the trial's design, though not explicitly discussed as limitations of prior work.
“Early-phase clinical studies demonstrated a manageable safety profile for delandistrogene moxeparvovec. In these studies, delandistrogene moxeparvovec micro-dystrophin expression was robust with sarcolemmal localization up to 60 weeks after treatment and demonstrated a sustained functional stabilization through 4 years in four males with DMD”
“Early-phase clinical studies demonstrated a manageable safety profile for delandistrogene moxeparvovec. In these studies, delandistrogene moxeparvovec micro-dystrophin expression was robust with sarcolemmal localization up to 60 weeks after treatment and demonstrated a sustained functional stabilization through 4 years in four males with DMD”
Randomization was performed via interactive response technology with stratification by age and NSAA score. Blinding was comprehensive (patients, caregivers, investigators, site staff) except for the unblinded pharmacist. Inclusion/exclusion criteria are detailed. The modified intent-to-treat population is defined. Power analysis is not explicitly reported in the text, but the protocol was amended to adjust sample size, implying a power calculation was performed. Outlier handling is addressed through pre-specified analysis populations and handling of missing data (e.g., one patient with missing data due to back pain). Controls are appropriate (placebo). Independent replication is not applicable for a single pivotal trial.
“Patients were randomized (1:1 ratio) by interactive response technology to either a single IV administration of commercial process delandistrogene moxeparvovec material (1.33 × 10 14 vector genomes per kilogram (vg/kg), linear standard quantitative polymerase chain reaction (PCR)), or placebo (0.9% sodium chloride solution) through a peripheral limb vein and stratified by age group (≥4 years to <6 years or ≥6 years to <8 years) at randomization and by NSAA total score (≤22 or >22) at screening.”
“All patients, parents/caregivers, investigators and site staff were blinded, except for the unblinded site pharmacist.”
“Version 1 (17 November 2020) to Version 2 (2 August 2021) The primary reasons necessitating updates to the protocol were to add a blinded crossover design, so that patients randomized to placebo in Part 1 of the study had the opportunity to receive delandistrogene moxeparvovec in Part 2, and patients randomized to delandistrogene moxeparvovec in Part 1 received placebo in Part 2 to maintain the blind; to further clarify and refine the inclusion and exclusion criteria as well as stratification factors; to adjust the sample size; and to add a transgene ELISA endpoint.”
“All patients, parents/caregivers, investigators and site staff were blinded, except for the unblinded site pharmacist.”
“A patient must meet all of the following criteria to be eligible to participate in this study: Is male at birth (self-reported), ambulatory and ≥4 years to <8 years of age at the time of randomization.”
Sex is reported (all male at birth) and justified by the X-linked nature of DMD. Age, weight, and health status are reported in Table 1. Demographics include race, ethnicity, and steroid type. Species/strain and housing conditions are not applicable for a human trial.
“Sex is not shown in this table; per inclusion criterion 1, patients must be male at birth to be eligible to participate in this study.”
“Age, mean (s.d.), years | 5.98 (1.06) | 6.08 (1.05) | 6.03 (1.05)”
“Sex is not shown in this table; per inclusion criterion 1, patients must be male at birth to be eligible to participate in this study.”
“Age, mean (s.d.), years | 5.98 (1.06) | 6.08 (1.05) | 6.03 (1.05)”
The paper states the trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and that the protocol and amendments were approved by an institutional review board and ethics committee at each site. Informed consent was obtained from parents/legal guardians, and patient assent when indicated. Regulatory compliance is stated by naming the Declaration of Helsinki and GCP.
“The trial protocol and all amendments were approved by an institutional review board and ethics committee at each site.”
“Informed consent was obtained from parent(s)/legal guardian(s), and patients’ assent was obtained when indicated.”
“The trial protocol and all amendments were approved by an institutional review board and ethics committee at each site.”
“Informed consent was obtained from parent(s)/legal guardian(s), and patients’ assent was obtained when indicated.”
The drug is named with its vector, dose (1.33 × 10^14 vg/kg), and administration route. The placebo is 0.9% sodium chloride. Antibodies used in the western blot are identified with vendor and catalog numbers (e.g., DYS3, Leica Biosystems). Software for image analysis is identified (ImageQuant TL version 8.2). Cell lines and mycoplasma testing are not applicable.
“single-administration intravenous delandistrogene moxeparvovec (1.33 × 10 14 vector genomes per kilogram; n = 63) or placebo ( n = 62)”
“Membranes with transferred proteins were probed using an anti-dystrophin primary antibody (DYS3, 1:20; Leica Biosystems) and then anti-mouse immunoglobulin G-conjugated horseradish peroxidase (Amersham ECL anti-mouse immunoglobulin G peroxidase-linked species-specific whole antibody (from sheep)) (NA931V, 1:1,000; Cytiva).”
“ImageQuant TL version 8.2 software (Cytiva) was used to analyze the bands.”
“single IV administration of commercial process delandistrogene moxeparvovec material (1.33 × 10 14 vector genomes per kilogram (vg/kg), linear standard quantitative polymerase chain reaction (PCR)), or placebo (0.9% sodium chloride solution)”
“Membranes with transferred proteins were probed using an anti-dystrophin primary antibody (DYS3, 1:20; Leica Biosystems) and then anti-mouse immunoglobulin G-conjugated horseradish peroxidase (Amersham ECL anti-mouse immunoglobulin G peroxidase-linked species-specific whole antibody (from sheep)) (NA931V, 1:1,000; Cytiva).”
“ImageQuant TL version 8.2 software (Cytiva) was used to analyze the bands.”
The primary analysis uses a mixed model for repeated measures (implied by LSM and CI), and the global statistical test is described. Effect sizes with 95% CIs are reported for all endpoints. Exact p-values are given for the primary endpoint (P = 0.2441) and the global test (P = 0.0044). Software is not explicitly named for the statistical analysis, but the methods are standard. Data presentation includes forest plots and line graphs with CIs. Mathematical plausibility is not applicable for large-N continuous outcomes.
“between-group difference, 0.65; 95% confidence interval (CI), −0.45, 1.74; P = 0.2441”
“Time to Rise (−0.64 (−1.06, −0.23)), 10-meter Walk/Run (−0.42 (−0.71, −0.13))”
“The between-group difference was not statistically significant (0.65 (s.e. = 0.55) points; 95% CI, −0.45, 1.74; P = 0.2441; Fig. ).”
“The LSM change (95% CI) from baseline to week 52 on the TTR was −0.27 s (−0.56, 0.02) for delandistrogene moxeparvovec versus 0.37 s (0.08, 0.67) for placebo, with a between-group difference of −0.64 s (95% CI, −1.06, −0.23).”
The data availability statement says de-identified patient-level data cannot be disclosed due to confidentiality, but qualified researchers may request access by contacting medinfo@sarepta.com, subject to review. This is a managed-access route but lacks a named platform or committee, making it 'reported_but_inadequate'. Repository deposit and accession numbers are not applicable for patient-level data. Code sharing is not applicable as no bespoke code is mentioned.
“Qualified researchers may request access to the data that support the findings of Part 1 of this study and clinical study documents from Sarepta Therapeutics, Inc. by contacting medinfo@sarepta.com, subject to review by the study sponsors on a case-by-case basis.”
“The datasets presented in this article are not readily available as this study is ongoing, and access to the data is limited to those that support the findings of this study. De-identified patient-level data cannot be disclosed due to confidentiality agreements and the risk of re-identification. Qualified researchers may request access to the data that support the findings of Part 1 of this study and clinical study documents from Sarepta Therapeutics, Inc. by contacting medinfo@sarepta.com, subject to review by the study sponsors on a case-by-case basis.”
Methods are comprehensive. Trial registration is provided (NCT05096221). Limitations are discussed in the Discussion, including the short placebo duration and potential unblinding due to side effects. Conclusions are proportional, acknowledging the primary endpoint was not met. Funding and competing interests are disclosed. A reporting guideline is not explicitly referenced, but the paper follows standard clinical trial reporting.
“ClinicalTrials.gov: NCT05096221 (https://classic.clinicaltrials.gov/ct2/show/NCT05096221)”
“Potential study limitations include the placebo group being limited to 1 year, due to ethical concerns of withholding disease-modifying treatment from patients in need of treatment.”
“Sponsored by Sarepta Therapeutics, Inc. and funded by Sarepta Therapeutics, Inc. and F. Hoffmann-La Roche, Ltd.”
“ClinicalTrials.gov: NCT05096221 (https://classic.clinicaltrials.gov/ct2/show/NCT05096221)”
“Potential study limitations include the placebo group being limited to 1 year, due to ethical concerns of withholding disease-modifying treatment from patients in need of treatment.”
“Sponsored by Sarepta Therapeutics, Inc. and funded by Sarepta Therapeutics, Inc. and F. Hoffmann-La Roche, Ltd.”
Registered (6 IDs: ClinicalTrials.gov). No reporting guideline cited.
Broken references and links
None foundReferences 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.
Checked — nothing surfaced.
Checked 57 references by DOI: 37 verified — 20 no DOI (shown, not verified).
- NO DOIELEVIDYS (delandistrogene moxeparvovec-rokl). Highlights of prescribing informationNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIFDA expands approval of gene therapy for patients with Duchenne muscular dystrophyNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIRegistered Medical Product DirectoryNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIQatar National FormularyNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIPharmacy & Pharmaceutical Products Regulation (PPR)No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIList of registered pharmaceutical manufacturers and productsNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIDrug and Dietary Supplement Price ListNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIThe Israeli Drug RegistryNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIA gene transfer therapy study to evaluate the safety and efficacy of SRP-9001 (delandistrogene moxeparvovec) in participants with Duchenne muscular dystrophy (DMD) (EMBARK)No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIT-cell response to micro-dystrophin in a patient treated with delandistrogene moxeparvovec gene therapy: a case of immune-mediated myositisNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIZOLGENSMA (onasemnogene abeparvovec-xioi). Highlights of prescribing informationNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIA gene transfer therapy study to evaluate the safety and efficacy of delandistrogene moxeparvovec (SRP-9001) following imlifidase infusion in participants with Duchenne muscular dystrophy (DMD) determined to have pre-existing antibodies to recombinant adeno-associated virus serotype (rAAVrh74)No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIQualification opinion on stride velocity 95th centile as a secondary endpoint in Duchenne muscular dystrophy measured by a valid and suitable wearable deviceNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIQualification opinion for stride velocity 95th centile as primary endpoint in studies in ambulatory Duchenne muscular dystrophy studiesNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIA gene transfer therapy study to evaluate the safety and efficacy of SRP-9001 (delandistrogene moxeparvovec) in non-ambulatory and ambulatory participants with Duchenne muscular dystrophy (DMD) (ENVISION)No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIA two-part, open-label systemic gene delivery study to evaluate the safety and expression of RO7494222 (SRP-9001) in subjects under the age of four with Duchenne muscular dystrophy (ENVOL)No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIA gene delivery study to evaluate the safety of and expression from SRP-9001 in Duchenne muscular dystrophy (DMD) (ENDEAVOR)No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIA gene transfer therapy study to evaluate the safety of delandistrogene moxeparvovec (SRP-9001) in participants with Duchenne muscular dystrophy (DMD)No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIA randomized, double-blind, placebo-controlled study of SRP-9001 for Duchenne muscular dystrophy (DMD)No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOICollection of race and ethnicity data in clinical trials and clinical studies for FDA-regulated medical productsNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
2 data/code links checked; 2 live.
- datahttps://classic.clinicaltrials.gov/ct2/show/NCT05096221LIVEHTTP 200Resolves, but the content could not be matched to the paper.
- datahttps://clinicaltrials.gov/ct2/show/NCT05096221LIVEHTTP 200Resolves, but the content could not be matched to the paper.
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, grammar, clarity.
- MINORconsistencyAbstract“10-meter Walk/Run (−0.42 (−0.71, −0.13))”→ Ensure consistent use of en-dash vs hyphen in ranges.Minor formatting inconsistency.
- MINORgrammarDiscussion“the separation on TTR and 10MWR were consistent”→ Change 'were' to 'was' for subject-verb agreement.Grammatical error.
- MINORclarityMethods, Trial design“The random allocation sequence was saved in the interactive response technology system, which automatically assigned treatment based on sequence.”→ Clarify that the sequence was generated and stored, and the system assigned treatment accordingly.Slightly awkward phrasing.
- MINORconsistencyAbstract“least squares mean 2.57 (delandistrogene moxeparvovec) versus 1.92 (placebo) points; between-group difference, 0.65; 95% confidence interval (CI), −0.45, 1.74; P = 0.2441”→ Ensure consistent use of 'least squares mean' vs 'LSM' throughout.Minor inconsistency in terminology.
- MINORclarityResults, Secondary outcomes“The LSM change (95% CI) from baseline to week 52 on the TTR was −0.27 s (−0.56, 0.02) for delandistrogene moxeparvovec versus 0.37 s (0.08, 0.67) for placebo”→ Clarify that negative values indicate improvement for TTR.The sign convention is explained in figure legends but could be clearer in text.
- MINORgrammarDiscussion, paragraph 5“The heterogeneity of disease progression is a challenge when designing DMD clinical trials, specifically trials of short duration .”→ Consider rephrasing for clarity: 'The heterogeneity of disease progression poses a challenge when designing DMD clinical trials, particularly those of short duration.'Minor grammatical improvement.
The published work is methodologically robust and generally well-reported, but an informed reader should weigh the vague data availability statement, the lack of a reported power calculation, and the retrospective registration of a related trial. The paper would benefit from a correction or clarification of the data access mechanism and the statistical software used.
- 1.HIGHdata codeIn the Data Availability section, specify a named data-access committee or platform (e.g., YODA, Vivli) and the conditions and timeframe for access, instead of the vague 'case-by-case basis'.The current statement is vague and does not meet common data-sharing standards, which limits reproducibility.
- 2.HIGHstatisticsIn the Methods, explicitly name the statistical software used (e.g., SAS version 9.4) for the analysis.Naming the software is essential for reproducibility and was flagged by both reviewers.
- 3.HIGHreportingIn the Methods or a separate section, reference the CONSORT reporting guideline and provide the completed checklist as supplementary material.Explicitly following a reporting guideline improves transparency and is expected for clinical trials.
- 4.HIGHrigorIn the Methods, provide the actual power calculation or sample size justification, including the assumed effect size, alpha, and power.The sample size was adjusted during amendments but the power calculation is not reported, which is a key design detail.
- 5.HIGHrigorTemper the claim that delandistrogene moxeparvovec 'may reduce the odds of progressing to a TTR of more than 5 s by up to 91%' to reflect the wide confidence interval (0.01 to 0.61) and the post hoc nature of the analysis.The claim overstates the evidence; the CI suggests the true reduction could be much smaller.
- 6.MEDIUMreportingIn the Introduction, explicitly discuss limitations of prior early-phase studies (e.g., small sample sizes, lack of control) to strengthen the scientific premise.Both reviewers noted that limitations of prior work are only implicitly addressed.
- 7.MEDIUMreportingClarify the handling of missing data for secondary endpoints, such as the reasons for missing SV95C data and the imputation methods used.Transparent missing-data handling is important for the validity of secondary analyses.
- 8.MEDIUMcopyeditFix the subject-verb agreement in the Discussion: change 'the separation on TTR and 10MWR were consistent' to 'was consistent'.Grammatical error that should be corrected for professional presentation.
- 9.MEDIUMcopyeditClarify the sign convention for TTR in the Results text, noting that negative values indicate improvement, to avoid misinterpretation.The sign convention is only explained in figure legends, which may confuse readers.
- 10.LOWcopyeditEnsure consistent use of en-dash vs hyphen in ranges (e.g., '−0.42 (−0.71, −0.13)') throughout the manuscript.Minor formatting inconsistency that affects polish.
- 11.LOWcopyeditEnsure consistent use of 'least squares mean' vs 'LSM' throughout the manuscript.Minor terminology inconsistency.
- 12.LOWcopyeditRephrase the sentence in the Discussion about heterogeneity of disease progression for clarity.Minor grammatical improvement suggested by the copyedit pass.
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.