Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C.

Name: Kaimen Rigor review — Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C.
Item: Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C.
Rating: 96
Author: Alpha1

Bremova-Ertl T, Ramaswami U, Brands M, Foltan T, Gautschi M, Gissen P, Gowing F, Hahn A, Jones S, Kay R, Kolnikova M, Arash-Kaps L, Marquardt T, Mengel E, Park JH, Reichmannová S, Schneider SA, Sivananthan S, Walterfang M, Wibawa P, Strupp M, Martakis K

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Kaimen Rigor review — 2.25★ (Weak), 0 critical, 2 high issues for “Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C.”

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Alpha1 Editorial

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

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Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C.

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DOI

10.1056/NEJMoa2310151

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3303cc3fdb52293e9888d9d66817743b951f85226b98ed4474d2739cf0e5b982

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Issued Aug 16, 2026Engine 7.39.0

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C.

Paper source

Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C.

Read full text

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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

2.25 / 5

Weak — serious problems found

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

CitationsUnresolved reference ×4−1★
IntegrityIntegrity concern−0.5★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
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: 16 reported means were read, and their group size is not stated where the values are printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.
No data or code availability links were detected to verify.

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary endpoint is the SARA total score, a clinical rating scale for ataxia severity. Although it is a functional scale, it has not been validated in Niemann-Pick disease type C, and the paper explicitly states there is no validated biomarker or surrogate endpoint for the disease. The efficacy claim rests on a change in this scale without established clinical meaningfulness for this condition.
“The SARA is a validated clinical scale that measures the severity of neurologic signs and symptoms with internal consistency in patients with spinocerebellar ataxias but has not been validated in patients with Niemann–Pick disease type C.”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The primary effect is a mean difference of -1.28 points on the SARA total score (range 0-40). The minimal clinically important difference for SARA in Niemann-Pick disease type C is not established, and the paper does not anchor this change to clinical meaningfulness. The effect size is small relative to the scale range.
“least-squares mean difference, −1.28 points; 95% confidence interval, −1.91 to −0.65; P<0.001”
Find in source

Findings by category

101ArithmeticNumerical inconsistencies 202OverreachOverstated conclusions 03AuthenticityNone found 104DisclosureReporting gaps 105AvailabilityBroken references and links · partly checked 06Copyedit2 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. The main methodological strengths include rigorous randomization, blinding, pre-specified analysis, and comprehensive reporting of demographics and ethics. The primary weakness is the vague data sharing statement, which lacks details on how to access the data.

Both reviewers classified the study as interventional, which is adopted. The evaluation covers all eight dimensions; several sub-criteria were marked not applicable due to the human clinical trial context (e.g., no animal housing, no cell lines). The statistics verification checked only 1 test and found it consistent; this does not confirm overall statistical correctness.

Numerical inconsistencies

1 finding · worst low

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.

Internal contradictions in the reported numbersAssessed

Recomputed 1 test: 1 consistent, 0 inconsistent; 1 via agent-written checks.

Overstated conclusions

2 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

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

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

Data authenticity concerns

None found

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.

Checked — nothing surfaced.

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 research on NALL's mechanism and animal models, and a phase 2b trial, providing a strong foundation. The rationale linking NALL's effects to the study objectives is clear. Limitations of prior work are implicitly addressed by the phase 3 design, though not explicitly discussed.

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 with prior work and a logical rationale for the trial.

Evidence

paraphrase[Introduction, paragraph 2]

“In an Npc1 −/− mouse model of Niemann–Pick disease type C, treatment with NALL delayed the onset of functional decline ... and prolonged survival.”

paraphrase[Introduction, paragraph 3]

“A multinational, assessor-blinded, phase 2b clinical trial involving children and adults with Niemann–Pick disease type C showed that treatment with NALL resulted in reductions in symptoms and improvements in functioning and quality of life after 6 weeks of treatment.”

absence[Introduction]

Limitations of prior work are not explicitly discussed.

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise with prior work cited and a logical rationale linking the mechanism of NALL to the study objectives.

Evidence

paraphrase[Introduction, paragraph 3]

“In an Npc1 −/− mouse model of Niemann–Pick disease type C, treatment with NALL delayed the onset of functional decline ... and prolonged survival.”

paraphrase[Introduction, paragraph 4]

paraphrase[Introduction, paragraph 2]

“The agent enters enzyme-controlled pathways that correct metabolic dysfunction and improves adenosine triphosphate (ATP) energy production.”

Randomization was performed by a CRO using computerized interactive response technology, with 1:1 allocation. Blinding was double-blind with patients, families, investigators, and sponsor representatives unaware of assignments. A sample size calculation was provided. Inclusion/exclusion criteria were pre-specified. Missing data handling was described. The trial is a crossover design with appropriate analysis.

Sub-criteria

controlsN/A

power analysisADEQUATE

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 with proper randomization, blinding, and pre-specified analysis.

Evidence

“Randomization was performed by Medpace, a clinical research organization, with the use of computerized interactive response technology.”

MethodsFind in source

paraphrase[Methods, Trial Procedures]

“The patients, the families and caregivers of the patients, the investigators and trial teams, and the representatives of the sponsor were unaware of the trial-group assignments until the database was locked for analysis.”

paraphrase[Methods, Statistical Analysis]

“A sample of 46 patients was estimated to provide the trial with 80% power, at a one-sided significance level of 5%, to detect a mean between-group difference (NALL vs. placebo) of 1.0 point in the total score on the SARA”

PASSReviewer 2· 95% conf

The trial design is rigorous with proper randomization, blinding, power analysis, and pre-specified inclusion/exclusion criteria.

Evidence

“Randomization was performed by Medpace, a clinical research organization, with the use of computerized interactive response technology.”

MethodsFind in source

paraphrase[Methods, Trial Procedures]

paraphrase[Methods, Statistical Analysis]

The paper reports age group, sex, race, age at diagnosis, disease duration, and miglustat use. Both sexes are included, so sex justification is not applicable. Age and health status are reported. Species/strain and housing are not applicable for a human trial.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Demographic and clinical characteristics are well reported.

Evidence

“Sex — no. (%) Female 27 (45) Male 33 (55)”

Table 1Find in source

“Age group — no. (%) Pediatric, <18 yr 23 (38) Adult, ≥18 yr 37 (62)”

Table 1Find in source

paraphrase[Table 1]

“Race or ethnic group — no. (%) ... White 54 (90) Other 4 (7)”

PASSReviewer 2· 90% conf

Demographic and clinical characteristics are well reported, including age, sex, race, and disease duration.

Evidence

“Sex — no. (%) Female 27 (45) Male 33 (55)”

Table 1Find in source

“Age group — no. (%) Pediatric, <18 yr 23 (38) Adult, ≥18 yr 37 (62)”

Table 1Find in source

“Race or ethnic group — no. (%)† American Indian or Alaska native 0 Asian 0 Black or African American 2 (3) Native Hawaiian or other Pacific Islander 0 White 54 (90) Other 4 (7)”

Table 1Find in source

The trial was approved by a central research ethics committee or institutional review board at each center. Written informed consent was obtained. The trial was registered (ClinicalTrials.gov and EudraCT). Regulatory compliance is implied by the approval and registration.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Ethical approval and informed consent are adequately reported.

Evidence

“The trial was approved by a central research ethics committee or an institutional review board at each center.”

MethodsFind in source

paraphrase[Methods, Patients]

“had provided written informed consent (or consent had been provided by a legal representative)”

paraphrase[Abstract]

“ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.”

PASSReviewer 2· 90% conf

Ethical approval and informed consent are adequately reported.

Evidence

“The trial was approved by a central research ethics committee or an institutional review board at each center.”

MethodsFind in source

paraphrase[Methods, Patients]

“had provided written informed consent (or consent had been provided by a legal representative)”

paraphrase[Abstract]

“ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.”

The investigational product NALL is named with dose and regimen. The placebo is described as matching. Statistical software (SAS 9.4) is identified. No antibodies, cell lines, or other biological resources are used, so those criteria are not applicable.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

The investigational product is adequately identified, and statistical software is named.

Evidence

paraphrase[Methods, Trial Procedures]

“NALL or matching placebo was administered orally two to three times per day, with patients 4 to 12 years of age receiving weight-based doses (2 to 4 g per day) and those 13 years of age or older receiving a dose of 4 g per day.”

paraphrase[Methods, Statistical Analysis]

“Statistical analyses were performed with SAS software, version 9.4 (SAS Institute).”

PASSReviewer 2· 85% conf

The investigational product (NALL) and placebo are adequately described, and statistical software is identified.

Evidence

paraphrase[Methods, Trial Procedures]

paraphrase[Methods, Statistical Analysis]

“Statistical analyses were performed with SAS software, version 9.4 (SAS Institute).”

The primary analysis used a mixed-effects model with ANCOVA, and the paper reports exact p-values (P<0.001) and 95% CIs. Secondary endpoints are reported with CIs without p-values, which is appropriate. Software is identified. Data presentation includes individual patient data in figures and per-group n. Mathematical plausibility checks are not applicable due to continuous outcomes and large N.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical methods are appropriate and well reported, with exact p-values and confidence intervals.

Evidence

paraphrase[Methods, Statistical Analysis]

“The primary efficacy analyses of the SARA and mSARA total scores were conducted with the use of an analysis of covariance model”

paraphrase[Results, Primary End Point]

“least-squares mean difference, −1.28 points; 95% confidence interval, −1.91 to −0.65; P<0.001”

paraphrase[Methods, Statistical Analysis]

“the results for secondary end points are presented as point estimates and 95% confidence intervals without P values”

PASSReviewer 2· 90% conf

Statistical methods are appropriate and well-described, with exact p-values for the primary endpoint and effect sizes with confidence intervals.

Evidence

paraphrase[Results, Primary End Point]

“least-squares mean difference, −1.28 points; 95% confidence interval, −1.91 to −0.65; P<0.001”

paraphrase[Results, Secondary End Points]

“The mean differences (NALL vs. placebo) in the changes in scores were −0.6 points (95% CI, −1.1 to −0.1) for the investigator-rated CGI-I”

paraphrase[Methods, Statistical Analysis]

“The primary efficacy analyses of the SARA and mSARA total scores were conducted with the use of an analysis of covariance model”

The paper states that a data sharing statement is available with the full text, but the specific mechanism is not described in the provided text. No repository or accession numbers are given. Code sharing is not applicable.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositNOT REPORTED

data availability statementINADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 80% conf

A data sharing statement is mentioned but not detailed in the provided text.

Evidence

“A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.”

End of articleFind in source

WARNReviewer 2· 80% conf

A data sharing statement is mentioned but not detailed in the provided text; no repository or accession numbers are given.

Evidence

“A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.”

End of articleFind in source

The trial is registered (NCT05163288). Methods are detailed. Limitations are explicitly discussed. Conclusions are appropriately cautious. Funding and COI are disclosed. Reporting guideline adherence is implied by NEJM standards but not explicitly stated.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineINADEQUATE

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, methods are complete, limitations are discussed, and conclusions are proportional.

Evidence

“ClinicalTrials.gov number, NCT05163288”

AbstractFind in source

paraphrase[Discussion]

“Our trial has several limitations, the first of which was the 12-week duration of active treatment.”

“Supported by IntraBio.”

DiscussionFind in source

PASSReviewer 2· 90% conf

The trial is registered, methods are detailed, limitations are discussed, and conclusions are proportional.

Evidence

“ClinicalTrials.gov number, NCT05163288”

AbstractFind in source

paraphrase[Discussion]

“Our trial has several limitations, the first of which was the 12-week duration of active treatment.”

“Supported by IntraBio.”

DiscussionFind in source

Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.

Broken references and links

1 finding · worst low

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.

References not resolvable to a published paperRecomputed

Checked 19 references by DOI: 14 verified — 4 DOI unresolved, 1 no DOI (shown, not verified).

Copyediting

2 minor

Wording, consistency and formatting errors that need correcting before submission.

No major wording or formatting errors. 2 minor suggestions below.

2 copyedit issues flagged: mostly typo, consistency.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published paper is robust and well-reported. An informed reader should note the vague data sharing statement and the lack of explicit reporting guideline adherence as minor transparency gaps, but these do not undermine the core findings. No erratum or correction appears warranted based on this audit.

1.
HIGHdata code
Provide a detailed data sharing statement in the manuscript, specifying the mechanism for requesting de-identified patient data (e.g., via a data access committee or a platform like Vivli) and the conditions for access.
The current statement is vague and does not meet the standard for data availability in clinical trials.
2.
HIGHreporting
Verify the four references not found in the registry (DOIs: 10.1046/j.0953-816x.2000.01435.x, 10.1038/s41598-021-88693-4, 10.1186/s13063-023-07377-0, 10.1212/01.wnl.0000324860.76232.6a) and correct or replace them if they are incorrect or fabricated.
References that cannot be located in any registry are a potential fabrication signal and must be resolved.
3.
MEDIUMreporting
Explicitly state adherence to a reporting guideline such as CONSORT in the methods or acknowledgments.
Enhances transparency and allows readers to verify that reporting standards were followed.
4.
MEDIUMreporting
Include the protocol and statistical analysis plan as supplementary materials or provide a link to them.
Allows readers to verify that the analysis was pre-specified and reduces concerns about selective reporting.
5.
MEDIUMreporting
Clarify the handling of missing data for secondary endpoints, as the paper notes no imputation was performed for these.
Provides a complete picture of how missing data were addressed across all analyses.
6.
MEDIUMreporting
Consider reporting the results of the mSARA analysis with a p-value or confidence interval, as it was a primary endpoint in the US.
Ensures consistency in reporting of primary endpoints across regulatory regions.
7.
MEDIUMreporting
Add a note on the generalizability of the findings given the exclusion of patients younger than 4 years and those with advanced disease.
Helps readers understand the population to which the results apply.
8.
LOWcopyedit
Ensure consistent use of spaces around ± symbols in the abstract (e.g., '−1.97±2.43' should be '−1.97 ± 2.43').
Minor formatting inconsistency that should be corrected for professional presentation.
9.
LOWcopyedit
Clarify the Table 1 footnote explaining why one patient is missing for placebo baseline scores.
The current footnote could be clearer to avoid confusion.

Full text (44,461 chars)Analyzed: Aug 16, 2026

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Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C.

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DOI

10.1056/NEJMoa2310151

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Record fingerprint

3303cc3fdb52293e9888d9d66817743b951f85226b98ed4474d2739cf0e5b982

Verify via API

Issued Aug 16, 2026Engine 7.39.0

Alpha1 assesses methodological rigor, not the importance of the findings. See how we calibrate →

Kaimen Rigor review

Kaimen Rigor reviewed

2.25 / 5

Weak — serious problems found

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

CitationsUnresolved reference ×4−1★
IntegrityIntegrity concern−0.5★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
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: 16 reported means were read, and their group size is not stated where the values are printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.
No data or code availability links were detected to verify.

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary endpoint is the SARA total score, a clinical rating scale for ataxia severity. Although it is a functional scale, it has not been validated in Niemann-Pick disease type C, and the paper explicitly states there is no validated biomarker or surrogate endpoint for the disease. The efficacy claim rests on a change in this scale without established clinical meaningfulness for this condition.
“The SARA is a validated clinical scale that measures the severity of neurologic signs and symptoms with internal consistency in patients with spinocerebellar ataxias but has not been validated in patients with Niemann–Pick disease type C.”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The primary effect is a mean difference of -1.28 points on the SARA total score (range 0-40). The minimal clinically important difference for SARA in Niemann-Pick disease type C is not established, and the paper does not anchor this change to clinical meaningfulness. The effect size is small relative to the scale range.
“least-squares mean difference, −1.28 points; 95% confidence interval, −1.91 to −0.65; P<0.001”
Find in source

Findings by category

Numerical inconsistencies

1 finding · worst low

Internal contradictions in the reported numbersAssessed

Recomputed 1 test: 1 consistent, 0 inconsistent; 1 via agent-written checks.

Overstated conclusions

2 findings · worst high

Efficacy rests on an unvalidated surrogate endpointAssessed
Treatment effect not shown to be clinically meaningfulAssessed

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

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

Data authenticity concerns

None found

Checked — nothing surfaced.

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

The paper establishes a clear scientific premise with prior work and a logical rationale for the trial.

Evidence

paraphrase[Introduction, paragraph 2]

“In an Npc1 −/− mouse model of Niemann–Pick disease type C, treatment with NALL delayed the onset of functional decline ... and prolonged survival.”

paraphrase[Introduction, paragraph 3]

absence[Introduction]

Limitations of prior work are not explicitly discussed.

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise with prior work cited and a logical rationale linking the mechanism of NALL to the study objectives.

Evidence

paraphrase[Introduction, paragraph 3]

“In an Npc1 −/− mouse model of Niemann–Pick disease type C, treatment with NALL delayed the onset of functional decline ... and prolonged survival.”

paraphrase[Introduction, paragraph 4]

paraphrase[Introduction, paragraph 2]

“The agent enters enzyme-controlled pathways that correct metabolic dysfunction and improves adenosine triphosphate (ATP) energy production.”

Sub-criteria

controlsN/A

power analysisADEQUATE

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 with proper randomization, blinding, and pre-specified analysis.

Evidence

“Randomization was performed by Medpace, a clinical research organization, with the use of computerized interactive response technology.”

MethodsFind in source

paraphrase[Methods, Trial Procedures]

paraphrase[Methods, Statistical Analysis]

PASSReviewer 2· 95% conf

The trial design is rigorous with proper randomization, blinding, power analysis, and pre-specified inclusion/exclusion criteria.

Evidence

“Randomization was performed by Medpace, a clinical research organization, with the use of computerized interactive response technology.”

MethodsFind in source

paraphrase[Methods, Trial Procedures]

paraphrase[Methods, Statistical Analysis]

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Demographic and clinical characteristics are well reported.

Evidence

“Sex — no. (%) Female 27 (45) Male 33 (55)”

Table 1Find in source

“Age group — no. (%) Pediatric, <18 yr 23 (38) Adult, ≥18 yr 37 (62)”

Table 1Find in source

paraphrase[Table 1]

“Race or ethnic group — no. (%) ... White 54 (90) Other 4 (7)”

PASSReviewer 2· 90% conf

Demographic and clinical characteristics are well reported, including age, sex, race, and disease duration.

Evidence

“Sex — no. (%) Female 27 (45) Male 33 (55)”

Table 1Find in source

“Age group — no. (%) Pediatric, <18 yr 23 (38) Adult, ≥18 yr 37 (62)”

Table 1Find in source

“Race or ethnic group — no. (%)† American Indian or Alaska native 0 Asian 0 Black or African American 2 (3) Native Hawaiian or other Pacific Islander 0 White 54 (90) Other 4 (7)”

Table 1Find in source

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Ethical approval and informed consent are adequately reported.

Evidence

“The trial was approved by a central research ethics committee or an institutional review board at each center.”

MethodsFind in source

paraphrase[Methods, Patients]

“had provided written informed consent (or consent had been provided by a legal representative)”

paraphrase[Abstract]

“ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.”

PASSReviewer 2· 90% conf

Ethical approval and informed consent are adequately reported.

Evidence

“The trial was approved by a central research ethics committee or an institutional review board at each center.”

MethodsFind in source

paraphrase[Methods, Patients]

“had provided written informed consent (or consent had been provided by a legal representative)”

paraphrase[Abstract]

“ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.”

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

The investigational product is adequately identified, and statistical software is named.

Evidence

paraphrase[Methods, Trial Procedures]

paraphrase[Methods, Statistical Analysis]

“Statistical analyses were performed with SAS software, version 9.4 (SAS Institute).”

PASSReviewer 2· 85% conf

The investigational product (NALL) and placebo are adequately described, and statistical software is identified.

Evidence

paraphrase[Methods, Trial Procedures]

paraphrase[Methods, Statistical Analysis]

“Statistical analyses were performed with SAS software, version 9.4 (SAS Institute).”

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical methods are appropriate and well reported, with exact p-values and confidence intervals.

Evidence

paraphrase[Methods, Statistical Analysis]

“The primary efficacy analyses of the SARA and mSARA total scores were conducted with the use of an analysis of covariance model”

paraphrase[Results, Primary End Point]

“least-squares mean difference, −1.28 points; 95% confidence interval, −1.91 to −0.65; P<0.001”

paraphrase[Methods, Statistical Analysis]

“the results for secondary end points are presented as point estimates and 95% confidence intervals without P values”

PASSReviewer 2· 90% conf

Statistical methods are appropriate and well-described, with exact p-values for the primary endpoint and effect sizes with confidence intervals.

Evidence

paraphrase[Results, Primary End Point]

“least-squares mean difference, −1.28 points; 95% confidence interval, −1.91 to −0.65; P<0.001”

paraphrase[Results, Secondary End Points]

“The mean differences (NALL vs. placebo) in the changes in scores were −0.6 points (95% CI, −1.1 to −0.1) for the investigator-rated CGI-I”

paraphrase[Methods, Statistical Analysis]

“The primary efficacy analyses of the SARA and mSARA total scores were conducted with the use of an analysis of covariance model”

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositNOT REPORTED

data availability statementINADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 80% conf

A data sharing statement is mentioned but not detailed in the provided text.

Evidence

“A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.”

End of articleFind in source

WARNReviewer 2· 80% conf

A data sharing statement is mentioned but not detailed in the provided text; no repository or accession numbers are given.

Evidence

“A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.”

End of articleFind in source

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineINADEQUATE

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, methods are complete, limitations are discussed, and conclusions are proportional.

Evidence

“ClinicalTrials.gov number, NCT05163288”

AbstractFind in source

paraphrase[Discussion]

“Our trial has several limitations, the first of which was the 12-week duration of active treatment.”

“Supported by IntraBio.”

DiscussionFind in source

PASSReviewer 2· 90% conf

The trial is registered, methods are detailed, limitations are discussed, and conclusions are proportional.

Evidence

“ClinicalTrials.gov number, NCT05163288”

AbstractFind in source

paraphrase[Discussion]

“Our trial has several limitations, the first of which was the 12-week duration of active treatment.”

“Supported by IntraBio.”

DiscussionFind in source

Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.

Broken references and links

1 finding · worst low

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.

References not resolvable to a published paperRecomputed

Checked 19 references by DOI: 14 verified — 4 DOI unresolved, 1 no DOI (shown, not verified).

Copyediting

2 minor

Wording, consistency and formatting errors that need correcting before submission.

No major wording or formatting errors. 2 minor suggestions below.

2 copyedit issues flagged: mostly typo, consistency.

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHdata code
Provide a detailed data sharing statement in the manuscript, specifying the mechanism for requesting de-identified patient data (e.g., via a data access committee or a platform like Vivli) and the conditions for access.
The current statement is vague and does not meet the standard for data availability in clinical trials.
2.
HIGHreporting
Verify the four references not found in the registry (DOIs: 10.1046/j.0953-816x.2000.01435.x, 10.1038/s41598-021-88693-4, 10.1186/s13063-023-07377-0, 10.1212/01.wnl.0000324860.76232.6a) and correct or replace them if they are incorrect or fabricated.
References that cannot be located in any registry are a potential fabrication signal and must be resolved.
3.
MEDIUMreporting
Explicitly state adherence to a reporting guideline such as CONSORT in the methods or acknowledgments.
Enhances transparency and allows readers to verify that reporting standards were followed.
4.
MEDIUMreporting
Include the protocol and statistical analysis plan as supplementary materials or provide a link to them.
Allows readers to verify that the analysis was pre-specified and reduces concerns about selective reporting.
5.
MEDIUMreporting
Clarify the handling of missing data for secondary endpoints, as the paper notes no imputation was performed for these.
Provides a complete picture of how missing data were addressed across all analyses.
6.
MEDIUMreporting
Consider reporting the results of the mSARA analysis with a p-value or confidence interval, as it was a primary endpoint in the US.
Ensures consistency in reporting of primary endpoints across regulatory regions.
7.
MEDIUMreporting
Add a note on the generalizability of the findings given the exclusion of patients younger than 4 years and those with advanced disease.
Helps readers understand the population to which the results apply.
8.
LOWcopyedit
Ensure consistent use of spaces around ± symbols in the abstract (e.g., '−1.97±2.43' should be '−1.97 ± 2.43').
Minor formatting inconsistency that should be corrected for professional presentation.
9.
LOWcopyedit
Clarify the Table 1 footnote explaining why one patient is missing for placebo baseline scores.
The current footnote could be clearer to avoid confusion.

Full text (44,461 chars)Analyzed: Aug 16, 2026