Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Effects of volenrelaxin in worsening heart failure with preserved ejection fraction: a phase 2 randomized trial.

Name: Kaimen Rigor review — Effects of volenrelaxin in worsening heart failure with preserved ejection fraction: a phase 2 randomized trial.
Item: Effects of volenrelaxin in worsening heart failure with preserved ejection fraction: a phase 2 randomized trial.
Rating: 100
Author: Alpha1

Borlaug BA, Testani JM, Petrie MC, Wang Z, Cunningham J, Adams KF Jr, Amir O, Bělohlávek J, Bocchi E, Freitas A Jr, Hominal M, Kadokami T, Merkely B, Miller CA, Nuñez J, Verma S, Yilmaz MB, Oru E, Sam F

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Effects of volenrelaxin in worsening heart failure with preserved ejection fraction: a phase 2 randomized trial.

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DOI

10.1038/s41591-025-03939-6

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Effects of volenrelaxin in worsening heart failure with preserved ejection fraction: a phase 2 randomized trial.

Paper source

Effects of volenrelaxin in worsening heart failure with preserved ejection fraction: a phase 2 randomized trial.

Read full text (PMC)

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$Kaimen Rigor review — 2★ (Weak), 0 critical, 0 high issues for “Effects of volenrelaxin in worsening heart failure with preserved ejection fraction: a phase 2 randomized trial.”$

Links back to this Kaimen Rigor review.

Alpha1 Editorial

This rigor review was examined and confirmed by Alpha1 Editorial · August 15, 2026

Kaimen Rigor review

Kaimen Rigor reviewed

2 / 5

Weak — serious problems found

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×4−2★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary efficacy claim is based on change in left atrial (LA) reservoir strain, a surrogate imaging biomarker, without demonstration of target engagement at the tested dose or citation of validated evidence linking LA reservoir strain to hard clinical outcomes. The paper itself notes the trial was stopped early due to worsening congestion and no significant effect on hard outcomes.
“The primary outcome was the change in LA reservoir strain at 26 weeks... Compared to placebo, 25-mg volenrelaxin improved LA reservoir strain (+3.9%, 95% confidence interval (CI): 1.1–6.6, P = 0.006)... In conclusion, despite some evidence for improvement in…”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The primary reported effect is a small absolute change in LA reservoir strain (+3.9%) compared to a baseline of ~18% (normal >39%), representing a modest relative improvement. The paper does not anchor this to a minimal clinically important difference or demonstrate meaningful clinical benefit, especially given the worsening congestion and lack of effect on hard outcomes.
“Compared to placebo, 25-mg volenrelaxin improved LA reservoir strain (+3.9%, 95% confidence interval (CI): 1.1–6.6, P = 0.006)... At baseline, participants had severely impaired LA reservoir strain (17.8%, normal > 39%)”
Find in source

Findings by category

101ArithmeticNumerical inconsistencies 202OverreachOverstated conclusions 103AuthenticityData authenticity concerns 04DisclosureNone found 05AvailabilityNone found 06Copyedit6 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 2 randomized controlled trial with rigorous design, clear reporting of demographics, ethics approval, and data availability. Minor reporting gaps include lack of explicit statistical software identification, incomplete inclusion/exclusion criteria in the main text, and a few copyedit issues.

Both reviewers classified the study as interventional, and I adopt that. The evaluation covered all eight dimensions; species/strain, housing, and cell-line criteria were not applicable for this human trial. The statistics verification recomputed 14 tests consistently, but this does not confirm overall statistical correctness.

Numerical inconsistencies

1 finding · worst low

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

Internal contradictions in the reported numbersAssessed

Recomputed 14 tests: 14 consistent, 0 inconsistent; 5 recomputed directly from the reported test statistics, 9 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

10 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 low

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

4 integrity concerns flagged (0 high).

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 introduction cites prior work on relaxin's vasodilatory, anti-inflammatory, and antifibrotic effects, and notes limitations of previous short-term trials. The rationale linking relaxin's effects to potential benefits in HFpEF is clearly articulated, and the study aims to address the gap of long-term relaxin therapy.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific premise by citing prior research on relaxin and HFpEF, and provides a logical rationale for the study hypothesis.

Evidence

paraphrase[Introduction, paragraph 1-2]

“Continuous intravenous infusion of short-acting recombinant human relaxin has demonstrated potentially beneficial acute effects in patients with acute HF, but previous trials were limited by the short-term (48-hour) exposure, which may explain why these acute beneficial effects did not translate into improvement in longer-term outcomes.”

“In the present study, we performed a multicenter, randomized, placebo-controlled trial to determine whether treatment with volenrelaxin for 26 weeks would improve LA function, reduce congestion and improve kidney function in patients with recent worsening HFpEF.”

Introduction ¶3Find in source

paraphrase[Introduction, paragraph 2]

“Volenrelaxin is a long-acting form of human relaxin modified to bind to serum albumin, extending its half-life to enable once-weekly dosing, allowing for longer-term RXFP1 activation.”

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise by citing prior research on relaxin and HFpEF, and provides a logical rationale for the study hypothesis.

Evidence

paraphrase[Introduction, paragraph 1-2]

Introduction ¶3Find in source

paraphrase[Introduction, paragraph 2]

“Volenrelaxin is a long-acting form of human relaxin modified to bind to serum albumin, extending its half-life to enable once-weekly dosing, allowing for longer-term RXFP1 activation.”

Randomization used a permuted block design with stratification, and blinding is described as double-blind. A power analysis is provided with assumptions. Inclusion/exclusion criteria are described, but not fully pre-specified in the main text (referenced to supplement). Outlier handling is not explicitly described, but the analysis population is defined (efficacy estimand). Controls are appropriate (placebo). Independent replication is not applicable for a single pivotal trial.

Sub-criteria

controlsADEQUATE

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingINADEQUATE

randomization unitADEQUATE

inclusion exclusionINADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The trial design is rigorous with adequate randomization, blinding, power analysis, and pre-specified endpoints, though some details on inclusion/exclusion and outlier handling are limited.

Evidence

“Randomization was performed by using a permuted block design using an interactive web response system and was stratified by (1) presence of atrial fibrillation or atrial flutter on screening electrocardiogram and (2) region of enrollment.”

MethodsFind in source

“eligible patients were randomized double blind (1:1:1:1) to receive volenrelaxin 25 mg, volenrelaxin 50 mg or volenrelaxin 100 mg per week or placebo subcutaneously”

MethodsFind in source

“Assuming an s.d. in LA reservoir strain of 8.5% and a two-sided α level of 0.05, 91 completers for 50-mg, 100-mg and placebo groups was calculated to provide 88% power to detect a treatment difference of 4% or more for the primary endpoint.”

Statistical analysisFind in source

PASSReviewer 2· 90% conf

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

Evidence

MethodsFind in source

“eligible patients were randomized double blind (1:1:1:1) to receive volenrelaxin 25 mg, volenrelaxin 50 mg or volenrelaxin 100 mg per week or placebo subcutaneously”

MethodsFind in source

Statistical analysisFind in source

Sex is reported for all participants, and age, BMI, and health status are detailed. Demographics include race and ethnicity, but the 'Other or mixed race' category has a small count. Species/strain and housing conditions are not applicable for a human trial.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Demographic and clinical characteristics are well reported, including sex, age, and health status, though some details like race/ethnicity are partially reported.

Evidence

“Mean age was 74 years; 49% were women; mean body mass index (BMI) was 30.6 kg m − 2”

Results ¶1Find in source

“Age (years) | 74.6 (9.1) | 74.1 (10.1) | 74.7 (8.1) | 72.4 (9.7) | 74.0 (9.3)”

Table 1Find in source

paraphrase[Table 1]

“Race | Asian | 7 (7.9) | 3 (3.8) | 4 (4.9) | 3 (3.8) | 17 (5.2)”

PASSReviewer 2· 90% conf

Demographic and clinical characteristics are well reported, including sex, age, and health status.

Evidence

“Mean age was 74 years; 49% were women; mean body mass index (BMI) was 30.6 kg m − 2”

Results ¶1Find in source

paraphrase[Table 1]

“Race: Asian 17 (5.2), Black or African American 18 (5.5), White 293 (89.1), Other or mixed race 1 (0.3)”

“31.9% of participants were determined to be in NYHA class III–IV at enrollment.”

Results ¶1Find in source

The paper states that the ethics committee at each investigative site approved the trial and all patients provided written informed consent. This satisfies both irb_ethics_statement and informed_consent. Regulatory compliance is implied but not explicitly named, but the statement is adequate.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceINADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Ethics approval and informed consent are adequately reported, with a named ethics committee and written consent.

Evidence

“The ethics committee at each investigative site approved the trial, and all patients provided written informed consent.”

Methods ¶1Find in source

“all patients provided written informed consent.”

Methods ¶1Find in source

PASSReviewer 2· 90% conf

Ethics approval and informed consent are adequately reported.

Evidence

“The ethics committee at each investigative site approved the trial, and all patients provided written informed consent.”

Methods ¶1Find in source

“all patients provided written informed consent.”

Methods ¶1Find in source

Volenrelaxin is named with doses and route, and the sponsor is identified. Assays are described with some vendor information (e.g., Roche cobas). Software for statistical analysis is not explicitly named, but the statistical methods are described. Since this is a drug trial, the investigational product is the key resource and is adequately identified.

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 (volenrelaxin) is adequately identified, and the statistical software is identified, though some assay details are incomplete.

Evidence

“eligible patients were randomized double blind (1:1:1:1) to receive volenrelaxin 25 mg, volenrelaxin 50 mg or volenrelaxin 100 mg per week or placebo subcutaneously”

MethodsFind in source

“Cystatin C was determined using a turbidimetric assay (Roche cobas chemistry analyzer).”

MethodsFind in source

PASSReviewer 2· 90% conf

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

Evidence

“The RELAXIN-LA (A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy and Safety of LY3540378 in Adults with Worsening Chronic Heart Failure with Preserved Ejection Fraction) trial”

Methods ¶1Find in source

“eligible patients were randomized double blind (1:1:1:1) to receive volenrelaxin 25 mg, volenrelaxin 50 mg or volenrelaxin 100 mg per week or placebo subcutaneously”

MethodsFind in source

The primary analysis uses MMRM, and tests are named. Exact p-values are reported for primary and secondary endpoints. Effect sizes are reported with 95% CIs. Software is not explicitly identified, but the methods are described. Data presentation includes per-group n and error bars. Mathematical plausibility checks were not performed due to lack of raw data, but no obvious errors were found.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedNOT REPORTED

assumptions verifiedINADEQUATE

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, though some assumptions are not explicitly verified.

Evidence

“Treatment comparison is assessed using two-sided t -test based on least square means from MMRM.”

Table 2Find in source

“Compared to placebo, 25-mg volenrelaxin improved LA reservoir strain (+3.9%, 95% confidence interval (CI): 1.1–6.6, P = 0.006)”

ResultsFind in source

“Compared to placebo, 25-mg volenrelaxin improved LA reservoir strain (+3.9%, 95% confidence interval (CI): 1.1–6.6, P = 0.006)”

ResultsFind in source

PASSReviewer 2· 90% conf

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

Evidence

“Treatment comparison is assessed using two-sided t -test based on least square means from MMRM.”

Table 2Find in source

“Compared to placebo, 25-mg volenrelaxin improved LA reservoir strain (+3.9%, 95% confidence interval (CI): 1.1–6.6, P = 0.006)”

ResultsFind in source

“Compared to placebo, 25-mg volenrelaxin improved LA reservoir strain (+3.9%, 95% confidence interval (CI): 1.1–6.6, P = 0.006)”

ResultsFind in source

The data availability statement provides a concrete mechanism for accessing individual participant data through Vivli, with conditions and timeframe. Repository deposit and accession numbers are not applicable for patient-level data. Code sharing is not applicable as no bespoke code is mentioned.

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

Data availability is well-described with a concrete access route via Vivli, and the trial is registered.

Evidence

“Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization, except for pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the United States and the European Union and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data have been made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data-sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report and blank or annotated case report forms, will be provided in a secure data-sharing environment. For details on submitting a request, see the instructions provided at https://vivli.org/ .”

Data availabilityFind in source

PASSReviewer 2· 90% conf

Data availability is adequately described with a concrete access route via Vivli.

Evidence

Data availabilityFind in source

The trial is registered (NCT05592275). Methods are detailed enough for replication. Limitations are discussed. Conclusions are proportional to the evidence. Funding and COI are disclosed. A reporting guideline is not explicitly mentioned, but the paper follows CONSORT-like structure.

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 manuscript is transparent with trial registration, detailed methods, and discussion of limitations, though a reporting guideline is not explicitly mentioned.

Evidence

“ClinicalTrials.gov identifier: NCT05592275 (https://clinicaltrials.gov/study/NCT05592275) .”

AbstractFind in source

“The major limitation relates to the fact that this trial was stopped early before the target enrollment was achieved, decreasing power.”

Discussion ¶7Find in source

“The RELAXIN-LA trial was funded by Eli Lilly and Company.”

AcknowledgementsFind in source

PASSReviewer 2· 90% conf

The manuscript is transparent with trial registration, reporting guideline, and comprehensive reporting of outcomes and limitations.

Evidence

“ClinicalTrials.gov identifier: NCT05592275 (https://clinicaltrials.gov/study/NCT05592275) .”

AbstractFind in source

“Further information on research design is available in the linked to this article.”

AbstractFind in source

“The major limitation relates to the fact that this trial was stopped early before the target enrollment was achieved, decreasing power.”

Discussion ¶7Find in source

Registered (1 ID: 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 43 references by DOI: 43 verified.

1 data/code link checked; 1 live.

Copyediting

6 minor

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

No major wording or formatting errors. 6 minor suggestions below.

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

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust and well-reported; an informed reader should weigh the early termination and reduced power as the main limitation. Minor reporting gaps (statistical software, explicit reporting guideline) and copyedit typos do not undermine the conclusions but could be addressed in a correction or noted in a reader's assessment.

1.
MEDIUMreporting
In the Methods, explicitly state the statistical software (e.g., SAS version) used for analyses.
Both reviewers flagged software_identified as inadequate; naming the software improves reproducibility.
2.
MEDIUMreporting
In the Methods, provide a more detailed description of inclusion/exclusion criteria in the main text rather than referring only to the supplement.
Reviewer 1 noted this as inadequate; full criteria in the main text improve transparency.
3.
MEDIUMreporting
In the Methods, explicitly state compliance with the Declaration of Helsinki or ICH-GCP guidelines.
Both reviewers noted regulatory_compliance as inadequate; explicit statement strengthens ethics reporting.
4.
MEDIUMreporting
In the Methods, mention adherence to CONSORT guidelines for reporting clinical trials.
Reviewer 1 noted reporting_guideline as not reported; explicit mention improves transparency.
5.
MEDIUMstatistics
In the Statistical methods, describe how assumptions of the MMRM were verified (e.g., normality of residuals).
Reviewer 1 noted assumptions_verified as inadequate; documenting assumption checks strengthens statistical rigor.
6.
LOWcopyedit
In the Abstract, remove the extraneous numbers '31 11 500671 3853 3861'.
Copyedit flagged this as a formatting artifact that should be cleaned.
7.
LOWcopyedit
In Author affiliations, correct 'Hospitasl' to 'Hospital' in affiliation 10.
Copyedit flagged a typographical error in the affiliation name.
8.
LOWcopyedit
In Table 1, ensure race percentages sum to 100% for each group, adjusting for rounding.
Copyedit flagged minor rounding inconsistencies in percentages.
9.
LOWreporting
In the Methods, clarify the nature of the protocol breach and the specific inclusion criterion that was not met.
Copyedit flagged this as a clarity issue; more specificity improves transparency.
10.
LOWdata code
In the Data Availability section, consider adding a statement about code availability if any custom analysis code was used.
Reviewer 2 suggested this to fully address code_sharing.
11.
LOWreporting
In the Discussion, add a sentence acknowledging the lack of independent replication and the need for confirmatory trials.
Reviewer 2 suggested this to strengthen the limitations discussion.
12.
LOWreporting
In the Methods, provide more detail on the blinding of the central core laboratory and the clinical endpoint committee.
Reviewer 2 suggested this to fully address blinding_levels.

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Effects of volenrelaxin in worsening heart failure with preserved ejection fraction: a phase 2 randomized trial.

Read full text (PMC)

DOI

10.1038/s41591-025-03939-6

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$Kaimen Rigor review — 2★ (Weak), 0 critical, 0 high issues for “Effects of volenrelaxin in worsening heart failure with preserved ejection fraction: a phase 2 randomized trial.”$

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Record fingerprint

607f2f9dd2b2468b82889d3a1d5b1580fd8e7112b57eb666acac3d97176872ab

Verify via API

Issued Aug 15, 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 / 5

Weak — serious problems found

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×4−2★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary efficacy claim is based on change in left atrial (LA) reservoir strain, a surrogate imaging biomarker, without demonstration of target engagement at the tested dose or citation of validated evidence linking LA reservoir strain to hard clinical outcomes. The paper itself notes the trial was stopped early due to worsening congestion and no significant effect on hard outcomes.
“The primary outcome was the change in LA reservoir strain at 26 weeks... Compared to placebo, 25-mg volenrelaxin improved LA reservoir strain (+3.9%, 95% confidence interval (CI): 1.1–6.6, P = 0.006)... In conclusion, despite some evidence for improvement in…”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The primary reported effect is a small absolute change in LA reservoir strain (+3.9%) compared to a baseline of ~18% (normal >39%), representing a modest relative improvement. The paper does not anchor this to a minimal clinically important difference or demonstrate meaningful clinical benefit, especially given the worsening congestion and lack of effect on hard outcomes.
“Compared to placebo, 25-mg volenrelaxin improved LA reservoir strain (+3.9%, 95% confidence interval (CI): 1.1–6.6, P = 0.006)... At baseline, participants had severely impaired LA reservoir strain (17.8%, normal > 39%)”
Find in source

Findings by category

101ArithmeticNumerical inconsistencies 202OverreachOverstated conclusions 103AuthenticityData authenticity concerns 04DisclosureNone found 05AvailabilityNone found 06Copyedit6 minor suggestions

Numerical inconsistencies

1 finding · worst low

Internal contradictions in the reported numbersAssessed

Recomputed 14 tests: 14 consistent, 0 inconsistent; 5 recomputed directly from the reported test statistics, 9 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

10 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 low

Other integrity concernAssessed

4 integrity concerns flagged (0 high).

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 paper establishes a clear scientific premise by citing prior research on relaxin and HFpEF, and provides a logical rationale for the study hypothesis.

Evidence

paraphrase[Introduction, paragraph 1-2]

Introduction ¶3Find in source

paraphrase[Introduction, paragraph 2]

“Volenrelaxin is a long-acting form of human relaxin modified to bind to serum albumin, extending its half-life to enable once-weekly dosing, allowing for longer-term RXFP1 activation.”

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise by citing prior research on relaxin and HFpEF, and provides a logical rationale for the study hypothesis.

Evidence

paraphrase[Introduction, paragraph 1-2]

Introduction ¶3Find in source

paraphrase[Introduction, paragraph 2]

“Volenrelaxin is a long-acting form of human relaxin modified to bind to serum albumin, extending its half-life to enable once-weekly dosing, allowing for longer-term RXFP1 activation.”

Sub-criteria

controlsADEQUATE

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingINADEQUATE

randomization unitADEQUATE

inclusion exclusionINADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The trial design is rigorous with adequate randomization, blinding, power analysis, and pre-specified endpoints, though some details on inclusion/exclusion and outlier handling are limited.

Evidence

MethodsFind in source

“eligible patients were randomized double blind (1:1:1:1) to receive volenrelaxin 25 mg, volenrelaxin 50 mg or volenrelaxin 100 mg per week or placebo subcutaneously”

MethodsFind in source

Statistical analysisFind in source

PASSReviewer 2· 90% conf

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

Evidence

MethodsFind in source

“eligible patients were randomized double blind (1:1:1:1) to receive volenrelaxin 25 mg, volenrelaxin 50 mg or volenrelaxin 100 mg per week or placebo subcutaneously”

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· 90% conf

Demographic and clinical characteristics are well reported, including sex, age, and health status, though some details like race/ethnicity are partially reported.

Evidence

“Mean age was 74 years; 49% were women; mean body mass index (BMI) was 30.6 kg m − 2”

Results ¶1Find in source

“Age (years) | 74.6 (9.1) | 74.1 (10.1) | 74.7 (8.1) | 72.4 (9.7) | 74.0 (9.3)”

Table 1Find in source

paraphrase[Table 1]

“Race | Asian | 7 (7.9) | 3 (3.8) | 4 (4.9) | 3 (3.8) | 17 (5.2)”

PASSReviewer 2· 90% conf

Demographic and clinical characteristics are well reported, including sex, age, and health status.

Evidence

“Mean age was 74 years; 49% were women; mean body mass index (BMI) was 30.6 kg m − 2”

Results ¶1Find in source

paraphrase[Table 1]

“Race: Asian 17 (5.2), Black or African American 18 (5.5), White 293 (89.1), Other or mixed race 1 (0.3)”

“31.9% of participants were determined to be in NYHA class III–IV at enrollment.”

Results ¶1Find in source

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceINADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Ethics approval and informed consent are adequately reported, with a named ethics committee and written consent.

Evidence

“The ethics committee at each investigative site approved the trial, and all patients provided written informed consent.”

Methods ¶1Find in source

“all patients provided written informed consent.”

Methods ¶1Find in source

PASSReviewer 2· 90% conf

Ethics approval and informed consent are adequately reported.

Evidence

“The ethics committee at each investigative site approved the trial, and all patients provided written informed consent.”

Methods ¶1Find in source

“all patients provided written informed consent.”

Methods ¶1Find 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 (volenrelaxin) is adequately identified, and the statistical software is identified, though some assay details are incomplete.

Evidence

“eligible patients were randomized double blind (1:1:1:1) to receive volenrelaxin 25 mg, volenrelaxin 50 mg or volenrelaxin 100 mg per week or placebo subcutaneously”

MethodsFind in source

“Cystatin C was determined using a turbidimetric assay (Roche cobas chemistry analyzer).”

MethodsFind in source

PASSReviewer 2· 90% conf

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

Evidence

Methods ¶1Find in source

“eligible patients were randomized double blind (1:1:1:1) to receive volenrelaxin 25 mg, volenrelaxin 50 mg or volenrelaxin 100 mg per week or placebo subcutaneously”

MethodsFind in source

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedNOT REPORTED

assumptions verifiedINADEQUATE

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, though some assumptions are not explicitly verified.

Evidence

“Treatment comparison is assessed using two-sided t -test based on least square means from MMRM.”

Table 2Find in source

“Compared to placebo, 25-mg volenrelaxin improved LA reservoir strain (+3.9%, 95% confidence interval (CI): 1.1–6.6, P = 0.006)”

ResultsFind in source

“Compared to placebo, 25-mg volenrelaxin improved LA reservoir strain (+3.9%, 95% confidence interval (CI): 1.1–6.6, P = 0.006)”

ResultsFind in source

PASSReviewer 2· 90% conf

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

Evidence

“Treatment comparison is assessed using two-sided t -test based on least square means from MMRM.”

Table 2Find in source

“Compared to placebo, 25-mg volenrelaxin improved LA reservoir strain (+3.9%, 95% confidence interval (CI): 1.1–6.6, P = 0.006)”

ResultsFind in source

“Compared to placebo, 25-mg volenrelaxin improved LA reservoir strain (+3.9%, 95% confidence interval (CI): 1.1–6.6, P = 0.006)”

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

Data availability is well-described with a concrete access route via Vivli, and the trial is registered.

Evidence

Data availabilityFind in source

PASSReviewer 2· 90% conf

Data availability is adequately described with a concrete access route via Vivli.

Evidence

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 manuscript is transparent with trial registration, detailed methods, and discussion of limitations, though a reporting guideline is not explicitly mentioned.

Evidence

“ClinicalTrials.gov identifier: NCT05592275 (https://clinicaltrials.gov/study/NCT05592275) .”

AbstractFind in source

“The major limitation relates to the fact that this trial was stopped early before the target enrollment was achieved, decreasing power.”

Discussion ¶7Find in source

“The RELAXIN-LA trial was funded by Eli Lilly and Company.”

AcknowledgementsFind in source

PASSReviewer 2· 90% conf

The manuscript is transparent with trial registration, reporting guideline, and comprehensive reporting of outcomes and limitations.

Evidence

“ClinicalTrials.gov identifier: NCT05592275 (https://clinicaltrials.gov/study/NCT05592275) .”

AbstractFind in source

“Further information on research design is available in the linked to this article.”

AbstractFind in source

“The major limitation relates to the fact that this trial was stopped early before the target enrollment was achieved, decreasing power.”

Discussion ¶7Find in source

Registered (1 ID: 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 43 references by DOI: 43 verified.

1 data/code link checked; 1 live.

Copyediting

6 minor

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

No major wording or formatting errors. 6 minor suggestions below.

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

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
MEDIUMreporting
In the Methods, explicitly state the statistical software (e.g., SAS version) used for analyses.
Both reviewers flagged software_identified as inadequate; naming the software improves reproducibility.
2.
MEDIUMreporting
In the Methods, provide a more detailed description of inclusion/exclusion criteria in the main text rather than referring only to the supplement.
Reviewer 1 noted this as inadequate; full criteria in the main text improve transparency.
3.
MEDIUMreporting
In the Methods, explicitly state compliance with the Declaration of Helsinki or ICH-GCP guidelines.
Both reviewers noted regulatory_compliance as inadequate; explicit statement strengthens ethics reporting.
4.
MEDIUMreporting
In the Methods, mention adherence to CONSORT guidelines for reporting clinical trials.
Reviewer 1 noted reporting_guideline as not reported; explicit mention improves transparency.
5.
MEDIUMstatistics
In the Statistical methods, describe how assumptions of the MMRM were verified (e.g., normality of residuals).
Reviewer 1 noted assumptions_verified as inadequate; documenting assumption checks strengthens statistical rigor.
6.
LOWcopyedit
In the Abstract, remove the extraneous numbers '31 11 500671 3853 3861'.
Copyedit flagged this as a formatting artifact that should be cleaned.
7.
LOWcopyedit
In Author affiliations, correct 'Hospitasl' to 'Hospital' in affiliation 10.
Copyedit flagged a typographical error in the affiliation name.
8.
LOWcopyedit
In Table 1, ensure race percentages sum to 100% for each group, adjusting for rounding.
Copyedit flagged minor rounding inconsistencies in percentages.
9.
LOWreporting
In the Methods, clarify the nature of the protocol breach and the specific inclusion criterion that was not met.
Copyedit flagged this as a clarity issue; more specificity improves transparency.
10.
LOWdata code
In the Data Availability section, consider adding a statement about code availability if any custom analysis code was used.
Reviewer 2 suggested this to fully address code_sharing.
11.
LOWreporting
In the Discussion, add a sentence acknowledging the lack of independent replication and the need for confirmatory trials.
Reviewer 2 suggested this to strengthen the limitations discussion.
12.
LOWreporting
In the Methods, provide more detail on the blinding of the central core laboratory and the clinical endpoint committee.
Reviewer 2 suggested this to fully address blinding_levels.

Full text (64,513 chars)Analyzed: Aug 15, 2026