Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Efficacy and safety of fezolinetant for moderate-severe vasomotor symptoms associated with menopause in individuals unsuitable for hormone therapy: phase 3b randomised controlled trial.

Name: Kaimen Rigor review — Efficacy and safety of fezolinetant for moderate-severe vasomotor symptoms associated with menopause in individuals unsuitable for hormone therapy: phase 3b randomised controlled trial.
Item: Efficacy and safety of fezolinetant for moderate-severe vasomotor symptoms associated with menopause in individuals unsuitable for hormone therapy: phase 3b randomised controlled trial.
Rating: 59
Author: Alpha1

Schaudig K, Wang X, Bouchard C, Hirschberg AL, Cano A, Shapiro C M M, Stute P, Wu X, Miyazaki K, Scrine L, Nappi RE

Paper source

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Kaimen Rigor review — 3★ (Adequate), 0 critical, 0 high issues for “Efficacy and safety of fezolinetant for moderate-severe vasomotor symptoms associated with menopause in individuals unsuitable for hormone therapy: phase 3b randomised controlled trial.”

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Alpha1 Editorial

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

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Efficacy and safety of fezolinetant for moderate-severe vasomotor symptoms associated with menopause in individuals unsuitable for hormone therapy: phase 3b randomised controlled trial.

Schaudig K, Wang X, Bouchard C, Hirschberg AL, Cano A, Shapiro C M M, Stute P, Wu X, Miyazaki K, Scrine L, Nappi RE

Read full text (PMC)

DOI

10.1136/bmj-2024-079525

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Efficacy and safety of fezolinetant for moderate-severe vasomotor symptoms associated with menopause in individuals unsuitable for hormone therapy: phase 3b randomised controlled trial.

Schaudig K, Wang X, Bouchard C, Hirschberg AL, Cano A, Shapiro C M M, Stute P, Wu X, Miyazaki K, Scrine L, Nappi RE

Paper source

Efficacy and safety of fezolinetant for moderate-severe vasomotor symptoms associated with menopause in individuals unsuitable for hormone therapy: phase 3b randomised controlled trial.

Read full text (PMC)

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Links back to this Kaimen Rigor review.

Alpha1 Editorial

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

Kaimen Rigor review

Kaimen Rigor reviewed

3 / 5

Adequate — real issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern−0.5★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
StatisticsPrinted percentage does not match its own count (capped)−0.25★
LinksDead data/code link−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.

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary endpoint is the frequency of moderate-severe vasomotor symptoms, a patient-reported symptom, not a hard clinical outcome. The paper does not provide evidence of target engagement at the tested dose (e.g., PK/PD data) nor does it cite validated evidence linking reduction in vasomotor symptom frequency to a hard clinical outcome. The efficacy claim is based on this surrogate measure.
“The primary endpoint was mean change in daily frequency of moderate-severe vasomotor symptoms from baseline to week 24.”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The primary effect is a reduction in vasomotor symptom frequency from 10.58 to 2.61 events/day (a 75.66% reduction) compared to placebo (59.12% reduction), with a between-group difference of -1.93 events/day. While statistically significant, the clinical meaningfulness of this difference is not anchored to a minimal clinically important difference or other established threshold. The paper does not provide a justification for why this magnitude is clinically meaningful.
“At week 24, fezolinetant significantly reduced the frequency (least squares mean difference –1.93, 95% confidence interval (CI) –2.64 to –1.22; P<0.001)”
Find in source
03Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
96.7% does not match the reported count 435/452
“most of the participants (435 (96.7%) were white”
ResultsFind in source
04Declared data/code link does not resolve
mediumAvailabilityrecomputedFull detail
Dead link — nothing to verify.
“https://www.trialsummaries.com/Home/LandingPage”
Find in source

Findings by category

201ArithmeticNumerical inconsistencies 202OverreachOverstated conclusions 03AuthenticityNone found 04DisclosureNone found 105AvailabilityBroken references and links 06Copyedit5 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 3b randomized controlled trial with strong methodological rigor across all eight dimensions. The paper clearly establishes the scientific premise, uses appropriate design and statistical methods, and provides comprehensive ethical, resource, and transparency documentation. Minor reporting gaps (e.g., statistical software not named, CONSORT not explicitly referenced) and a few copyedit issues (typos, misplaced DOI) do not undermine the overall integrity.

This is an interventional study (phase 3b RCT). Both reviewers agreed on the study type. The evaluation covered all eight dimensions; several sub-criteria were marked not applicable (e.g., animal-related items, independent replication) due to the human trial nature. The statistics verification covered only a subset of reported tests (4 tests), and the one 'inconsistent' finding was not specified; it may be a threshold-only p-value that cannot be machine-verified. The citation check found no retracted or non-existent references.

Numerical inconsistencies

2 findings · worst medium

Values that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.

Printed percentage does not match its own countRecomputed
Internal contradictions in the reported numbersAssessed

Recomputed 3 tests: 3 consistent, 0 inconsistent; 3 via agent-written checks. 1 printed percentage that does not match its own count.

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

8 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

None found

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.

Checked — nothing surfaced.

Eight Dimensions8 pass

The paper cites prior work on the prevalence and burden of vasomotor symptoms, limitations of hormone therapy, and existing non-hormonal options. It explicitly references the SKYLIGHT 1 and 2 phase 3 trials and explains that DAYLIGHT extends the placebo-controlled period to 24 weeks and enrolls a population unsuitable for hormone therapy. The rationale for the study is logically derived from the identified unmet need and the mechanism of fezolinetant. Limitations of prior research (e.g., shorter placebo control, broader population) are addressed by the study design.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The introduction establishes a clear unmet need for non-hormonal treatments for vasomotor symptoms and cites prior phase 3 studies (SKYLIGHT 1 and 2) as the basis for this phase 3b trial.

Evidence

“Fezolinetant was shown to be efficacious and well tolerated for treating moderate-severe vasomotor symptoms associated with menopause in phase 3 studies SKYLIGHT 1 and SKYLIGHT 2, which both included a 12 week placebo control period followed by active treatment extension to 52 weeks.”

Introduction ¶5Find in source

“A substantial unmet need therefore exists for safe and effective options for non-hormonal treatment of vasomotor symptoms associated with menopause.”

Introduction ¶4Find in source

“To further investigate the clinical benefits of fezolinetant for the treatment of moderate-severe vasomotor symptoms, we performed a phase 3b trial (DAYLIGHT), which included a 24 week placebo control period and enrolled a population considered unsuitable for hormone therapy.”

Introduction ¶5Find in source

PASSReviewer 2· 90% conf

The introduction establishes the unmet need for non-hormonal treatments and cites prior phase 3 studies (SKYLIGHT 1 and 2) as the basis for this phase 3b trial.

Evidence

Introduction ¶5Find in source

“The study included a longer placebo control period (24 weeks) than previous phase 3 studies”

DiscussionFind in source

Randomization used interactive response technology with stratification by smoking status. Blinding is described as double-blind. Power analysis is provided for the primary endpoint. Inclusion/exclusion criteria are described (age, symptom severity, unsuitability for hormone therapy). The analysis population (safety and full analysis sets) is defined, addressing missing data. Controls are inherent in the placebo arm. Independent replication is not applicable for a single pivotal trial.

Sub-criteria

controlsADEQUATE

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· 90% conf

The trial is a randomized, double-blind, placebo-controlled phase 3b study with adequate randomization, blinding, power analysis, and pre-specified endpoints.

Evidence

“Individuals aged 40-65 years with moderate-severe vasomotor symptoms associated with menopause and considered unsuitable candidates for hormone therapy were randomised 1:1 using interactive response technology to fezolinetant 45 mg or placebo once daily and stratified by smoking status (current and non-smoker (former or never)).”

MethodsFind in source

“For a pairwise comparison of the primary endpoint using a two sample t test at a two sided 5% α, we determined that 220 participants in each group would provide at least 80% power to detect a difference from placebo of –1.8, assuming a standard deviation (SD) of 5.6.”

Statistical analysisFind in source

“The present study was a phase 3b, randomised, double blind, placebo controlled trial to assess the efficacy and safety of fezolinetant for treating moderate-severe vasomotor symptoms associated with menopause in individuals considered unsuitable for hormone therapy.”

MethodsFind in source

PASSReviewer 2· 95% conf

The trial is well-designed with clear randomization, blinding, power analysis, and pre-specified endpoints.

Evidence

MethodsFind in source

Statistical analysisFind in source

“The present study was a phase 3b, randomised, double blind, placebo controlled trial”

MethodsFind in source

The study enrolled only women (individuals with menopause), so sex is reported and justified by the condition. Age (mean 54.5, SD 4.7) and weight/BMI are reported in Table 1. Health status is implied by inclusion criteria (moderate-severe VMS, unsuitable for HT). Demographics include race (96.7% white) and categories of HT unsuitability. Species/strain and housing are not applicable as this is a human trial.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedADEQUATE

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Demographic and baseline characteristics are well reported, including age, sex, race, and BMI; sex is all female by design, and age/health status are reported.

Evidence

“Mean (SD) age (years) | 54.9 (4.8) | 54.1 (4.6) | 54.5 (4.7)”

Table 1Find in source

“White | 217 (96.0) | 218 (97.3) | 435 (96.7)”

Table 1Find in source

“Participants 453 individuals aged 40-65 years with moderate-severe vasomotor symptoms associated with menopause”

AbstractFind in source

PASSReviewer 2· 90% conf

Demographic and baseline characteristics are well reported, including age, sex, race, and BMI.

Evidence

“Mean (SD) age (years) | 54.9 (4.8) | 54.1 (4.6) | 54.5 (4.7)”

Table 1Find in source

“White | 217 (96.0) | 218 (97.3) | 435 (96.7)”

Table 1Find in source

“individuals aged 40-65 years with moderate-severe vasomotor symptoms associated with menopause”

AbstractFind in source

The ethics statement lists the specific ethics committee or IRB for each of the 16 countries, which is more than adequate. Written informed consent is explicitly stated. Regulatory compliance with Declaration of Helsinki, Good Clinical Practice, and ICH guidelines is stated. No animal research is involved.

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 approval from named ethics committees at each site and written informed consent are documented, along with compliance with Declaration of Helsinki and GCP.

Evidence

paraphrase[Ethics statements]

“An independent ethics committee or institutional review board reviewed ethical, scientific, and medical appropriateness of the study before data collection at each site: Canada: Advarra IRB (Ontario, Canada); Netherlands: Medical Research Ethics Committees United (MEC-U), St Antonius Ziekenhuis (Nieuwegein, Netherlands); ...”

“Written informed consent was obtained from all participants before any study related procedures.”

MethodsFind in source

“This study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and International Council for Harmonisation guidelines.”

EthicsFind in source

PASSReviewer 2· 95% conf

Ethical approval from named ethics committees and informed consent are documented.

Evidence

paraphrase[Ethics statements]

“Written informed consent was obtained from all participants before any study related procedures.”

MethodsFind in source

“This study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and International Council for Harmonisation guidelines.”

EthicsFind in source

Fezolinetant is named as the investigational drug, with dose (45 mg) and regimen (once daily). The comparator is placebo. No antibodies, cell lines, or other reagents are used. The trial is registered (ClinicalTrials.gov NCT05033886). Statistical software is not explicitly named, but this is not a key biological resource.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedNOT REPORTED

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational product (fezolinetant 45 mg) is identified, and the trial is registered; no other key biological/chemical resources are used.

Evidence

“Intervention Fezolinetant 45 mg or placebo once daily for 24 weeks.”

AbstractFind in source

“Trial registration ClinicalTrials.gov NCT05033886 (https://clinicaltrials.gov/ct2/show/NCT05033886) ; EudraCT 2021-001685-38.”

AbstractFind in source

PASSReviewer 2· 90% conf

The investigational drug fezolinetant is identified with dose and regimen; no other key biological resources are used.

Evidence

“Fezolinetant 45 mg or placebo once daily for 24 weeks.”

AbstractFind in source

absence[Methods, Statistical analysis]

Statistical software is not explicitly named.

The primary analysis uses a mixed model for repeated measures, with least squares mean differences and 95% CIs. Exact p-values are reported (e.g., P<0.001). Effect sizes with CIs are provided. Statistical software is not explicitly named, but this is a minor omission. Data presentation includes tables with per-group n and dispersion. Mathematical plausibility checks: baseline means and SDs are plausible; percentages sum correctly (e.g., 96.7% + 3.3% = 100%). No inconsistencies found.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedNOT REPORTED

assumptions verifiedADEQUATE

mathematical plausibilityPASS

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical methods are appropriate and well-described, with exact p-values and confidence intervals for primary and secondary endpoints; no arithmetic errors detected.

Evidence

paraphrase[Results, Primary endpoint]

“Fezolinetant significantly reduced the frequency of vasomotor symptoms compared with placebo at week 24 (least squares mean difference –1.93, 95% confidence interval (CI) –2.64 to –1.22; P<0.001).”

“We performed a mixed model for repeated measures analysis with a missing at random assumption on change in the average daily frequency (or severity) of moderate-severe vasomotor symptoms from baseline to week 24.”

Statistical analysisFind in source

PASSReviewer 2· 90% conf

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

Evidence

Statistical analysisFind in source

“least squares mean difference –1.93, 95% confidence interval (CI) –2.64 to –1.22; P<0.001”

ResultsFind in source

“least squares mean difference –1.93, 95% confidence interval (CI) –2.64 to –1.22”

ResultsFind in source

The data availability statement names the platform (www.clinicalstudydatarequest.com) and specifies that anonymized participant-level data, trial-level data, and protocols are available on request. This meets the criteria for reported_and_adequate. No code is shared, but no bespoke code is mentioned. Repository deposit and accession numbers are not applicable for patient-level data.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

A data availability statement provides a concrete route for accessing anonymized participant-level data via a managed-access platform (ClinicalStudyDataRequest).

Evidence

paraphrase[Data availability statement]

“Researchers may request access to anonymised participant level data, trial level data, and protocols from Astellas sponsored clinical trials at www.clinicalstudydatarequest.com.”

PASSReviewer 2· 90% conf

Data availability statement provides a concrete access route via a managed-access platform.

Evidence

“Researchers may request access to anonymised participant level data, trial level data, and protocols from Astellas sponsored clinical trials at www.clinicalstudydatarequest.com”

Data availabilityFind in source

Trial registration is provided (NCT05033886). Methods are comprehensive. All pre-specified outcomes (primary, secondary, exploratory) are reported. Limitations are discussed (e.g., predominantly white population). Conclusions are proportional to the evidence. Funding and competing interests are disclosed. A reporting guideline (CONSORT) is not explicitly referenced, but the paper includes a flow diagram and follows standard reporting.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineNOT REPORTED

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The trial is registered, methods are detailed, limitations are discussed, and funding/COI are disclosed; no reporting guideline is explicitly mentioned, but the paper follows CONSORT-like structure.

Evidence

“Trial registration ClinicalTrials.gov NCT05033886 (https://clinicaltrials.gov/ct2/show/NCT05033886) ; EudraCT 2021-001685-38.”

AbstractFind in source

“A potential limitation of this study was that participants were from 16 countries (Canada, the Netherlands, Belgium, France, Spain, Finland, Hungary, Italy, Czech Republic, UK, Denmark, Sweden, Norway, Poland, Germany, and Turkey), with most self-identifying as white.”

DiscussionFind in source

paraphrase[Funding and Competing interests sections]

“Funding: This study was funded by Astellas Pharma. ... Competing interests: All authors have completed the ICMJE uniform disclosure form ...”

PASSReviewer 2· 90% conf

The trial is registered, methods are detailed, limitations are discussed, and funding/COI are disclosed.

Evidence

“Trial registration ClinicalTrials.gov NCT05033886 (https://clinicaltrials.gov/ct2/show/NCT05033886) ; EudraCT 2021-001685-38.”

AbstractFind in source

paraphrase[Discussion, Strengths and weaknesses]

“A potential limitation of this study was that participants were from 16 countries ... with most self-identifying as white.”

“Funding: This study was funded by Astellas Pharma.”

FundingFind in source

Registered (3 IDs: ClinicalTrials.gov, EudraCT). No reporting guideline cited.

Broken references and links

1 finding · worst medium

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.

Dead data/code linksRecomputed

Checked 28 references by DOI: 22 verified — 6 no DOI (shown, not verified).

6 of 7 data/code links checked; 5 live, 1 dead; 1 not probed.

Copyediting

5 minor

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

No major wording or formatting errors. 5 minor suggestions below.

5 copyedit issues flagged: mostly consistency, typo.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust and well-reported; an informed reader should weigh the minor reporting gaps (statistical software not named, CONSORT not explicitly referenced) and the copyedit issues (typos, misplaced DOI) as low-severity concerns. No erratum or re-analysis is warranted based on the available evidence.

1.
MEDIUMreporting
In the Methods section, explicitly name the statistical software (e.g., SAS version) used for all analyses.
Both reviewers noted the statistical software is not identified, which is a minor reporting gap that could be easily fixed.
2.
MEDIUMreporting
Add an explicit statement in the Methods or a dedicated section confirming adherence to the CONSORT reporting guideline, and consider providing the checklist as supplementary material.
The paper follows a CONSORT-like structure but does not explicitly reference the guideline, which is a minor transparency gap.
3.
MEDIUMcopyedit
Fix the typo 'Transminases increased' to 'Transaminases increased' in Table 6 and in the Results, Safety section.
The copyedit pass flagged this spelling error in two locations.
4.
MEDIUMcopyedit
Remove the misplaced DOI (10.1097/gme.0b013e31813429d6) from the data availability statement, as it appears to reference a different article.
The copyedit pass flagged this as a formatting error that could confuse readers.
5.
LOWcopyedit
Remove the duplicate page numbers 'e079525 e079525' from the abstract header.
The copyedit pass flagged this as a formatting inconsistency.
6.
LOWreporting
Consider providing a more detailed description of the blinding procedures (e.g., who was blinded, how allocation was concealed) in the Methods.
One reviewer suggested this as an improvement to enhance transparency.
7.
LOWstatistics
Clarify the handling of missing data for the PROMIS endpoint, as the number of participants with data differs from the full analysis set.
One reviewer raised this as a potential transparency issue.
8.
LOWreporting
Provide exact p-values for secondary endpoints that are reported as P<0.001, if possible, to enhance transparency.
One reviewer suggested this as an improvement for statistical reporting.

Full text (46,003 chars)Analyzed: Aug 16, 2026

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Read alongside

Efficacy and safety of fezolinetant for moderate-severe vasomotor symptoms associated with menopause in individuals unsuitable for hormone therapy: phase 3b randomised controlled trial.

Schaudig K, Wang X, Bouchard C, Hirschberg AL, Cano A, Shapiro C M M, Stute P, Wu X, Miyazaki K, Scrine L, Nappi RE

Read full text (PMC)

DOI

10.1136/bmj-2024-079525

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Record fingerprint

0b8da0982b32c02749ff8152d63aa44c12b666419de2000fed31104563ffd7df

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

3 / 5

Adequate — real issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern−0.5★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
StatisticsPrinted percentage does not match its own count (capped)−0.25★
LinksDead data/code link−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.

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary endpoint is the frequency of moderate-severe vasomotor symptoms, a patient-reported symptom, not a hard clinical outcome. The paper does not provide evidence of target engagement at the tested dose (e.g., PK/PD data) nor does it cite validated evidence linking reduction in vasomotor symptom frequency to a hard clinical outcome. The efficacy claim is based on this surrogate measure.
“The primary endpoint was mean change in daily frequency of moderate-severe vasomotor symptoms from baseline to week 24.”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The primary effect is a reduction in vasomotor symptom frequency from 10.58 to 2.61 events/day (a 75.66% reduction) compared to placebo (59.12% reduction), with a between-group difference of -1.93 events/day. While statistically significant, the clinical meaningfulness of this difference is not anchored to a minimal clinically important difference or other established threshold. The paper does not provide a justification for why this magnitude is clinically meaningful.
“At week 24, fezolinetant significantly reduced the frequency (least squares mean difference –1.93, 95% confidence interval (CI) –2.64 to –1.22; P<0.001)”
Find in source
03Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
96.7% does not match the reported count 435/452
“most of the participants (435 (96.7%) were white”
ResultsFind in source
04Declared data/code link does not resolve
mediumAvailabilityrecomputedFull detail
Dead link — nothing to verify.
“https://www.trialsummaries.com/Home/LandingPage”
Find in source

Findings by category

201ArithmeticNumerical inconsistencies 202OverreachOverstated conclusions 03AuthenticityNone found 04DisclosureNone found 105AvailabilityBroken references and links 06Copyedit5 minor suggestions

Numerical inconsistencies

2 findings · worst medium

Printed percentage does not match its own countRecomputed
Internal contradictions in the reported numbersAssessed

Recomputed 3 tests: 3 consistent, 0 inconsistent; 3 via agent-written checks. 1 printed percentage that does not match its own count.

Overstated conclusions

2 findings · worst high

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

8 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

None found

Checked — nothing surfaced.

Eight Dimensions8 pass

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The introduction establishes a clear unmet need for non-hormonal treatments for vasomotor symptoms and cites prior phase 3 studies (SKYLIGHT 1 and 2) as the basis for this phase 3b trial.

Evidence

Introduction ¶5Find in source

“A substantial unmet need therefore exists for safe and effective options for non-hormonal treatment of vasomotor symptoms associated with menopause.”

Introduction ¶4Find in source

Introduction ¶5Find in source

PASSReviewer 2· 90% conf

The introduction establishes the unmet need for non-hormonal treatments and cites prior phase 3 studies (SKYLIGHT 1 and 2) as the basis for this phase 3b trial.

Evidence

Introduction ¶5Find in source

“The study included a longer placebo control period (24 weeks) than previous phase 3 studies”

DiscussionFind in source

Sub-criteria

controlsADEQUATE

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· 90% conf

The trial is a randomized, double-blind, placebo-controlled phase 3b study with adequate randomization, blinding, power analysis, and pre-specified endpoints.

Evidence

MethodsFind in source

Statistical analysisFind in source

MethodsFind in source

PASSReviewer 2· 95% conf

The trial is well-designed with clear randomization, blinding, power analysis, and pre-specified endpoints.

Evidence

MethodsFind in source

Statistical analysisFind in source

“The present study was a phase 3b, randomised, double blind, placebo controlled trial”

MethodsFind in source

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedADEQUATE

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Demographic and baseline characteristics are well reported, including age, sex, race, and BMI; sex is all female by design, and age/health status are reported.

Evidence

“Mean (SD) age (years) | 54.9 (4.8) | 54.1 (4.6) | 54.5 (4.7)”

Table 1Find in source

“White | 217 (96.0) | 218 (97.3) | 435 (96.7)”

Table 1Find in source

“Participants 453 individuals aged 40-65 years with moderate-severe vasomotor symptoms associated with menopause”

AbstractFind in source

PASSReviewer 2· 90% conf

Demographic and baseline characteristics are well reported, including age, sex, race, and BMI.

Evidence

“Mean (SD) age (years) | 54.9 (4.8) | 54.1 (4.6) | 54.5 (4.7)”

Table 1Find in source

“White | 217 (96.0) | 218 (97.3) | 435 (96.7)”

Table 1Find in source

“individuals aged 40-65 years with moderate-severe vasomotor symptoms associated with menopause”

AbstractFind in source

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 approval from named ethics committees at each site and written informed consent are documented, along with compliance with Declaration of Helsinki and GCP.

Evidence

paraphrase[Ethics statements]

“Written informed consent was obtained from all participants before any study related procedures.”

MethodsFind in source

“This study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and International Council for Harmonisation guidelines.”

EthicsFind in source

PASSReviewer 2· 95% conf

Ethical approval from named ethics committees and informed consent are documented.

Evidence

paraphrase[Ethics statements]

“Written informed consent was obtained from all participants before any study related procedures.”

MethodsFind in source

“This study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and International Council for Harmonisation guidelines.”

EthicsFind in source

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedNOT REPORTED

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational product (fezolinetant 45 mg) is identified, and the trial is registered; no other key biological/chemical resources are used.

Evidence

“Intervention Fezolinetant 45 mg or placebo once daily for 24 weeks.”

AbstractFind in source

“Trial registration ClinicalTrials.gov NCT05033886 (https://clinicaltrials.gov/ct2/show/NCT05033886) ; EudraCT 2021-001685-38.”

AbstractFind in source

PASSReviewer 2· 90% conf

The investigational drug fezolinetant is identified with dose and regimen; no other key biological resources are used.

Evidence

“Fezolinetant 45 mg or placebo once daily for 24 weeks.”

AbstractFind in source

absence[Methods, Statistical analysis]

Statistical software is not explicitly named.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedNOT REPORTED

assumptions verifiedADEQUATE

mathematical plausibilityPASS

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical methods are appropriate and well-described, with exact p-values and confidence intervals for primary and secondary endpoints; no arithmetic errors detected.

Evidence

paraphrase[Results, Primary endpoint]

Statistical analysisFind in source

PASSReviewer 2· 90% conf

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

Evidence

Statistical analysisFind in source

“least squares mean difference –1.93, 95% confidence interval (CI) –2.64 to –1.22; P<0.001”

ResultsFind in source

“least squares mean difference –1.93, 95% confidence interval (CI) –2.64 to –1.22”

ResultsFind in source

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

A data availability statement provides a concrete route for accessing anonymized participant-level data via a managed-access platform (ClinicalStudyDataRequest).

Evidence

paraphrase[Data availability statement]

“Researchers may request access to anonymised participant level data, trial level data, and protocols from Astellas sponsored clinical trials at www.clinicalstudydatarequest.com.”

PASSReviewer 2· 90% conf

Data availability statement provides a concrete access route via a managed-access platform.

Evidence

“Researchers may request access to anonymised participant level data, trial level data, and protocols from Astellas sponsored clinical trials at www.clinicalstudydatarequest.com”

Data availabilityFind in source

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineNOT REPORTED

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The trial is registered, methods are detailed, limitations are discussed, and funding/COI are disclosed; no reporting guideline is explicitly mentioned, but the paper follows CONSORT-like structure.

Evidence

“Trial registration ClinicalTrials.gov NCT05033886 (https://clinicaltrials.gov/ct2/show/NCT05033886) ; EudraCT 2021-001685-38.”

AbstractFind in source

DiscussionFind in source

paraphrase[Funding and Competing interests sections]

“Funding: This study was funded by Astellas Pharma. ... Competing interests: All authors have completed the ICMJE uniform disclosure form ...”

PASSReviewer 2· 90% conf

The trial is registered, methods are detailed, limitations are discussed, and funding/COI are disclosed.

Evidence

“Trial registration ClinicalTrials.gov NCT05033886 (https://clinicaltrials.gov/ct2/show/NCT05033886) ; EudraCT 2021-001685-38.”

AbstractFind in source

paraphrase[Discussion, Strengths and weaknesses]

“A potential limitation of this study was that participants were from 16 countries ... with most self-identifying as white.”

“Funding: This study was funded by Astellas Pharma.”

FundingFind in source

Registered (3 IDs: ClinicalTrials.gov, EudraCT). No reporting guideline cited.

Broken references and links

1 finding · worst medium

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.

Dead data/code linksRecomputed

Checked 28 references by DOI: 22 verified — 6 no DOI (shown, not verified).

6 of 7 data/code links checked; 5 live, 1 dead; 1 not probed.

Copyediting

5 minor

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

No major wording or formatting errors. 5 minor suggestions below.

5 copyedit issues flagged: mostly consistency, typo.

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
MEDIUMreporting
In the Methods section, explicitly name the statistical software (e.g., SAS version) used for all analyses.
Both reviewers noted the statistical software is not identified, which is a minor reporting gap that could be easily fixed.
2.
MEDIUMreporting
Add an explicit statement in the Methods or a dedicated section confirming adherence to the CONSORT reporting guideline, and consider providing the checklist as supplementary material.
The paper follows a CONSORT-like structure but does not explicitly reference the guideline, which is a minor transparency gap.
3.
MEDIUMcopyedit
Fix the typo 'Transminases increased' to 'Transaminases increased' in Table 6 and in the Results, Safety section.
The copyedit pass flagged this spelling error in two locations.
4.
MEDIUMcopyedit
Remove the misplaced DOI (10.1097/gme.0b013e31813429d6) from the data availability statement, as it appears to reference a different article.
The copyedit pass flagged this as a formatting error that could confuse readers.
5.
LOWcopyedit
Remove the duplicate page numbers 'e079525 e079525' from the abstract header.
The copyedit pass flagged this as a formatting inconsistency.
6.
LOWreporting
Consider providing a more detailed description of the blinding procedures (e.g., who was blinded, how allocation was concealed) in the Methods.
One reviewer suggested this as an improvement to enhance transparency.
7.
LOWstatistics
Clarify the handling of missing data for the PROMIS endpoint, as the number of participants with data differs from the full analysis set.
One reviewer raised this as a potential transparency issue.
8.
LOWreporting
Provide exact p-values for secondary endpoints that are reported as P<0.001, if possible, to enhance transparency.
One reviewer suggested this as an improvement for statistical reporting.

Full text (46,003 chars)Analyzed: Aug 16, 2026