Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

AAV gene therapy for Duchenne muscular dystrophy: the EMBARK phase 3 randomized trial.

Name: Kaimen Rigor review — AAV gene therapy for Duchenne muscular dystrophy: the EMBARK phase 3 randomized trial.
Item: AAV gene therapy for Duchenne muscular dystrophy: the EMBARK phase 3 randomized trial.
Rating: 59
Author: Alpha1

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

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Kaimen Rigor review — 1★ (Critical), 0 critical, 5 high issues for “AAV gene therapy for Duchenne muscular dystrophy: the EMBARK phase 3 randomized trial.”

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This rigor review was examined and confirmed by Alpha1 Editorial · August 16, 2026

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AAV gene therapy for Duchenne muscular dystrophy: the EMBARK phase 3 randomized trial.

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DOI

10.1038/s41591-024-03304-z

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

AAV gene therapy for Duchenne muscular dystrophy: the EMBARK phase 3 randomized trial.

Paper source

AAV gene therapy for Duchenne muscular dystrophy: the EMBARK phase 3 randomized trial.

Read full text (PMC)

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Links back to this Kaimen Rigor review.

Alpha1 Editorial

This rigor review was examined and confirmed by Alpha1 Editorial · August 16, 2026

Kaimen Rigor review

Kaimen Rigor reviewed

1 / 5

Critical — serious problems across many checks

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

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★

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Not verified in this report

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.

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
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).”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
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”
Find in source
03Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
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
mediumOverreachreviewer-assessedFull detail
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
mediumAuthenticityreviewer-assessedFull detail
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

Findings by category

201ArithmeticNumerical inconsistencies 302OverreachOverstated conclusions 103AuthenticityData authenticity concerns 104DisclosureReporting gaps 05AvailabilityNone found 06Copyedit6 minor suggestions

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 medium

Values 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.

Overstated conclusions

3 findings · worst high

Conclusions 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).

Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.

Data authenticity concerns

1 finding · worst medium

An 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).

Reporting gaps

1 finding · worst medium

Required 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

Eight Dimensions7 pass · 1 warn

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.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedINADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific premise by citing prior research on DMD pathology, existing treatments, and early-phase gene therapy studies, and logically links this to the trial's objectives.

Evidence

paraphrase[Introduction, paragraph 1]

“Duchenne muscular dystrophy (DMD) is caused by pathogenic variants in the X-linked DMD gene, leading to an absence of functional dystrophin and continuous muscle damage, beginning from birth.”

“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”

Introduction ¶3Find in source

paraphrase[Introduction]

“The introduction does not explicitly discuss limitations of prior studies, but the larger phase 3 design with a placebo control addresses the need for more definitive evidence.”

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise by citing prior research on DMD, the need for therapies, and early-phase studies of delandistrogene moxeparvovec, with a logical rationale linking the premise to the trial objectives.

Evidence

paraphrase[Introduction, paragraph 1]

“Duchenne muscular dystrophy (DMD) is caused by pathogenic variants in the X-linked DMD gene, leading to an absence of functional dystrophin and continuous muscle damage, beginning from birth.”

Introduction ¶3Find in source

paraphrase[Introduction, paragraph 3]

“Here we report results from Part 1 (52 weeks) of EMBARK ... a large, phase 3, two-part, multinational, randomized, double-blind, placebo-controlled trial assessing delandistrogene moxeparvovec safety and efficacy in patients with DMD aged ≥4 years to <8 years.”

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.

Sub-criteria

controlsADEQUATE

power analysisINADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The trial design is rigorous: randomized, double-blind, placebo-controlled, with stratification, pre-specified endpoints, and a clear analysis population. Sample size was adjusted during protocol amendments.

Evidence

“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.”

MethodsFind in source

“All patients, parents/caregivers, investigators and site staff were blinded, except for the unblinded site pharmacist.”

MethodsFind in source

“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.”

MethodsFind in source

PASSReviewer 2· 95% conf

The trial design is rigorous: randomized, double-blind, placebo-controlled, with stratification, pre-specified endpoints, and a clear analysis population. Randomization method, blinding, and inclusion/exclusion criteria are well described.

Evidence

paraphrase[Methods, Trial design]

“Patients were randomized (1:1 ratio) by interactive response technology to either a single IV administration of commercial process delandistrogene moxeparvovec material ... or placebo ... and stratified by age group ... and by NSAA total score ... at screening.”

“All patients, parents/caregivers, investigators and site staff were blinded, except for the unblinded site pharmacist.”

MethodsFind in source

“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.”

MethodsFind in source

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.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedADEQUATE

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Biological variables are well reported: sex (all male, justified by disease), age, weight, and detailed demographics including race, ethnicity, and steroid use. Species/strain and housing are not applicable for a human trial.

Evidence

“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.”

Table 1Find in source

“Age, mean (s.d.), years | 5.98 (1.06) | 6.08 (1.05) | 6.03 (1.05)”

Table 1Find in source

paraphrase[Table 1]

“Race group, n (%) | Asian | 8 (12.7) | 11 (17.7) | 19 (15.2)”

PASSReviewer 2· 90% conf

Biological variables are well reported: sex (all male, justified by disease etiology), age, weight, and health status are provided in baseline characteristics. Demographics including race and ethnicity are reported.

Evidence

“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.”

Table 1Find in source

“Age, mean (s.d.), years | 5.98 (1.06) | 6.08 (1.05) | 6.03 (1.05)”

Table 1Find in source

paraphrase[Table 1]

“Race group, n (%) | Asian | 8 (12.7) | 11 (17.7) | 19 (15.2)”

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.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approvals are adequately reported: the trial was conducted per Declaration of Helsinki and GCP, approved by IRBs/ethics committees at each site, and informed consent/assent was obtained.

Evidence

“The trial protocol and all amendments were approved by an institutional review board and ethics committee at each site.”

MethodsFind in source

“Informed consent was obtained from parent(s)/legal guardian(s), and patients’ assent was obtained when indicated.”

MethodsFind in source

paraphrase[Methods, Trial oversight]

“This trial was conducted in accordance with the provisions of the Declaration of Helsinki and Good Clinical Practice guidelines.”

PASSReviewer 2· 95% conf

Ethical approvals are adequately reported: the trial was conducted in accordance with the Declaration of Helsinki and GCP, approved by an institutional review board and ethics committee at each site, and informed consent was obtained from parents/legal guardians.

Evidence

“The trial protocol and all amendments were approved by an institutional review board and ethics committee at each site.”

MethodsFind in source

“Informed consent was obtained from parent(s)/legal guardian(s), and patients’ assent was obtained when indicated.”

MethodsFind in source

paraphrase[Methods, Trial oversight]

“This trial was conducted in accordance with the provisions of the Declaration of Helsinki and Good Clinical Practice guidelines.”

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.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedADEQUATE

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational product (delandistrogene moxeparvovec) is identified with dose and regimen, and the placebo is described. Antibodies, cell lines, and mycoplasma testing are not applicable. Software used for analysis is identified.

Evidence

“single-administration intravenous delandistrogene moxeparvovec (1.33 × 10 14 vector genomes per kilogram; n = 63) or placebo ( n = 62)”

AbstractFind in source

“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).”

MethodsFind in source

“ImageQuant TL version 8.2 software (Cytiva) was used to analyze the bands.”

MethodsFind in source

PASSReviewer 2· 90% conf

The investigational product (delandistrogene moxeparvovec) is identified with dose and regimen, and the placebo is described. Antibodies and reagents used in the western blot analysis are identified with vendors and catalog numbers.

Evidence

“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)”

MethodsFind in source

“ImageQuant TL version 8.2 software (Cytiva) was used to analyze the bands.”

MethodsFind in source

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.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedNOT REPORTED

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

Statistical methods are appropriate for a clinical trial: primary and secondary endpoints are analyzed with mixed models, p-values are exact, and effect sizes with CIs are reported. Assumptions are handled by design, and software is identified.

Evidence

“between-group difference, 0.65; 95% confidence interval (CI), −0.45, 1.74; P = 0.2441”

AbstractFind in source

“Time to Rise (−0.64 (−1.06, −0.23)), 10-meter Walk/Run (−0.42 (−0.71, −0.13))”

AbstractFind in source

absence[Methods]

Statistical software is not explicitly named.

PASSReviewer 2· 90% conf

Statistical methods are appropriate and well-reported: tests are named, effect sizes with confidence intervals are provided, and the analysis uses a pre-specified model. Exact p-values are reported for the primary endpoint and global test.

Evidence

“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. ).”

ResultsFind in source

“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).”

ResultsFind in source

paraphrase[Results, Sensitivity analyses]

“The pre-specified global statistical test on a composite of six functional endpoints ... showed a difference ( P = 0.0044) between delandistrogene moxeparvovec and placebo.”

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.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementINADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 90% conf

A data availability statement is present but vague: it states data are not readily available and requests are reviewed case-by-case, but does not name a specific platform or committee. No code is shared.

Evidence

“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.”

Data availabilityFind in source

WARNReviewer 2· 90% conf

A data availability statement is present but vague: it states data are not readily available and requests are subject to sponsor review, without a clear mechanism or timeframe. No code is shared.

Evidence

“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.”

Data availabilityFind in source

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.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineNOT REPORTED

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The trial is registered (NCT05096221), methods are detailed, all pre-specified outcomes are reported, limitations are discussed, conclusions are proportional, and funding/COI are disclosed. No reporting guideline is explicitly mentioned.

Evidence

“ClinicalTrials.gov: NCT05096221 (https://classic.clinicaltrials.gov/ct2/show/NCT05096221)”

AbstractFind in source

“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.”

DiscussionFind in source

“Sponsored by Sarepta Therapeutics, Inc. and funded by Sarepta Therapeutics, Inc. and F. Hoffmann-La Roche, Ltd.”

FundingFind in source

PASSReviewer 2· 95% conf

The manuscript is transparent: methods are detailed, the trial is registered, limitations are discussed, conclusions are proportional, and funding/COI are disclosed. A reporting guideline is not explicitly mentioned but the paper follows CONSORT-like structure.

Evidence

“ClinicalTrials.gov: NCT05096221 (https://classic.clinicaltrials.gov/ct2/show/NCT05096221)”

AbstractFind in source

“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.”

Discussion ¶8Find in source

“Sponsored by Sarepta Therapeutics, Inc. and funded by Sarepta Therapeutics, Inc. and F. Hoffmann-La Roche, Ltd.”

FundingFind in source

Registered (6 IDs: ClinicalTrials.gov). No reporting guideline cited.

Broken references and links

None found

References 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).

2 data/code links checked; 2 live.

Copyediting

6 minor

Wording, 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.

Kaimen Rigor Action ItemsFinal pass before journal submission

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 code
In 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.
HIGHstatistics
In 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.
HIGHreporting
In 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.
HIGHrigor
In 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.
HIGHrigor
Temper 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.
MEDIUMreporting
In 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.
MEDIUMreporting
Clarify 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.
MEDIUMcopyedit
Fix 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.
MEDIUMcopyedit
Clarify 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.
LOWcopyedit
Ensure 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.
LOWcopyedit
Ensure consistent use of 'least squares mean' vs 'LSM' throughout the manuscript.
Minor terminology inconsistency.
12.
LOWcopyedit
Rephrase the sentence in the Discussion about heterogeneity of disease progression for clarity.
Minor grammatical improvement suggested by the copyedit pass.

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AAV gene therapy for Duchenne muscular dystrophy: the EMBARK phase 3 randomized trial.

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DOI

10.1038/s41591-024-03304-z

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Issued Aug 16, 2026Engine 7.39.0

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Kaimen Rigor review

Kaimen Rigor reviewed

1 / 5

Critical — serious problems across many checks

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

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★

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Not verified in this report

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.

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
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).”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
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”
Find in source
03Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
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
mediumOverreachreviewer-assessedFull detail
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
mediumAuthenticityreviewer-assessedFull detail
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

Findings by category

201ArithmeticNumerical inconsistencies 302OverreachOverstated conclusions 103AuthenticityData authenticity concerns 104DisclosureReporting gaps 05AvailabilityNone found 06Copyedit6 minor suggestions

Numerical inconsistencies

2 findings · worst medium

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.

Overstated conclusions

3 findings · worst high

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).

Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.

Data authenticity concerns

1 finding · worst medium

Other integrity concernAssessed

4 integrity concerns flagged (0 high).

Reporting gaps

1 finding · worst medium

Data/code availability incompleteAssessed

Eight Dimensions7 pass · 1 warn

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedINADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Evidence

paraphrase[Introduction, paragraph 1]

“Duchenne muscular dystrophy (DMD) is caused by pathogenic variants in the X-linked DMD gene, leading to an absence of functional dystrophin and continuous muscle damage, beginning from birth.”

Introduction ¶3Find in source

paraphrase[Introduction]

“The introduction does not explicitly discuss limitations of prior studies, but the larger phase 3 design with a placebo control addresses the need for more definitive evidence.”

PASSReviewer 2· 90% conf

Evidence

paraphrase[Introduction, paragraph 1]

“Duchenne muscular dystrophy (DMD) is caused by pathogenic variants in the X-linked DMD gene, leading to an absence of functional dystrophin and continuous muscle damage, beginning from birth.”

Introduction ¶3Find in source

paraphrase[Introduction, paragraph 3]

Sub-criteria

controlsADEQUATE

power analysisINADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Evidence

MethodsFind in source

“All patients, parents/caregivers, investigators and site staff were blinded, except for the unblinded site pharmacist.”

MethodsFind in source

PASSReviewer 2· 95% conf

Evidence

paraphrase[Methods, Trial design]

“All patients, parents/caregivers, investigators and site staff were blinded, except for the unblinded site pharmacist.”

MethodsFind in source

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedADEQUATE

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Evidence

“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.”

Table 1Find in source

“Age, mean (s.d.), years | 5.98 (1.06) | 6.08 (1.05) | 6.03 (1.05)”

Table 1Find in source

paraphrase[Table 1]

“Race group, n (%) | Asian | 8 (12.7) | 11 (17.7) | 19 (15.2)”

PASSReviewer 2· 90% conf

Evidence

“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.”

Table 1Find in source

“Age, mean (s.d.), years | 5.98 (1.06) | 6.08 (1.05) | 6.03 (1.05)”

Table 1Find in source

paraphrase[Table 1]

“Race group, n (%) | Asian | 8 (12.7) | 11 (17.7) | 19 (15.2)”

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approvals are adequately reported: the trial was conducted per Declaration of Helsinki and GCP, approved by IRBs/ethics committees at each site, and informed consent/assent was obtained.

Evidence

“The trial protocol and all amendments were approved by an institutional review board and ethics committee at each site.”

MethodsFind in source

“Informed consent was obtained from parent(s)/legal guardian(s), and patients’ assent was obtained when indicated.”

MethodsFind in source

paraphrase[Methods, Trial oversight]

“This trial was conducted in accordance with the provisions of the Declaration of Helsinki and Good Clinical Practice guidelines.”

PASSReviewer 2· 95% conf

Evidence

“The trial protocol and all amendments were approved by an institutional review board and ethics committee at each site.”

MethodsFind in source

“Informed consent was obtained from parent(s)/legal guardian(s), and patients’ assent was obtained when indicated.”

MethodsFind in source

paraphrase[Methods, Trial oversight]

“This trial was conducted in accordance with the provisions of the Declaration of Helsinki and Good Clinical Practice guidelines.”

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedADEQUATE

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Evidence

“single-administration intravenous delandistrogene moxeparvovec (1.33 × 10 14 vector genomes per kilogram; n = 63) or placebo ( n = 62)”

AbstractFind in source

MethodsFind in source

“ImageQuant TL version 8.2 software (Cytiva) was used to analyze the bands.”

MethodsFind in source

PASSReviewer 2· 90% conf

Evidence

MethodsFind in source

“ImageQuant TL version 8.2 software (Cytiva) was used to analyze the bands.”

MethodsFind in source

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedNOT REPORTED

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

Evidence

“between-group difference, 0.65; 95% confidence interval (CI), −0.45, 1.74; P = 0.2441”

AbstractFind in source

“Time to Rise (−0.64 (−1.06, −0.23)), 10-meter Walk/Run (−0.42 (−0.71, −0.13))”

AbstractFind in source

absence[Methods]

Statistical software is not explicitly named.

PASSReviewer 2· 90% conf

Evidence

“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. ).”

ResultsFind in source

paraphrase[Results, Sensitivity analyses]

“The pre-specified global statistical test on a composite of six functional endpoints ... showed a difference ( P = 0.0044) between delandistrogene moxeparvovec and placebo.”

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementINADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 90% conf

Evidence

Data availabilityFind in source

WARNReviewer 2· 90% conf

A data availability statement is present but vague: it states data are not readily available and requests are subject to sponsor review, without a clear mechanism or timeframe. No code is shared.

Evidence

Data availabilityFind in source

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineNOT REPORTED

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Evidence

“ClinicalTrials.gov: NCT05096221 (https://classic.clinicaltrials.gov/ct2/show/NCT05096221)”

AbstractFind in source

“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.”

DiscussionFind in source

“Sponsored by Sarepta Therapeutics, Inc. and funded by Sarepta Therapeutics, Inc. and F. Hoffmann-La Roche, Ltd.”

FundingFind in source

PASSReviewer 2· 95% conf

Evidence

“ClinicalTrials.gov: NCT05096221 (https://classic.clinicaltrials.gov/ct2/show/NCT05096221)”

AbstractFind in source

“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.”

Discussion ¶8Find in source

“Sponsored by Sarepta Therapeutics, Inc. and funded by Sarepta Therapeutics, Inc. and F. Hoffmann-La Roche, Ltd.”

FundingFind in source

Registered (6 IDs: ClinicalTrials.gov). No reporting guideline cited.

Broken references and links

None found

References 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).

2 data/code links checked; 2 live.

Copyediting

6 minor

Wording, 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.

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHdata code
In 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.
HIGHstatistics
In 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.
HIGHreporting
In 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.
HIGHrigor
In 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.
HIGHrigor
Temper 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.
MEDIUMreporting
In 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.
MEDIUMreporting
Clarify 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.
MEDIUMcopyedit
Fix 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.
MEDIUMcopyedit
Clarify 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.
LOWcopyedit
Ensure 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.
LOWcopyedit
Ensure consistent use of 'least squares mean' vs 'LSM' throughout the manuscript.
Minor terminology inconsistency.
12.
LOWcopyedit
Rephrase the sentence in the Discussion about heterogeneity of disease progression for clarity.
Minor grammatical improvement suggested by the copyedit pass.

Full text (85,266 chars · analyzed ~88%, head + tail)Analyzed: Aug 16, 2026