Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia.
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
- DOI
- 10.1056/NEJMoa2404656
- Record issued
- 2026-08-16
- Engine
- 7.39.0
- Exported
- 2026-09-20
Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/a48fcfd5-11bb-4b31-87c5-9767505e1cda is authoritative.
How this rating was calculated
- 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★
- 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.
- 01Efficacy rests on an unvalidated surrogate endpoint
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”
- 02Treatment effect not shown to be clinically meaningful
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])”
- 03Other integrity concern
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
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 lowValues 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.
- CONSISTENTreported p < .001 · recomputed p = <.001Reviewers 1, 2Primary endpoint: percent change in glucocorticoid dose (crinecerfont vs placebo) - LSMD and CI
“LSMD (95% CI) | P-value | | Percent change in glucocorticoid dose while androstenedione was controlled (week 24) | 122 | −27.3±2.4 | 60 | −10.3±3.2 | −17.0 (−23.8, −10.2) | <0.001”
Taken as given: The LSMD is -17.0 with 95% CI (-23.8, -10.2).; The CI is two-sided at 95%.; The p-value is two-sided.Method: Recomputed p-value from the LSMD and its 95% CI using the normal approximation.How we recomputed it: pCI(-17.0, -23.8, -10.2, 0) - CONSISTENTreported p < .001 · recomputed p = <.001Reviewers 1, 2Key secondary endpoint: serum androstenedione change at week 4 - LSMD and CI
“Serum androstenedione (week 4) – ng/dL | 122 | −299±37.7 | 60 | 45.5±51.0 | −345 (−457, −232) | <0.001”
Taken as given: The LSMD is -345 with 95% CI (-457, -232).; The CI is two-sided at 95%.; The p-value is two-sided.Method: Recomputed p-value from the LSMD and its 95% CI using the normal approximation.How we recomputed it: pCI(-345, -457, -232, 0)
- lowinternal contradictionThe abstract states 176 (96.7%) reached 24 weeks, but the results section says 117/122 crinecerfont and 57/60 placebo completed, which sums to 174 (95.6%). The discrepancy is minor and may be due to different definitions of 'reached' vs 'completed'.
Of 182 randomized participants (122 crinecerfont, 60 placebo), 176 (96.7%) reached 24 weeks. ... Of 182 randomized participants, >95% completed the study (117/122 crinecerfont, 57/60 placebo).
Abstractreviewer’s wording
Overstated conclusions
2 findings · worst highConclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.
- Efficacy rests on an unvalidated surrogate endpointAssessed
- Treatment effect not shown to be clinically meaningfulAssessed
6 major claims checked against the paper's own evidence: all adequately supported.
- supportedReviewers 1, 2Crinecerfont permitted reduction of supraphysiological glucocorticoid doses, including to physiological range, in adults with CAH.The primary endpoint showed a significantly greater GC dose reduction with crinecerfont, and a higher proportion achieved physiological doses.Evidence: Primary endpoint: LSMD -17.0%, P<0.001; 62.7% vs 17.5% achieved physiological dose.
“In this trial, crinecerfont permitted reduction of supraphysiological glucocorticoid doses, including to physiological range, following evaluation of adrenal androgen levels in patients with CAH.”
ConclusionFind in source - supportedReviewer 1Crinecerfont lowered androstenedione levels compared with placebo.The key secondary endpoint showed a significant reduction in androstenedione at week 4.Evidence: LSMD -345 ng/dL, P<0.001.
“At week 4, androstenedione levels decreased with crinecerfont (−299 ng/dL) but increased with placebo (+45.5 ng/dL) (LSMD: −345 ng/dL; P<0.001).”
AbstractFind in source - supportedReviewer 1Crinecerfont was acceptably tolerated.Safety data show similar TEAE rates and no deaths.Evidence: Any TEAE 82.8% vs 81.4%; no deaths.
Crinecerfont appeared to be acceptably tolerated, with similar incidences of TEAEs in both groups.
Resultsreviewer’s wording - supportedReviewer 2Crinecerfont markedly lowered androstenedione and 17OHP compared with placebo after the initial 4-week GC stable period.The week 4 androstenedione endpoint and 17OHP results support this claim.Evidence: Androstenedione LSMD -345 ng/dL (P<0.001); 17OHP decreased substantially with crinecerfont.
Consistent with data from the phase 2 trials, crinecerfont markedly lowered androstenedione and 17OHP compared with placebo after the initial 4-week GC stable period.
Discussion ¶2reviewer’s wording - supportedReviewer 2Crinecerfont therapy allowed both GC reduction to this goal and maintenance of prespecified androstenedione control in 62.7% of participants, compared with 17.5% in the placebo group.The key secondary endpoint directly supports this claim.Evidence: 62.7% vs 17.5% achieved physiological GC dose with androstenedione control (P<0.001).
“The major finding of this trial is that crinecerfont therapy allowed both GC reduction to this goal and maintenance of prespecified androstenedione control in 62.7% of participants, compared with 17.5% in the placebo group.”
Discussion ¶2Find in source - supportedReviewer 2Crinecerfont appeared to be acceptably tolerated.Safety data show similar TEAE rates and no deaths.Evidence: Any TEAE 82.8% vs 81.4%; serious TEAEs 3.3% vs 0; no deaths.
Crinecerfont appeared to be acceptably tolerated, with similar incidences of TEAEs in both groups.
Resultsreviewer’s wording
Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.
- INADEQUATESurrogate endpointThe 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”
- INADEQUATEEffect sizeThe 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])”
Data authenticity concerns
1 finding · worst mediumAn adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.
- Other integrity concernAssessed
2 integrity concerns flagged (0 high).
- mediumotherTrial 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
Reporting gaps
1 finding · worst mediumRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
- Data/code availability incompleteAssessed
The introduction cites prior 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.
“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.”
“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.”
“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.”
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.
“Our study included a 24-week, randomized, double-blind, placebo-controlled period”
“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.”
“Our study included a 24-week, randomized, double-blind, placebo-controlled period”
“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.”
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.
“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)”
“White – no. (%) | 164 (90.1) | 107 (87.7) | 57 (95.0)”
“Baseline mean GC dose was 17.6 mg/m 2 /day HCe with elevated mean androstenedione of 620 ng/dL (~2–3 times ULN)”
“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)”
“White – no. (%) | 164 (90.1) | 107 (87.7) | 57 (95.0)”
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.
“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.”
“All participants provided written informed consent.”
“conducted in compliance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice guidelines”
“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.”
“All participants provided written informed consent.”
“conducted in compliance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice guidelines”
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.
“participants were randomized (2:1) to crinecerfont 100 mg or placebo twice daily with morning and evening meals.”
“participants were randomized (2:1) to crinecerfont 100 mg or placebo twice daily with morning and evening meals.”
“All androgens and androgen precursors were measured at a central laboratory (Quest Diagnostics ® ) by liquid chromatography with tandem mass spectrometry.”
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).
“Homeostatic model assessment for insulin resistance (week 24) | 122 | −0.65±0.21 | 60 | −0.36±0.28 | −0.29 (−0.89, 0.32) | |”
“LSMD: −17.0%, P<0.001”
“−17.0 (−23.8, −10.2)”
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.
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.
“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”
“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, which might have limited interpretation of end points associated with androgen excess.”
“Financial support for the study was provided by Neurocrine Biosciences, Inc.”
Registered (4 IDs: ClinicalTrials.gov). No reporting guideline cited.
Broken references and links
None foundReferences checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.
Checked — nothing surfaced.
Checked 42 references by DOI: 42 verified.
Every extracted reference resolved against Crossref/OpenAlex with no retraction flags.
4 data/code links checked; 4 live.
- datahttps://clinicaltrials.gov/ct2/show/NCT04490915LIVEHTTP 200Resolves, but the content could not be matched to the paper.
- datahttps://clinicaltrials.gov/ct2/show/NCT03525886LIVEHTTP 200Resolves, but the content could not be matched to the paper.
- datahttps://clinicaltrials.gov/ct2/show/NCT04045145LIVEHTTP 200Resolves, but the content could not be matched to the paper.
- datahttps://clinicaltrials.gov/ct2/show/NCT04806451LIVEHTTP 200Resolves, but the content could not be matched to the paper.
Copyediting
4 minorWording, 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.
- MINORconsistencyAbstract“CAHtalyst Adult Study investigators”→ Consider adding a period or formatting as a proper group name.Minor formatting inconsistency.
- MINORclarityMethods, Statistical Analyses“A 2-sided Cochran-Mantel-Haenszel test was used to analyze categorical end points (e.g., achievement of reduction to a physiological GC dose with androstenedione control), with results presented as the number and percentage of participants and P-value for test of association.”→ Consider clarifying that the test is for general association, not specifically for the endpoint.Minor clarity issue.
- MINORconsistencyAbstract“CAHtalyst Adult Study investigators”→ Consider adding a period or formatting for consistency.Minor formatting.
- MINORclarityMethods, Statistical Analyses“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.”→ Clarify that the effect size is for the primary endpoint.Minor clarity.
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 codeAdd 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.HIGHreportingResolve 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.MEDIUMstatisticsName 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.MEDIUMreportingMention 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 codeConsider 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.LOWcopyeditFix 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.LOWcopyeditClarify 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.LOWcopyeditClarify in the power analysis sentence that the effect size of 0.55 is for the primary endpoint.Minor clarity improvement.
The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”
- Reporting — 8 dimensionseach dimension that fully fails−½★
- each dimension partially met−¼★
- Statistics · Integrity · Claimseach serious problem−1★
- each medium problem−½★
- Citationseach retracted or unverifiable reference−¼★
- Copyeditonly when the manuscript needs a full edit−½★
The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.
The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.
Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.
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