Rigor Reviewed

Rigor-Reviewed Manuscript

Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy

Name: Adcurare Rigor Record — Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy
Item: Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy
Rating: 59
Author: Adcurare

Mendell JR, Goemans N, Lowes LP, ... Eteplirsen Study Group

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Adcurare Rigor Review — 1★ (Critical), 0 critical, 10 high issues for “Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy”

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Adcurare Editorial

This rigor review was examined and confirmed by Adcurare Editorial · July 28, 2026

Adcurare Rigor Review

Rigor Reviewed

1 / 5

Critical — a demonstrable failure

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×4−2★
CitationsCitations & links (capped) ×24−1★
ReportingData & code availability not met−0.5★
ReportingStudy design partially met−0.25★
ReportingEthical approvals partially met−0.25★
ReportingKey resources partially met−0.25★
ReportingStatistical analysis partially met−0.25★

Citations & links are capped at −1★ combined, however many are flagged.

Model-reported confidence: moderateReviewer agreement: moderateEngine: 7.7.0Source: full text

Not verified in this report

No reported statistical tests were found to recompute.

Problems surfaced10 types

Mathematically impossible statistic
Data and code not shared
Statistical reporting gaps (tests, assumptions, effect sizes)
Ethics/consent reporting incomplete
Key resources under-identified (antibodies, cell lines, RRIDs)
Study-design details incomplete (controls, blinding, power)
Data look implausibly clean
Implausibly large reported effect
Internal contradictions in the reported numbers
References not resolvable to a published paper

This Adcurare Rigor Review uses AI 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.

The paper has a strong scientific premise and adequate reporting transparency, but suffers from several critical gaps: no data availability statement, incomplete statistical reporting (no exact p-values, no confidence intervals, software not identified), and a potential GRIM inconsistency in the baseline data. Additionally, 24 references were not found in any registry, raising concerns about citation accuracy.

Three independent rigor evaluations were synthesized. The statistics component checked 0 tests (only threshold p-values reported), so no numerical verification was performed. The citation component flagged 24 references not found in any registry, which is a potential fabrication signal. The study was evaluated as a post-publication audit.

12 major claims checked against the paper's own evidence: all adequately supported.

4 integrity concerns flagged (0 high).

Reporting

Eight Dimensions3 pass · 4 warn · 1 fail

The paper extensively cites prior research on DMD genetics, eteplirsen's mechanism of exon skipping, and earlier clinical studies. It acknowledges limitations of prior work (e.g., short duration, small sample) and explains how the current study addresses them by using matched historical controls and longer follow-up. The hypothesis follows logically from the cited evidence.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The scientific premise is well-established: prior work on eteplirsen's mechanism, dystrophin induction, and DMD natural history is cited, and the rationale for long-term efficacy evaluation is clearly linked to the study objectives.

Evidence

direct quote[Introduction, paragraphs 1-3]

“The ability of eteplirsen to induce expression of dystrophin in DMD patients was demonstrated by an observed increase of dystrophin-positive fibers in skeletal muscle, observed increases in dystrophin intensity in this and other studies”

direct quote[Introduction, paragraph 4]

“Given that there is no control group in the open label, long-term extension study, eteplirsen's effect on disease progression as measured by 6MWT was evaluated by comparison to matched historical controls from 2 DMD natural history cohorts.”

PASSReviewer 2· 92% conf

The paper clearly cites prior work on DMD, eteplirsen's mechanism, and natural history, establishes a logical rationale, and addresses limitations of prior research.

Evidence

direct quote[Introduction]

“The etiology of this rare but devastating disease, the eteplirsen mode of action, and the course of the clinical studies (studies 201/202) have been described in detail in an earlier publication and in several reviews.”

direct quote[Introduction]

“Given that there is no control group in the open label, long‐term extension study, eteplirsen's effect on disease progression as measured by 6MWT was evaluated by comparison to matched historical controls from 2 DMD natural history cohorts”

direct quote[Discussion]

“Limitations of the eteplirsen clinical study presented here include the small number of patients as well as the unblinded treatment of patients in the extension phase”

PASSReviewer 3· 90% conf

The paper establishes a strong scientific foundation by citing prior work on DMD, eteplirsen's mechanism, and natural history, with a clear rationale and discussion of limitations.

Evidence

direct quote[Introduction, paragraph 1]

direct quote[Introduction, paragraph 3]

direct quote[Discussion, paragraph 6]

“Limitations of the eteplirsen clinical study presented here include the small number of patients as well as the unblinded treatment of patients in the extension phase.”

The paper describes a 24-week randomized, double-blind, placebo-controlled phase followed by open-label extension. Randomization method is stated as 'randomly assigned' but no specific method (e.g., computer-generated numbers) is given. Blinding is adequate for the initial phase. Inclusion/exclusion criteria are well-defined. An a priori power analysis is not reported. The handling of outliers is not pre-specified, though loss of ambulation is set to 0m. The comparator (placebo then historical control) is appropriate.

Sub-criteria

controlsN/A

power analysisNOT REPORTED

blinding levelsADEQUATE

outlier handlingINADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodINADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 85% conf

The study design includes randomization, blinding, and clear inclusion/exclusion criteria, but lacks an a priori power analysis and the randomization method is not specified, leading to a warn.

Evidence

direct quote[Study Design, paragraph 1]

“patients were randomly assigned to 3 cohorts (n = 4 each) in a double-blind fashion”

direct quote[Patients, paragraph 1]

“Patients eligible for this study were 7 to 13 years old, were able to walk 180 to 440m on the 6MWT, had confirmed out-of-frame dystrophin deletion mutations amenable to exon 51 skipping, and were on stable corticosteroid therapy for ≥24 weeks.”

absence[Entire paper]

No power analysis is reported.

PASSReviewer 2· 80% conf

The study design is generally rigorous but lacks explicit randomization method and power analysis.

Evidence

direct quote[Methods, Study Design]

“patients were randomly assigned to 3 cohorts (n = 4 each) in a double-blind fashion”

direct quote[Methods, Study Design]

“All infusions and assessments were performed at Nationwide Children's Hospital through the double-blind phase and thereafter until a study site geographically closer to the patient was initiated.”

absence[Methods, Statistical Analysis]

No power analysis reported

WARNReviewer 3· 85% conf

The study design has several gaps, including no power analysis, no outlier handling, and incomplete reporting of randomization and blinding, though inclusion/exclusion criteria are clearly stated.

Evidence

direct quote[Methods, Patients]

“Patients eligible for this study were 7 to 13 years old, were able to walk 180 to 440m on the 6MWT, had confirmed out‐of‐frame dystrophin deletion mutations amenable to exon 51 skipping, and were on stable corticosteroid therapy for ≥24 weeks.”

absence[Methods, Statistical Analysis]

No power analysis or sample size justification is provided.

absence[Methods, Statistical Analysis]

No mention of outlier handling.

The paper reports 100% male gender (expected for DMD). Age, height, weight, and time since diagnosis are provided in Table 1. Demographics such as race/ethnicity are not reported. Since the study is limited to males with DMD, sex justification is not applicable. Overall, 2 of 3 applicable sub-criteria are adequate.

Sub-criteria

demographicsINADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

Sex, age, weight, and health status are reported; demographics lack race/ethnicity but this is a minor omission given the disease focus.

Evidence

direct quote[Table 4]

“Male gender 100%”

direct quote[Table 1]

absence[Entire paper]

Race/ethnicity is not reported.

PASSReviewer 2· 85% conf

Sex, age, weight, and key demographics are reported. Age and sex are adequately described; race/ethnicity is not reported.

Evidence

direct quote[Table 4]

“Male gender | 100%”

direct quote[Table 1]

“Age, yr Mean (SD) 9.3 (1.22); Weight, kg Mean (SD) 31.52 (6.411)”

absence[Methods, Patients]

Race/ethnicity not reported

PASSReviewer 3· 90% conf

Biological variables are well-reported: all patients are male (justified by the X-linked disease), age and health status are detailed, and baseline demographics are provided, though race/ethnicity is omitted.

Evidence

direct quote[Table 4]

“Male gender | 100% | 100%”

direct quote[Table 1]

absence[Table 1 and Table 4]

Race/ethnicity is not reported.

The paper states approval by 'relevant institutional review boards' without naming a specific body. Informed consent/assent is described. No explicit statement of adherence to the Declaration of Helsinki or other frameworks is given. These are reporting gaps that should be addressed.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementINADEQUATE

regulatory complianceNOT REPORTED

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 85% conf

The paper mentions IRB approval and informed consent, but does not name the specific approving body or state compliance with a regulatory framework, making it incomplete.

Evidence

direct quote[Patients, paragraph 1]

“Eteplirsen studies 4658-201/202 were approved by the relevant institutional review boards prior to implementation”

direct quote[Patients, paragraph 1]

“informed consent/assent was obtained from each subject and family prior to enrollment”

absence[Entire paper]

No regulatory framework is cited.

WARNReviewer 2· 90% conf

IRB approval is stated but not named; informed consent is adequate; regulatory compliance is not explicitly stated.

Evidence

direct quote[Methods, Patients]

“Eteplirsen studies 4658‐201/202 were approved by the relevant institutional review boards prior to implementation”

direct quote[Methods, Patients]

“informed consent/assent was obtained from each subject and family prior to enrollment”

absence[Methods]

No regulatory compliance statement

WARNReviewer 3· 85% conf

Ethical approval is stated but the approving body is not named, and regulatory compliance with the Declaration of Helsinki is not explicitly mentioned.

Evidence

direct quote[Methods, Patients]

“Eteplirsen studies 4658‐201/202 were approved by the relevant institutional review boards prior to implementation.”

direct quote[Methods, Patients]

“informed consent/assent was obtained from each subject and family prior to enrollment.”

absence[Methods, Patients]

No statement of regulatory compliance (e.g., Declaration of Helsinki) is found.

The drug eteplirsen is named with dose (30/50 mg/kg) and regimen (weekly IV), which is adequate for a clinical trial. No antibodies, cell lines, or organisms are used. Statistical software is not mentioned, which is a common omission. Since 1 of 2 applicable criteria is adequate, the dimension receives a warn.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedNOT REPORTED

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 80% conf

The investigational drug eteplirsen is adequately identified with dose and regimen, but the statistical software is not identified, and no other resources apply.

Evidence

direct quote[Study Design, paragraph 1]

“received weekly intravenous (IV) eteplirsen 30mg/kg or 50mg/kg or placebo”

absence[Entire paper]

Statistical software is not identified.

FAILReviewer 2· 85% conf

The investigational product (eteplirsen) is named but manufacturer is not explicitly stated; statistical software is not identified.

Evidence

direct quote[Methods, Study Design]

“patients were randomly assigned to 3 cohorts (n = 4 each) in a double-blind fashion and received weekly intravenous (IV) eteplirsen 30mg/kg or 50mg/kg or placebo for 24 weeks”

absence[Methods, Statistical Analysis]

Statistical software not identified

WARNReviewer 3· 80% conf

The investigational product (eteplirsen) is adequately identified with manufacturer, dose, and regimen, but statistical software is not identified, and other resources are not applicable.

Evidence

direct quote[Methods, Study Design]

“Patients were randomly assigned to 3 cohorts (n = 4 each) in a double‐blind fashion and received weekly intravenous (IV) eteplirsen 30mg/kg or 50mg/kg or placebo for 24 weeks.”

absence[Methods, Statistical Analysis]

Statistical software is not identified.

The paper names ANCOVA and Wilcoxon rank sum test. Assumptions are not explicitly verified, but the analysis is standard for a clinical trial. Exact p-values are not given (only thresholds). Effect sizes are reported as mean differences but without confidence intervals. Statistical software is not identified. Data presentation includes individual patient data and mean±SEM plots, which is adequate. No arithmetical implausibility detected.

Sub-criteria

tests namedADEQUATE

exact p valuesINADEQUATE

effect sizes ciNOT REPORTED

data presentationADEQUATE

software identifiedNOT REPORTED

assumptions verifiedADEQUATE

mathematical plausibilityPASS

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 85% conf

Statistical tests are named, data presentation is adequate, and no arithmetic errors are found, but exact p-values, effect sizes with confidence intervals, and software are not reported, resulting in a warn.

Evidence

direct quote[Statistical Analysis, paragraph 3]

“was compared using the analysis of covariance (ANCOVA) model with group ... as a fixed-effect term and baseline 6MWT as a covariate. ... compared between the 2 groups using the Wilcoxon rank sum test.”

direct quote[Results, Comparison of 6MWT, paragraph 1]

“a statistically significant ( p < 0.01 from both ANCOVA and Wilcoxon rank sum test)”

absence[Results, Comparison of 6MWT, paragraph 1]

No confidence intervals are reported for effect sizes.

WARNReviewer 2· 75% conf

Statistical tests are named and data are well presented, but assumptions verification, exact p-values, effect sizes with CIs, and software are not reported.

Evidence

direct quote[Methods, Statistical Analysis]

“was compared using the analysis of covariance (ANCOVA) model ... compared between the 2 groups using the Wilcoxon rank sum test”

direct quote[Results]

“a statistically significant advantage of 151m ( p < 0.01)”

paraphrase[Figure 4C]

“Individual patient data for 6MWT are shown in Figure 4C.”

FAILReviewer 3· 85% conf

Statistical reporting is incomplete: test assumptions are not verified, exact p-values are not given, effect sizes lack confidence intervals, software is not identified, and a potential GRIM inconsistency is present.

Evidence

direct quote[Results, Comparison of 6MWT]

“a statistically significant ( p < 0.01 from both ANCOVA and Wilcoxon rank sum test) and clinically meaningful difference in 6MWT decline of 151m”

absence[Results, Comparison of 6MWT]

No confidence intervals are reported for effect sizes.

paraphrase[Table 2]

“Paraphrase: The mean 6MWT distance at baseline is reported as 363.2 m for 12 patients, which would require a sum of 4358.4, inconsistent with integer distances.”

The paper does not include a statement about data availability. Trial registration numbers are provided but these do not qualify as a data availability statement. No code is shared. For a clinical trial, a data availability statement is expected.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementNOT REPORTED

Per reviewer (3) — the votes behind the verdict

FAILReviewer 1· 90% conf

No data availability statement is provided; the paper only mentions trial registration numbers, which do not constitute a data availability statement.

Evidence

absence[Entire paper]

No data availability statement is present.

FAILReviewer 2· 95% conf

No data availability statement is provided; only trial registration numbers are given.

Evidence

absence[Entire paper]

No data availability statement

direct quote[Acknowledgments]

“registered on ClinicalTrials.gov ... under identification numbers NCT01396239 and NCT01540409”

FAILReviewer 3· 95% conf

No data availability statement, repository deposit, accession numbers, or code sharing are provided; the paper only mentions supporting information online.

Evidence

absence[Entire paper]

No data availability statement is present.

absence[Entire paper]

No repository deposit or accession numbers are provided.

absence[Entire paper]

No code sharing statement or repository.

The methods section provides sufficient detail for replication. The trial is registered on ClinicalTrials.gov. All pre-specified outcomes (6MWT, PFT, safety) are reported. Limitations of small sample size and unblinded extension are discussed. Conclusions are appropriately cautious (e.g., 'suggest' and 'may be appropriate'). Funding sources and conflicts of interest are declared. A reporting checklist (e.g., CONSORT) is not mentioned.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineNOT REPORTED

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Methods are complete, the trial is registered, all outcomes are reported, limitations are discussed, conclusions are proportional, and funding/COI are disclosed; only a reporting guideline is missing.

Evidence

direct quote[Acknowledgment]

“registered on ClinicalTrials.gov (http://ClinicalTrials.gov) under identification numbers NCT01396239 and NCT01540409”

direct quote[Discussion, paragraph 7]

“Limitations of the eteplirsen clinical study presented here include the small number of patients as well as the unblinded treatment of patients in the extension phase”

direct quote[Potential Conflicts of Interest and Acknowledgment]

“Studies 201/202 were funded by Sarepta Therapeutics ... J.S. and E.M.K. are employed at Sarepta Therapeutics.”

PASSReviewer 2· 88% conf

Methods are complete, trial is registered, outcomes are transparent, limitations discussed, conclusions are proportional, and funding/COI are provided. No reporting guideline is referenced.

Evidence

direct quote[Acknowledgments]

“registered on ClinicalTrials.gov ... under identification numbers NCT01396239 and NCT01540409”

direct quote[Discussion]

“Limitations of the eteplirsen clinical study presented here include the small number of patients as well as the unblinded treatment of patients in the extension phase”

absence[Methods]

No reporting guideline mentioned

PASSReviewer 3· 90% conf

The manuscript is well-structured with detailed methods, clinical trial registration, discussion of limitations, proportional conclusions, and funding disclosure, although no reporting guideline is referenced.

Evidence

direct quote[Acknowledgment]

“Studies 201/202 were funded by Sarepta Therapeutics and registered on ClinicalTrials.gov under identification numbers NCT01396239 and NCT01540409.”

direct quote[Discussion, paragraph 6]

“Limitations of the eteplirsen clinical study presented here include the small number of patients as well as the unblinded treatment of patients in the extension phase.”

direct quote[Potential Conflicts of Interest]

“J.S. and E.M.K. are employed at Sarepta Therapeutics. The study data were generated at Nationwide Children's Hospital, and they were not involved in that process.”

6 copyedit issues flagged: mostly consistency, clarity, typo.

Checked 47 references: 22 verified — 24 unresolved, 1 not checked.

Reproducibility

3 data/code links checked; 3 live.

Registered (2 IDs: ClinicalTrials.gov). No reporting guideline cited.

Adcurare Rigor Action ItemsFinal pass before journal submission

As a published paper, this work has significant reporting and data integrity issues that an informed reader should weigh carefully. The lack of a data availability statement, the potential GRIM inconsistency, and the missing reference verifications undermine the ability to independently assess the results. A correction or erratum addressing these issues, and possibly an independent re-analysis of the raw data, would be warranted to strengthen the paper's credibility.

1.
HIGHstatistics
Clarify the baseline 6MWT mean of 363.2 m for 12 patients: if distances are integers, correct the mean or provide the raw data to resolve the GRIM inconsistency (sum should be 4358.4, not integer).
This inconsistency raises questions about data accuracy; if confirmed, it requires a correction.
2.
HIGHdata code
Add a data availability statement specifying how to access the individual patient data (e.g., via the corresponding author or a managed-access repository) in a dedicated section.
Without a data availability statement, the paper's findings cannot be independently verified, which is a key requirement for reproducibility.
3.
HIGHother
Verify that all 24 references flagged as not found in any registry (e.g., 'Exon skipping therapy for Duchenne muscular dystrophy', 'Targeting RNA to treat neuromuscular disease', etc.) are correctly cited and exist in a citable form; if any cannot be verified, correct or remove them.
References not found in any registry may be fabricated, which is a serious integrity concern.
4.
HIGHstatistics
Report exact p-values (e.g., p = 0.003) instead of threshold values (p < 0.01) for all statistical tests in the Results section.
Exact p-values allow readers to assess the strength of evidence fully.
5.
HIGHstatistics
Include 95% confidence intervals for the primary effect size (151 m difference on 6MWT) in the Results section.
Confidence intervals provide precision of the effect estimate and are essential for interpretation.
6.
HIGHstatistics
Identify the statistical software (e.g., SAS, R) with version number in the Statistical Analysis section.
Software identification is standard for reproducibility and allows readers to understand the analysis environment.
7.
HIGHethics
State the specific IRB that approved the study (e.g., Nationwide Children's Hospital IRB) and include a protocol number in the Ethics section.
A named IRB is required for ethical oversight and allows verification of approval.
8.
HIGHethics
Include a statement of compliance with a recognized regulatory framework (e.g., Declaration of Helsinki) in the Ethics section.
Regulatory compliance is a standard expectation for clinical trials.
9.
HIGHreporting
Add a power analysis or sample size justification for the historical control comparison in the Methods section.
A power analysis helps readers assess whether the study had adequate sensitivity to detect the claimed effect.
10.
HIGHreporting
Mention adherence to a reporting guideline (e.g., CONSORT) and submit the checklist.
Reporting guidelines improve completeness and transparency of clinical trial reports.
11.
MEDIUMreporting
Report race/ethnicity demographics in Table 1 to improve generalizability assessment.
Demographic data help readers understand the population studied and potential limitations in generalizability.
12.
MEDIUMreporting
Pre-specify outlier handling criteria (e.g., imputation methods for loss of ambulation) in the Statistical Analysis section.
Transparent handling of missing data and outliers is important for the credibility of the analysis.
13.
MEDIUMcopyedit
Correct the study number discrepancy in the Discussion: '4568-201/202' should be '4658-201/202' to match the Methods section.
Inconsistent numbering may confuse readers and suggests a lack of careful proofreading.
14.
LOWcopyedit
Clarify the term 'placebo/delayed cohort' in Table 5 footnote to 'placebo/delayed-treatment cohort'.
The term is ambiguous and could be misinterpreted.
15.
LOWreporting
Explicitly state the manufacturer of eteplirsen (Sarepta Therapeutics) in the Methods when describing the drug.
While implied, explicit identification of the manufacturer is good practice for key resources.

Full text (46,967 chars)Analyzed: Jul 28, 2026

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