Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia.

Name: Kaimen Rigor review — Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia.
Item: Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia.
Rating: 96
Author: Alpha1

Auchus RJ, Hamidi O, Pivonello R, Bancos I, Russo G, Witchel SF, Isidori AM, Rodien P, Srirangalingam U, Kiefer FW, Falhammar H, Merke DP, Reisch N, Sarafoglou K, Cutler GB Jr, Sturgeon J, Roberts E, Lin VH, Chan JL, Farber RH, CAHtalyst Adult Trial Investigators

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Kaimen Rigor review — 2.75★ (Weak), 0 critical, 2 high issues for “Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia.”

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

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Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia.

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DOI

10.1056/NEJMoa2404656

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Issued Aug 16, 2026Engine 7.39.0

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia.

Paper source

Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia.

Read full text (PMC)

Embed this Rigor badge

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

2.75 / 5

Weak — serious problems found

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×2−1★
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: 9 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 endpoint is the percent change in glucocorticoid dose while maintaining androstenedione control. Androstenedione is a surrogate biomarker for clinical outcomes in congenital adrenal hyperplasia. The paper does not provide evidence that androstenedione is a validated surrogate for hard clinical outcomes, nor does it demonstrate target engagement at the tested dose beyond biomarker changes. The claim of clinical benefit rests on this surrogate.
“The primary efficacy end point was the percent change from baseline at week 24 in GC daily dose while maintaining androstenedione control”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The primary effect is a reduction in glucocorticoid dose by 27.3% from baseline, but the clinical meaningfulness of this reduction is not anchored to a minimal clinically important difference or a direct clinical outcome. The reduction is presented as statistically significant but lacks a clear anchor to clinical benefit beyond the surrogate biomarker.
“GC dose reduction at week 24 (while androstenedione control was maintained) was significantly greater with crinecerfont than placebo (LS mean percent change from baseline of −27.3% versus −10.3% [LSMD: −17.0%, P<0.001])”
Find in source
03Other integrity concern
mediumAuthenticityreviewer-assessedFull detail
Trial NCT03525886 was first submitted to ClinicalTrials.gov on 2018-05-02, after the registered study start date of 2018-04-10. 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.
NCT03525886
reviewer’s wording

Findings by category

101ArithmeticNumerical inconsistencies 202OverreachOverstated conclusions 103AuthenticityData authenticity concerns 104DisclosureReporting gaps 05AvailabilityNone found 06Copyedit4 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 phase 3 randomized controlled trial with rigorous design, clear reporting of methods, and appropriate statistical analysis. The main weaknesses are the lack of a clear data availability statement and the failure to name the statistical software, both minor reporting gaps. A minor internal inconsistency in participant counts and retrospective registration of one phase 2 trial are noted but do not undermine the main findings.

Both reviewers agreed on study type (interventional) and on all dimension statuses. The statistics verification covered only 2 tests (those with test statistics/df or effect+CI); other p-values were not machine-verified. The integrity check flagged a minor internal contradiction in participant counts and retrospective registration of NCT03525886, which are noted but do not affect dimension statuses.

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 2 tests: 2 consistent, 0 inconsistent; 2 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

6 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

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

2 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 research on CAH pathophysiology, the limitations of current glucocorticoid therapy, and phase 2 proof-of-concept studies of crinecerfont. The rationale linking CRF1 antagonism to reduced ACTH and adrenal androgens is clearly articulated. The study objectives follow logically from the cited evidence.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The paper establishes a clear scientific premise with adequate citation of prior work and a logical rationale for the study.

Evidence

paraphrase[Introduction, paragraph 3]

“Crinecerfont is a novel orally administered CRF 1 antagonist that reduced key hormone biomarkers in phase 2 studies in adults ( NCT03525886 ) and adolescents ( NCT04045145 ) with CAH.”

“One promising new strategy for reducing adrenal androgen overproduction through a GC-independent mechanism is CRF type 1 receptor (CRF 1 ) antagonism to reduce ACTH secretion, thus potentially allowing for physiological GC dosing.”

Introduction ¶2Find in source

“Conversely, the few prospective studies that have evaluated reduction of supraphysiological glucocorticoid doses in a range relevant to CAH have demonstrated improvements in markers of cardiovascular and metabolic disease and bone health.”

Discussion ¶2Find in source

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise with adequate citation of prior work and a logical rationale for the study.

Evidence

paraphrase[Introduction, paragraph 3]

“Crinecerfont is a novel orally administered CRF 1 antagonist that reduced key hormone biomarkers in phase 2 studies in adults ( NCT03525886 ) and adolescents ( NCT04045145 ) with CAH.”

Introduction ¶2Find in source

absence[Introduction]

Limitations of prior research are not explicitly discussed.

Randomization was performed using interactive response technology, stratified by GC dose, GC type, and sex. The trial was double-blind. A sample size calculation provided >90% power to detect an effect size of 0.55. Inclusion/exclusion criteria were pre-specified. The analysis population (ITT) and missing data imputation were defined.

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 adequate randomization, blinding, power analysis, and pre-specified inclusion/exclusion criteria.

Evidence

paraphrase[Methods, Randomization and Trial Interventions]

“Randomization by interactive response technology was stratified by GC dose (<20 or ≥20 mg/m 2 /day HCe), GC type, and sex.”

“Our study included a 24-week, randomized, double-blind, placebo-controlled period”

MethodsFind in source

“A sample of 165 participants (110 crinecerfont, 55 placebo) was estimated to provide >90% power to detect an effect size as small as 0.55 for the primary end point with 2-sided type 1 error of 0.05.”

Statistical analysisFind in source

PASSReviewer 2· 95% conf

The trial design is rigorous with adequate randomization, blinding, power analysis, and pre-specified endpoints.

Evidence

paraphrase[Methods, Randomization and Trial Interventions]

“Randomization by interactive response technology was stratified by GC dose (<20 or ≥20 mg/m 2 /day HCe), GC type, and sex.”

“Our study included a 24-week, randomized, double-blind, placebo-controlled period”

MethodsFind in source

Statistical analysisFind in source

The paper reports sex, age, body weight, BMI, and comorbidities. Both sexes are enrolled, so sex justification is not applicable. Demographics include race/ethnicity. Health status is described via baseline hormone levels and comorbidities.

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· 95% conf

Demographics and baseline characteristics are well reported, including sex, age, and health status.

Evidence

“Age – yr | 30.8±9.9 | 31.3±9.8 | 29.8±10.2 | | Male – no. (%) | 92 (50.5) | 61 (50.0) | 31 (51.7)”

Table 1Find in source

“White – no. (%) | 164 (90.1) | 107 (87.7) | 57 (95.0)”

Table 1Find in source

“Baseline mean GC dose was 17.6 mg/m 2 /day HCe with elevated mean androstenedione of 620 ng/dL (~2–3 times ULN)”

ResultsFind in source

PASSReviewer 2· 90% conf

Demographics and baseline characteristics are well reported, including sex, age, and health status.

Evidence

“Age – yr | 30.8±9.9 | 31.3±9.8 | 29.8±10.2 | | Male – no. (%) | 92 (50.5) | 61 (50.0) | 31 (51.7)”

Table 1Find in source

“White – no. (%) | 164 (90.1) | 107 (87.7) | 57 (95.0)”

Table 1Find in source

paraphrase[Results, Participants]

“Common comorbidities (self-reported in ≥10% of the randomized population or by sex) were irregular menses, acne, and hirsutism in female participants, anxiety, osteopenia, depression, hypertension, and hyperlipidemia.”

The protocol was approved by Independent Ethics Committees or Institutional Review Boards at each site. All participants provided written informed consent. Compliance with ICH-GCP guidelines is stated.

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 and informed consent are adequately reported.

Evidence

“The protocol was reviewed and approved by Independent Ethics Committees or Institutional Review Boards at each study site and by national health authorities for each country.”

MethodsFind in source

“All participants provided written informed consent.”

MethodsFind in source

“conducted in compliance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice guidelines”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethical approvals and informed consent are adequately documented.

Evidence

“The protocol was reviewed and approved by Independent Ethics Committees or Institutional Review Boards at each study site and by national health authorities for each country.”

MethodsFind in source

“All participants provided written informed consent.”

MethodsFind in source

“conducted in compliance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice guidelines”

MethodsFind in source

Crinecerfont is named as an oral CRF1 antagonist, with dose and regimen specified. The sponsor (Neurocrine Biosciences) is identified. Statistical software is not explicitly named, but the analysis methods are described. No other biological/chemical resources are used.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedINADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational product (crinecerfont) is adequately identified, and statistical software is identified.

Evidence

“participants were randomized (2:1) to crinecerfont 100 mg or placebo twice daily with morning and evening meals.”

MethodsFind in source

absence[Methods, Statistical Analyses]

Statistical software is not explicitly named.

PASSReviewer 2· 90% conf

The investigational drug and key reagents are adequately identified.

Evidence

“participants were randomized (2:1) to crinecerfont 100 mg or placebo twice daily with morning and evening meals.”

MethodsFind in source

“All androgens and androgen precursors were measured at a central laboratory (Quest Diagnostics ® ) by liquid chromatography with tandem mass spectrometry.”

MethodsFind in source

absence[Methods, Statistical Analyses]

Statistical software is not identified.

The primary analysis used ANCOVA with LSMD and 95% CI. Categorical endpoints used Cochran-Mantel-Haenszel test. P-values are reported as <0.001 for primary and key secondary endpoints. Effect sizes with CIs are provided. Missing data were imputed using multiple imputation. The paper reports exact p-values for non-significant endpoints (e.g., HOMA-IR).

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedINADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

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

Evidence

paraphrase[Methods, Statistical Analyses]

“An analysis of covariance model was used to evaluate continuous end points ... A 2-sided Cochran-Mantel-Haenszel test was used to analyze categorical end points”

paraphrase[Table 2]

“Homeostatic model assessment for insulin resistance (week 24) | 122 | −0.65±0.21 | 60 | −0.36±0.28 | −0.29 (−0.89, 0.32) | |”

Table 2Find in source

PASSReviewer 2· 90% conf

Statistical methods are appropriate and well-described, with exact p-values and effect sizes with CIs.

Evidence

paraphrase[Methods, Statistical Analyses]

“An analysis of covariance model was used to evaluate continuous end points ... A 2-sided Cochran-Mantel-Haenszel test was used to analyze categorical end points”

“LSMD: −17.0%, P<0.001”

ResultsFind in source

“−17.0 (−23.8, −10.2)”

Table 2Find in source

The paper states that data are available from the corresponding author upon request, but no platform or conditions are specified. No data repository or accession numbers are provided. No custom code is mentioned.

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

Data availability is vague; no repository deposit or code sharing is mentioned.

Evidence

paraphrase[Methods, Trial Design and Oversight]

“The Sponsor and authors vouch for the accuracy and completeness of the data and affirm the fidelity of the trial to the protocol (available at NEJM.org).”

absence[Entire paper]

No repository deposit is mentioned.

WARNReviewer 2· 80% conf

Data availability is vague; no repository deposit or code sharing is mentioned.

Evidence

absence[Entire paper]

No data availability statement is present.

The trial is registered at ClinicalTrials.gov (NCT04490915). Methods are detailed. Limitations are explicitly discussed. Conclusions are proportional to the evidence. Funding and COI disclosures are provided.

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· 95% conf

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

Evidence

paraphrase[Abstract]

“ClinicalTrials.gov number, NCT04490915”

“The trial also had certain limitations, which included the restriction to participants who had been receiving supraphysiological GC doses, the short time frame to observe changes in clinical end points related to GC exposure, and the focus on achieving the lowest GC dose”

Discussion ¶4Find in source

paraphrase[Funding and Disclosures sections]

“Financial support for the study was provided by Neurocrine Biosciences, Inc. ... Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.”

PASSReviewer 2· 90% conf

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

Evidence

paraphrase[Abstract]

“ClinicalTrials.gov number, NCT04490915”

DiscussionFind in source

“Financial support for the study was provided by Neurocrine Biosciences, Inc.”

FundingFind in source

Registered (4 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 42 references by DOI: 42 verified.

4 data/code links checked; 4 live.

Copyediting

4 minor

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

No major wording or formatting errors. 4 minor suggestions below.

4 copyedit issues flagged: mostly consistency, clarity.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published paper is robust overall, with strong design and reporting. An informed reader should weigh the minor reporting gaps (data availability, software identification, CONSORT mention) and the small internal inconsistency in participant counts; none of these warrant an erratum, but the data availability statement could be improved in any correction or re-analysis.

1.
HIGHdata code
Add a clear data availability statement in the Methods or a dedicated section, specifying that individual participant data may be available through a managed access process (e.g., via Neurocrine or a data-sharing platform) with conditions and timeframe.
The current statement is vague or absent, and a clear data-sharing mechanism is expected for a clinical trial.
2.
HIGHreporting
Resolve the internal contradiction in participant counts: abstract states 176 (96.7%) reached 24 weeks, but results sum to 174 (95.6%); clarify the definition of 'reached' vs 'completed' and ensure consistency.
An internal inconsistency in participant numbers could confuse readers and undermine trust in the reported results.
3.
MEDIUMstatistics
Name the statistical software (e.g., SAS version 9.4) used for analyses in the Statistical Analyses section.
Identifying the software is a standard reporting expectation and aids reproducibility.
4.
MEDIUMreporting
Mention adherence to a reporting guideline such as CONSORT in the Methods or provide a checklist submission statement.
Explicitly referencing CONSORT improves transparency and aligns with journal expectations.
5.
MEDIUMdata code
Consider depositing de-identified aggregate data or statistical analysis code in a public repository (e.g., Zenodo, Figshare) to enhance transparency.
Sharing code or aggregate data would strengthen reproducibility, though managed access is acceptable for IPD.
6.
LOWcopyedit
Fix the formatting of 'CAHtalyst Adult Study investigators' in the Abstract (add a period or format as a proper group name).
Minor formatting inconsistency that could be cleaned up.
7.
LOWcopyedit
Clarify in the Statistical Analyses section that the Cochran-Mantel-Haenszel test is for general association, not specifically for the endpoint.
Minor clarity issue that could prevent misinterpretation.
8.
LOWcopyedit
Clarify in the power analysis sentence that the effect size of 0.55 is for the primary endpoint.
Minor clarity improvement.

Full text (35,153 chars)Analyzed: Aug 16, 2026

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Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia.

Read full text (PMC)

DOI

10.1056/NEJMoa2404656

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Record fingerprint

d001815c04cdea967c4aa7ac35bc294c88a14e56a4465d5de9e9f67af5e3c394

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

2.75 / 5

Weak — serious problems found

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×2−1★
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: 9 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 endpoint is the percent change in glucocorticoid dose while maintaining androstenedione control. Androstenedione is a surrogate biomarker for clinical outcomes in congenital adrenal hyperplasia. The paper does not provide evidence that androstenedione is a validated surrogate for hard clinical outcomes, nor does it demonstrate target engagement at the tested dose beyond biomarker changes. The claim of clinical benefit rests on this surrogate.
“The primary efficacy end point was the percent change from baseline at week 24 in GC daily dose while maintaining androstenedione control”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The primary effect is a reduction in glucocorticoid dose by 27.3% from baseline, but the clinical meaningfulness of this reduction is not anchored to a minimal clinically important difference or a direct clinical outcome. The reduction is presented as statistically significant but lacks a clear anchor to clinical benefit beyond the surrogate biomarker.
“GC dose reduction at week 24 (while androstenedione control was maintained) was significantly greater with crinecerfont than placebo (LS mean percent change from baseline of −27.3% versus −10.3% [LSMD: −17.0%, P<0.001])”
Find in source
03Other integrity concern
mediumAuthenticityreviewer-assessedFull detail
Trial NCT03525886 was first submitted to ClinicalTrials.gov on 2018-05-02, after the registered study start date of 2018-04-10. 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.
NCT03525886
reviewer’s wording

Findings by category

101ArithmeticNumerical inconsistencies 202OverreachOverstated conclusions 103AuthenticityData authenticity concerns 104DisclosureReporting gaps 05AvailabilityNone found 06Copyedit4 minor suggestions

Numerical inconsistencies

1 finding · worst low

Internal contradictions in the reported numbersAssessed

Recomputed 2 tests: 2 consistent, 0 inconsistent; 2 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

6 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

1 finding · worst medium

Other integrity concernAssessed

2 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 addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The paper establishes a clear scientific premise with adequate citation of prior work and a logical rationale for the study.

Evidence

paraphrase[Introduction, paragraph 3]

“Crinecerfont is a novel orally administered CRF 1 antagonist that reduced key hormone biomarkers in phase 2 studies in adults ( NCT03525886 ) and adolescents ( NCT04045145 ) with CAH.”

Introduction ¶2Find in source

Discussion ¶2Find in source

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise with adequate citation of prior work and a logical rationale for the study.

Evidence

paraphrase[Introduction, paragraph 3]

“Crinecerfont is a novel orally administered CRF 1 antagonist that reduced key hormone biomarkers in phase 2 studies in adults ( NCT03525886 ) and adolescents ( NCT04045145 ) with CAH.”

Introduction ¶2Find in source

absence[Introduction]

Limitations of prior research are not explicitly discussed.

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 adequate randomization, blinding, power analysis, and pre-specified inclusion/exclusion criteria.

Evidence

paraphrase[Methods, Randomization and Trial Interventions]

“Randomization by interactive response technology was stratified by GC dose (<20 or ≥20 mg/m 2 /day HCe), GC type, and sex.”

“Our study included a 24-week, randomized, double-blind, placebo-controlled period”

MethodsFind in source

Statistical analysisFind in source

PASSReviewer 2· 95% conf

The trial design is rigorous with adequate randomization, blinding, power analysis, and pre-specified endpoints.

Evidence

paraphrase[Methods, Randomization and Trial Interventions]

“Randomization by interactive response technology was stratified by GC dose (<20 or ≥20 mg/m 2 /day HCe), GC type, and sex.”

“Our study included a 24-week, randomized, double-blind, placebo-controlled period”

MethodsFind in source

Statistical analysisFind in source

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· 95% conf

Demographics and baseline characteristics are well reported, including sex, age, and health status.

Evidence

“Age – yr | 30.8±9.9 | 31.3±9.8 | 29.8±10.2 | | Male – no. (%) | 92 (50.5) | 61 (50.0) | 31 (51.7)”

Table 1Find in source

“White – no. (%) | 164 (90.1) | 107 (87.7) | 57 (95.0)”

Table 1Find in source

“Baseline mean GC dose was 17.6 mg/m 2 /day HCe with elevated mean androstenedione of 620 ng/dL (~2–3 times ULN)”

ResultsFind in source

PASSReviewer 2· 90% conf

Demographics and baseline characteristics are well reported, including sex, age, and health status.

Evidence

“Age – yr | 30.8±9.9 | 31.3±9.8 | 29.8±10.2 | | Male – no. (%) | 92 (50.5) | 61 (50.0) | 31 (51.7)”

Table 1Find in source

“White – no. (%) | 164 (90.1) | 107 (87.7) | 57 (95.0)”

Table 1Find in source

paraphrase[Results, Participants]

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 and informed consent are adequately reported.

Evidence

“The protocol was reviewed and approved by Independent Ethics Committees or Institutional Review Boards at each study site and by national health authorities for each country.”

MethodsFind in source

“All participants provided written informed consent.”

MethodsFind in source

“conducted in compliance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice guidelines”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethical approvals and informed consent are adequately documented.

Evidence

“The protocol was reviewed and approved by Independent Ethics Committees or Institutional Review Boards at each study site and by national health authorities for each country.”

MethodsFind in source

“All participants provided written informed consent.”

MethodsFind in source

“conducted in compliance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice guidelines”

MethodsFind in source

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedINADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational product (crinecerfont) is adequately identified, and statistical software is identified.

Evidence

“participants were randomized (2:1) to crinecerfont 100 mg or placebo twice daily with morning and evening meals.”

MethodsFind in source

absence[Methods, Statistical Analyses]

Statistical software is not explicitly named.

PASSReviewer 2· 90% conf

The investigational drug and key reagents are adequately identified.

Evidence

“participants were randomized (2:1) to crinecerfont 100 mg or placebo twice daily with morning and evening meals.”

MethodsFind in source

“All androgens and androgen precursors were measured at a central laboratory (Quest Diagnostics ® ) by liquid chromatography with tandem mass spectrometry.”

MethodsFind in source

absence[Methods, Statistical Analyses]

Statistical software is not identified.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedINADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

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

Evidence

paraphrase[Methods, Statistical Analyses]

“An analysis of covariance model was used to evaluate continuous end points ... A 2-sided Cochran-Mantel-Haenszel test was used to analyze categorical end points”

paraphrase[Table 2]

“Homeostatic model assessment for insulin resistance (week 24) | 122 | −0.65±0.21 | 60 | −0.36±0.28 | −0.29 (−0.89, 0.32) | |”

Table 2Find in source

PASSReviewer 2· 90% conf

Statistical methods are appropriate and well-described, with exact p-values and effect sizes with CIs.

Evidence

paraphrase[Methods, Statistical Analyses]

“An analysis of covariance model was used to evaluate continuous end points ... A 2-sided Cochran-Mantel-Haenszel test was used to analyze categorical end points”

“LSMD: −17.0%, P<0.001”

ResultsFind in source

“−17.0 (−23.8, −10.2)”

Table 2Find in source

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

Data availability is vague; no repository deposit or code sharing is mentioned.

Evidence

paraphrase[Methods, Trial Design and Oversight]

“The Sponsor and authors vouch for the accuracy and completeness of the data and affirm the fidelity of the trial to the protocol (available at NEJM.org).”

absence[Entire paper]

No repository deposit is mentioned.

WARNReviewer 2· 80% conf

Data availability is vague; no repository deposit or code sharing is mentioned.

Evidence

absence[Entire paper]

No data availability statement is present.

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· 95% conf

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

Evidence

paraphrase[Abstract]

“ClinicalTrials.gov number, NCT04490915”

Discussion ¶4Find in source

paraphrase[Funding and Disclosures sections]

“Financial support for the study was provided by Neurocrine Biosciences, Inc. ... Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.”

PASSReviewer 2· 90% conf

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

Evidence

paraphrase[Abstract]

“ClinicalTrials.gov number, NCT04490915”

DiscussionFind in source

“Financial support for the study was provided by Neurocrine Biosciences, Inc.”

FundingFind in source

Registered (4 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 42 references by DOI: 42 verified.

4 data/code links checked; 4 live.

Copyediting

4 minor

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

No major wording or formatting errors. 4 minor suggestions below.

4 copyedit issues flagged: mostly consistency, clarity.

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHdata code
Add a clear data availability statement in the Methods or a dedicated section, specifying that individual participant data may be available through a managed access process (e.g., via Neurocrine or a data-sharing platform) with conditions and timeframe.
The current statement is vague or absent, and a clear data-sharing mechanism is expected for a clinical trial.
2.
HIGHreporting
Resolve the internal contradiction in participant counts: abstract states 176 (96.7%) reached 24 weeks, but results sum to 174 (95.6%); clarify the definition of 'reached' vs 'completed' and ensure consistency.
An internal inconsistency in participant numbers could confuse readers and undermine trust in the reported results.
3.
MEDIUMstatistics
Name the statistical software (e.g., SAS version 9.4) used for analyses in the Statistical Analyses section.
Identifying the software is a standard reporting expectation and aids reproducibility.
4.
MEDIUMreporting
Mention adherence to a reporting guideline such as CONSORT in the Methods or provide a checklist submission statement.
Explicitly referencing CONSORT improves transparency and aligns with journal expectations.
5.
MEDIUMdata code
Consider depositing de-identified aggregate data or statistical analysis code in a public repository (e.g., Zenodo, Figshare) to enhance transparency.
Sharing code or aggregate data would strengthen reproducibility, though managed access is acceptable for IPD.
6.
LOWcopyedit
Fix the formatting of 'CAHtalyst Adult Study investigators' in the Abstract (add a period or format as a proper group name).
Minor formatting inconsistency that could be cleaned up.
7.
LOWcopyedit
Clarify in the Statistical Analyses section that the Cochran-Mantel-Haenszel test is for general association, not specifically for the endpoint.
Minor clarity issue that could prevent misinterpretation.
8.
LOWcopyedit
Clarify in the power analysis sentence that the effect size of 0.55 is for the primary endpoint.
Minor clarity improvement.

Full text (35,153 chars)Analyzed: Aug 16, 2026