Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Apitegromab for lean mass preservation during tirzepatide-induced weight loss: a randomized, double-blind, placebo-controlled phase 2 trial.

Name: Kaimen Rigor review — Apitegromab for lean mass preservation during tirzepatide-induced weight loss: a randomized, double-blind, placebo-controlled phase 2 trial.
Item: Apitegromab for lean mass preservation during tirzepatide-induced weight loss: a randomized, double-blind, placebo-controlled phase 2 trial.
Rating: 96
Author: Alpha1

Pratley RE, Denham DS, Trivedi R, Watkins E, Connery L, Barnes J, Yu D, Hong J, Simard C, Umans K, Liu L, Tirucherai GS, Marantz JL

Paper source

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Kaimen Rigor review — 1.75★ (Critical), 0 critical, 3 high issues for “Apitegromab for lean mass preservation during tirzepatide-induced weight loss: a randomized, double-blind, placebo-controlled phase 2 trial.”

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

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Apitegromab for lean mass preservation during tirzepatide-induced weight loss: a randomized, double-blind, placebo-controlled phase 2 trial.

Pratley RE, Denham DS, Trivedi R, Watkins E, Connery L, Barnes J, Yu D, Hong J, Simard C, Umans K, Liu L, Tirucherai GS, Marantz JL

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DOI

10.1038/s41591-026-04440-4

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Apitegromab for lean mass preservation during tirzepatide-induced weight loss: a randomized, double-blind, placebo-controlled phase 2 trial.

Pratley RE, Denham DS, Trivedi R, Watkins E, Connery L, Barnes J, Yu D, Hong J, Simard C, Umans K, Liu L, Tirucherai GS, Marantz JL

Paper source

Apitegromab for lean mass preservation during tirzepatide-induced weight loss: a randomized, double-blind, placebo-controlled phase 2 trial.

Read full text (PMC)

Embed this Rigor badge

Links back to this Kaimen Rigor review.

Alpha1 Editorial

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

Kaimen Rigor review

Kaimen Rigor reviewed

1.75 / 5

Critical — serious problems across many checks

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★
ReportingData & code availability partially met−0.25★

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 endpoint is change in lean body mass measured by DEXA, which is a surrogate for clinical outcomes such as physical function or health. Although the paper shows target engagement via increased latent myostatin levels, it does not cite validated evidence linking lean mass preservation to improved clinical outcomes in this context.
“Apitegromab resulted in a least square mean (80% confidence interval (CI)) of 1.9 (1.2−2.7) kg less lean mass loss than placebo (P = 0.001), despite similar total body weight loss between groups, representing a 54.9% retention of lean mass relative to placebo.”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The primary effect is a 1.9 kg difference in lean mass loss, which is a small fraction of total lean mass (baseline ~48-50 kg) and is not anchored to a minimal clinically important difference or functional benefit. The paper does not provide evidence that this magnitude of lean mass preservation translates to meaningful clinical outcomes.
“Apitegromab resulted in a least square mean (80% confidence interval (CI)) of 1.9 (1.2−2.7) kg less lean mass loss than placebo (P = 0.001), despite similar total body weight loss between groups, representing a 54.9% retention of lean mass relative to placebo.”
Find in source
03Other integrity concern
mediumAuthenticityreviewer-assessedFull detail
Trial NCT06445075 was first submitted to ClinicalTrials.gov on 2024-05-22, after the registered study start date of 2024-05-21. 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.
NCT06445075
reviewer’s wording

Findings by category

101ArithmeticNumerical inconsistencies 202OverreachOverstated conclusions 103AuthenticityData authenticity concerns 104DisclosureReporting gaps 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 and well-reported phase 2 randomized controlled trial with a clear scientific premise, rigorous design, and transparent reporting. The main weaknesses are a vague data availability statement and minor reporting gaps (outlier handling, model assumptions, explicit reporting guideline).

Both reviewers classified the study as interventional and agreed on all dimension statuses; no divergence required reconciliation. The statistics verification recomputed only 2 tests (those with test statistics/df or effect+CI); the rest of the statistical results are unverified. The citation check found no retracted or unresolved references. The preregistration check confirmed registration on ClinicalTrials.gov, but the integrity check noted the registration was submitted after the study start date (retrospective registration).

Numerical inconsistencies

1 finding · worst low

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

Internal contradictions in the reported numbersAssessed

Recomputed 2 tests: 2 consistent, 0 inconsistent; 2 via agent-written checks.

Overstated conclusions

2 findings · worst high

Conclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.

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

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

1 finding · worst medium

An adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.

Other integrity concernAssessed

4 integrity concerns flagged (0 high).

Reporting gaps

1 finding · worst medium

Required detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.

Data/code availability incompleteAssessed

Eight Dimensions7 pass · 1 warn

The introduction cites prior research on incretin mimetics and lean mass loss, and on myostatin biology and prior failed attempts at targeting myostatin, noting reasons such as off-target effects and suboptimal trial design. The rationale linking myostatin inhibition to lean mass preservation is logical and leads to the study objective. The paper also addresses limitations of prior research by highlighting the selective mechanism of apitegromab and appropriate trial design.

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: incretin mimetic therapies cause lean mass loss, and myostatin inhibition may preserve lean mass. Prior work is cited and limitations of prior myostatin-targeting attempts are acknowledged.

Evidence

paraphrase[Introduction, paragraph 1]

“Incretin mimetic therapy is accompanied by a loss of lean body mass that accounts for approximately 25−40% of total weight loss.”

paraphrase[Introduction, paragraph 3]

“Reasons for this include off-target side effects due to lack of target selectivity or inability to demonstrate efficacy due to inappropriate choice of disease or suboptimal trial design.”

“Apitegromab is an investigational, fully human monoclonal antibody that selectively binds precursor forms of myostatin to potently inhibit myostatin activation, without activity toward other TGFβ superfamily members.”

Introduction ¶3Find in source

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise with extensive prior work and a logical rationale for targeting myostatin to preserve lean mass during incretin-based weight loss.

Evidence

paraphrase[Introduction, paragraphs 1-3]

“Incretin mimetic therapy is accompanied by a loss of lean body mass that accounts for approximately 25−40% of total weight loss.”

paraphrase[Introduction, paragraph 3]

“Reasons for this include off-target side effects due to lack of target selectivity or inability to demonstrate efficacy due to inappropriate choice of disease or suboptimal trial design.”

“Collectively, these studies suggest that selective targeting of myostatin has therapeutic potential in preserving muscle as part of pharmacologic weight management.”

Introduction ¶4Find in source

Randomization was 1:1 via an interactive web response system without blocking or stratification, and blinding was described (sponsor, participants, investigators, site personnel blinded except pharmacist). A power analysis is reported: assuming SD 4.6 kg, 43 per arm yields ~75% power to detect 2 kg difference. Inclusion/exclusion criteria are extensive and pre-specified. The completer population is defined for efficacy, and ITT analyses were repeated. Outlier handling is not explicitly described, but the completer population and ITT sensitivity analyses address missing data. Controls are appropriate (placebo plus tirzepatide). Independent replication is not applicable for a single pivotal phase 2 trial.

Sub-criteria

controlsADEQUATE

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingINADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The trial is well-designed with clear randomization, blinding, power analysis, and pre-specified inclusion/exclusion criteria. The completer population for efficacy is defined, and the ITT analysis is supportive.

Evidence

“Participants were randomized (1:1 via an interactive web response system managed by an independent vendor, without blocking or stratification factors)”

MethodsFind in source

“The study sponsor, study participants, investigators and site personnel, with the exception of the pharmacist, were blinded to treatment assignments.”

MethodsFind in source

“Assuming a standard deviation of 4.6 kg, an evaluable sample size of 43 participants per study arm was determined to yield approximately 75% power to detect an effect size of 2 kg for the primary endpoint of lean body mass change from baseline at week 24.”

Statistical analysisFind in source

PASSReviewer 2· 95% conf

The trial design is rigorous: randomized, double-blind, placebo-controlled, with pre-specified inclusion/exclusion criteria, a power analysis, and a clear analysis population.

Evidence

“Participants were randomized (1:1 via an interactive web response system managed by an independent vendor, without blocking or stratification factors)”

MethodsFind in source

“The study sponsor, study participants, investigators and site personnel, with the exception of the pharmacist, were blinded to treatment assignments.”

MethodsFind in source

Statistical analysisFind in source

Table 1 reports sex (84.3% female in apitegromab, 80.4% in placebo), age (mean 44.2 and 42.6 years), weight, BMI, race, and other characteristics. Both sexes are included, so sex_justified is not applicable. Age, weight, and health status (BMI, comorbidities) are reported. Demographics are adequately reported. 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

Sex, age, weight, BMI, and other demographics are reported for both groups. Since both sexes are enrolled, sex justification is not applicable. Species/strain and housing are not applicable for a human trial.

Evidence

“Most participants were women (apitegromab, 84.3% (43/51); placebo, 80.4% (41/51)), and mean age (s.d.) was similar (apitegromab, 44.2 years (11.0); placebo, 42.6 years (11.5)).”

Results ¶1Find in source

paraphrase[Results, paragraph 1]

“At baseline, total body weight (s.d.) was 93.2 kg (14.9) and 98.8 kg (14.4), and body mass index (BMI) (s.d.) was 34.4 kg m−2 (4.1) and 36.4 kg m−2 (3.9) in the apitegromab and placebo groups, respectively.”

PASSReviewer 2· 90% conf

Biological variables are well reported for a human trial: sex, age, weight, BMI, and other demographics are provided in Table 1.

Evidence

“Female, n (%) | 43 (84.3) | 41 (80.4)”

Table 1Find in source

“Weight, mean (s.d.) (kg) | 93.2 (14.9) | 98.8 (14.4)”

Table 1Find in source

paraphrase[Table 1]

“Race, n (%) | White | 40 (78.4) | 38 (74.5)”

The Methods state: 'The trial protocol was approved by Advarra, a central institutional review board (IRB), as well as IRBs at participating sites and adhered to the Declaration of Helsinki and Good Clinical Practice guidelines.' This is a named ethics body with approval. Informed consent is mentioned: 'After a 4-week screening period and written informed consent...' Regulatory compliance is stated via Declaration of Helsinki and GCP. IACUC is not applicable for a human trial.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The trial was approved by a named central IRB (Advarra) and site IRBs, and adhered to the Declaration of Helsinki and GCP. Informed consent is mentioned.

Evidence

“The trial protocol was approved by Advarra, a central institutional review board (IRB), as well as IRBs at participating sites and adhered to the Declaration of Helsinki and Good Clinical Practice guidelines.”

MethodsFind in source

“After a 4-week screening period and written informed consent, site personnel administered an initial dose of tirzepatide 2.5 mg plus apitegromab or placebo (day 1).”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethical approvals are clearly documented: named IRB approval, informed consent, and compliance with Declaration of Helsinki and GCP.

Evidence

“The trial protocol was approved by Advarra, a central institutional review board (IRB), as well as IRBs at participating sites”

MethodsFind in source

“After a 4-week screening period and written informed consent”

MethodsFind in source

“adhered to the Declaration of Helsinki and Good Clinical Practice guidelines”

MethodsFind in source

Apitegromab is described as a fully human monoclonal antibody, and the dose (10 mg/kg every 4 weeks) is given. Tirzepatide is named with dose titration up to 15 mg weekly. DEXA scanners (Hologic and GE Lunar) are identified. Statistical software (SAS version 9.4) is identified. Antibodies, cell lines, mycoplasma, and organisms are not applicable for this clinical trial. Reagents are not applicable beyond the investigational products.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational product (apitegromab) and comparator (tirzepatide) are identified with dose and regimen. DEXA scanners are named. Statistical software is identified.

Evidence

paraphrase[Abstract]

“adults with overweight or obesity (n = 102) were randomized 1:1 to receive tirzepatide plus apitegromab (10 mg kg−1) or tirzepatide plus placebo.”

“Analyses were conducted using SAS version 9.4 software.”

Statistical analysisFind in source

PASSReviewer 2· 85% conf

The investigational product (apitegromab) and comparator (tirzepatide) are identified with dose and regimen; statistical software is identified.

Evidence

“randomized 1:1 to receive tirzepatide plus apitegromab (10 mg kg −1 ) or tirzepatide plus placebo”

AbstractFind in source

“Analyses were conducted using SAS version 9.4 software.”

Statistical analysisFind in source

The primary analysis uses a linear regression model controlling for baseline weight, baseline lean body mass, age, and sex. Two-sided p-values based on t-statistic are reported (e.g., P = 0.0014). Effect sizes with 80% CIs are reported throughout. Assumptions are not explicitly tested, but the use of a linear regression model with covariates is standard; for a clinical trial, this is adequate. Exact p-values are given for primary and secondary endpoints. Software is identified (SAS 9.4). Data presentation includes least square means with CIs and per-group n. Mathematical plausibility: I checked the AE percentages: 39/51 = 76.47% (reported 76%), 36/51 = 70.59% (reported 71%), 1/51 = 1.96% (reported 2%). These are consistent. The primary endpoint difference 1.9 kg with 80% CI (1.2-2.7) is plausible. No arithmetic errors detected.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedINADEQUATE

mathematical plausibilityPASS

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical tests are named (linear regression, t-statistic), effect sizes with CIs are reported, software is identified, and data presentation is appropriate for a clinical trial. Exact p-values are reported for key endpoints.

Evidence

“Least square means together with 80% CIs for each treatment group and the difference between groups in change from baseline at week 24 in lean body mass were estimated using a linear regression model controlling for baseline weight, baseline lean body mass, age and sex.”

Statistical analysisFind in source

“At week 24, apitegromab treatment significantly reduced lean mass loss, preserving 1.9 kg (1.2−2.7, least square means (80% confidence interval (CI))) of lean mass compared to placebo (nominal, P = 0.0014).”

ResultsFind in source

“Change in lean mass (kg) (80% CI) (primary endpoint) | −1.6 (−2.3, −0.8) | −3.5 (−4.1, −2.8) | 1.9 (1.2, 2.7) | 0.0014”

Table 2Find in source

PASSReviewer 2· 90% conf

Statistical methods are appropriate and well-described: linear regression models, exact p-values, effect sizes with CIs, and software identified.

Evidence

Statistical analysisFind in source

“preserving 1.9 kg (1.2−2.7, least square means (80% confidence interval (CI))) of lean mass compared to placebo (nominal, P = 0.0014)”

ResultsFind in source

“Change in lean mass (kg) (80% CI) (primary endpoint) | −1.6 (−2.3, −0.8) | −3.5 (−4.1, −2.8) | 1.9 (1.2, 2.7) | 0.0014”

Table 2Find in source

The data availability statement says: 'Scholar Rock, Inc. is committed to sharing deidentified clinical trial data with external investigators upon reasonable request.' It provides an email and a process, but it is not a named managed-access platform like YODA or Vivli. It is more concrete than a bare 'on request' but lacks a formal mechanism. Repository deposit and accession numbers are not applicable for patient-level data. Code sharing is not mentioned; since the analysis used standard software (SAS), it may not be applicable, but the paper does not state this.

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositN/A

data availability statementINADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 85% conf

A data availability statement is present but vague: it says data are available upon reasonable request to Scholar Rock, but does not specify a platform or conditions beyond a research proposal. No code sharing is mentioned.

Evidence

“Scholar Rock, Inc. is committed to sharing deidentified clinical trial data with external investigators upon reasonable request.”

Data availabilityFind in source

WARNReviewer 2· 80% conf

A data availability statement is present but vague, lacking a concrete access mechanism or timeframe beyond 'reasonable request'.

Evidence

“Scholar Rock, Inc. is committed to sharing deidentified clinical trial data with external investigators upon reasonable request.”

Data availabilityFind in source

Trial registration is provided (NCT06445075). Methods are comprehensive. Limitations are discussed in the Discussion, including completer analysis, small sample, predominantly female, and lack of objective physical activity. Conclusions are proportional, noting proof-of-concept. Funding and competing interests are disclosed. A reporting guideline is not explicitly named, but the paper mentions a 'Reporting Summary' linked to the article, which is typical for Nature journals.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineINADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The trial is registered (NCT06445075), methods are detailed, limitations are discussed, conclusions are proportional, and funding/COI are disclosed. A reporting guideline is not explicitly mentioned, but the paper includes a reporting summary.

Evidence

“ClinicalTrials.gov identifier: NCT06445075”

AbstractFind in source

“Several limitations should be considered when interpreting these results. The primary efficacy analysis is based on participants who completed the 24 weeks of treatment, although supportive analysis based on the intention-to-treat (ITT) population showed consistent findings.”

Discussion ¶4Find in source

“This work was supported by Scholar Rock, Inc. The funders had a role in the design and conduct of the trial; collection, management and analysis of the data; and the review of the manuscript.”

FundingFind in source

PASSReviewer 2· 90% conf

The manuscript is transparent: trial registration, detailed methods, limitations, and funding/COI statements are provided.

Evidence

“ClinicalTrials.gov identifier: NCT06445075”

AbstractFind in source

“Several limitations should be considered when interpreting these results.”

DiscussionFind in source

“This work was supported by Scholar Rock, Inc.”

FundingFind in source

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

Broken references and links

None found

References checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.

Checked — nothing surfaced.

Checked 20 references by DOI: 19 verified — 1 no DOI (shown, not verified).

3 data/code links checked; 3 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 consistency, clarity, punctuation.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust and generally trustworthy, but an informed reader should weigh the retrospective registration (NCT06445075 submitted after study start), the vague data availability mechanism, and the minor internal inconsistency in the primary p-value (0.001 vs 0.0014). These do not invalidate the findings but warrant clarification or a correction.

1.
HIGHreporting
In the Data availability section, specify a managed-access platform (e.g., Vivli or YODA) or a detailed data-sharing agreement process with a timeline for approval, to move from 'reasonable request' to a concrete mechanism.
The current statement is vague and does not meet the standard for a concrete data-sharing mechanism, which is a common reviewer concern.
2.
HIGHreporting
In the Methods or Reporting Summary, explicitly name the reporting guideline followed (e.g., CONSORT) and consider adding a CONSORT flow diagram.
Explicitly naming the reporting guideline strengthens transparency and is expected for clinical trials.
3.
HIGHstatistics
In the Statistical analysis section, add a statement on how outliers were handled and whether model assumptions (e.g., linearity, normality of residuals) were checked.
Both reviewers flagged outlier handling and assumptions as reported_but_inadequate; addressing these improves statistical rigor.
4.
MEDIUMreporting
Reconcile the primary endpoint p-value in the Abstract (P = 0.001) with the Results/Table 2 (P = 0.0014) to ensure consistency.
The integrity check flagged this internal contradiction; it is a minor rounding issue but should be corrected for accuracy.
5.
MEDIUMreporting
In the Methods, clarify the statement about semaglutide not being administered due to lack of drug availability, as semaglutide was not part of the trial design.
The integrity check noted this odd statement may be a leftover from a protocol amendment; clarifying avoids confusion.
6.
MEDIUMdata code
Add a statement about code availability, even if it is 'not applicable' because standard software was used.
The code_sharing sub-criterion is not reported; a brief statement addresses this gap.
7.
MEDIUMreporting
In the Discussion, expand on the unconventional use of 80% CIs and the 0.20 significance level, and their implications for interpretability.
Reviewer 2 suggested this; it helps readers understand the statistical choices.
8.
LOWcopyedit
Use 'least squares mean' consistently throughout the manuscript (Abstract and Results).
The copyedit pass flagged inconsistent terminology between 'least square mean' and 'least squares mean'.
9.
LOWcopyedit
Rephrase the primary endpoint sentence in Results for clarity: 'apitegromab preserved 1.9 kg (80% CI 1.2–2.7) more lean mass than placebo (nominal P = 0.0014)'.
The current phrasing is awkward and could be clearer.
10.
LOWcopyedit
In Table 3, ensure footnote 'c' is defined and use en dashes consistently for ranges and minus signs.
The copyedit pass flagged a missing footnote marker and inconsistent dash usage.

Full text (40,615 chars)Analyzed: Aug 15, 2026

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Apitegromab for lean mass preservation during tirzepatide-induced weight loss: a randomized, double-blind, placebo-controlled phase 2 trial.

Pratley RE, Denham DS, Trivedi R, Watkins E, Connery L, Barnes J, Yu D, Hong J, Simard C, Umans K, Liu L, Tirucherai GS, Marantz JL

Read full text (PMC)

DOI

10.1038/s41591-026-04440-4

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Record fingerprint

fbbc2fa59c700ef0c939200cee6a679f46b6909b1e9bd3ae3381d7a6816ea8d0

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

1.75 / 5

Critical — serious problems across many checks

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★
ReportingData & code availability partially met−0.25★

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 endpoint is change in lean body mass measured by DEXA, which is a surrogate for clinical outcomes such as physical function or health. Although the paper shows target engagement via increased latent myostatin levels, it does not cite validated evidence linking lean mass preservation to improved clinical outcomes in this context.
“Apitegromab resulted in a least square mean (80% confidence interval (CI)) of 1.9 (1.2−2.7) kg less lean mass loss than placebo (P = 0.001), despite similar total body weight loss between groups, representing a 54.9% retention of lean mass relative to placebo.”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The primary effect is a 1.9 kg difference in lean mass loss, which is a small fraction of total lean mass (baseline ~48-50 kg) and is not anchored to a minimal clinically important difference or functional benefit. The paper does not provide evidence that this magnitude of lean mass preservation translates to meaningful clinical outcomes.
“Apitegromab resulted in a least square mean (80% confidence interval (CI)) of 1.9 (1.2−2.7) kg less lean mass loss than placebo (P = 0.001), despite similar total body weight loss between groups, representing a 54.9% retention of lean mass relative to placebo.”
Find in source
03Other integrity concern
mediumAuthenticityreviewer-assessedFull detail
Trial NCT06445075 was first submitted to ClinicalTrials.gov on 2024-05-22, after the registered study start date of 2024-05-21. 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.
NCT06445075
reviewer’s wording

Findings by category

101ArithmeticNumerical inconsistencies 202OverreachOverstated conclusions 103AuthenticityData authenticity concerns 104DisclosureReporting gaps 05AvailabilityNone found 06Copyedit6 minor suggestions

Numerical inconsistencies

1 finding · worst low

Internal contradictions in the reported numbersAssessed

Recomputed 2 tests: 2 consistent, 0 inconsistent; 2 via agent-written checks.

Overstated conclusions

2 findings · worst high

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

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

1 finding · worst medium

Other integrity concernAssessed

4 integrity concerns flagged (0 high).

Reporting gaps

1 finding · worst medium

Data/code availability incompleteAssessed

Eight Dimensions7 pass · 1 warn

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Evidence

paraphrase[Introduction, paragraph 1]

“Incretin mimetic therapy is accompanied by a loss of lean body mass that accounts for approximately 25−40% of total weight loss.”

paraphrase[Introduction, paragraph 3]

“Reasons for this include off-target side effects due to lack of target selectivity or inability to demonstrate efficacy due to inappropriate choice of disease or suboptimal trial design.”

Introduction ¶3Find in source

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise with extensive prior work and a logical rationale for targeting myostatin to preserve lean mass during incretin-based weight loss.

Evidence

paraphrase[Introduction, paragraphs 1-3]

“Incretin mimetic therapy is accompanied by a loss of lean body mass that accounts for approximately 25−40% of total weight loss.”

paraphrase[Introduction, paragraph 3]

“Reasons for this include off-target side effects due to lack of target selectivity or inability to demonstrate efficacy due to inappropriate choice of disease or suboptimal trial design.”

“Collectively, these studies suggest that selective targeting of myostatin has therapeutic potential in preserving muscle as part of pharmacologic weight management.”

Introduction ¶4Find in source

Sub-criteria

controlsADEQUATE

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingINADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Evidence

“Participants were randomized (1:1 via an interactive web response system managed by an independent vendor, without blocking or stratification factors)”

MethodsFind in source

“The study sponsor, study participants, investigators and site personnel, with the exception of the pharmacist, were blinded to treatment assignments.”

MethodsFind in source

Statistical analysisFind in source

PASSReviewer 2· 95% conf

The trial design is rigorous: randomized, double-blind, placebo-controlled, with pre-specified inclusion/exclusion criteria, a power analysis, and a clear analysis population.

Evidence

“Participants were randomized (1:1 via an interactive web response system managed by an independent vendor, without blocking or stratification factors)”

MethodsFind in source

“The study sponsor, study participants, investigators and site personnel, with the exception of the pharmacist, were blinded to treatment assignments.”

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

Evidence

“Most participants were women (apitegromab, 84.3% (43/51); placebo, 80.4% (41/51)), and mean age (s.d.) was similar (apitegromab, 44.2 years (11.0); placebo, 42.6 years (11.5)).”

Results ¶1Find in source

paraphrase[Results, paragraph 1]

PASSReviewer 2· 90% conf

Biological variables are well reported for a human trial: sex, age, weight, BMI, and other demographics are provided in Table 1.

Evidence

“Female, n (%) | 43 (84.3) | 41 (80.4)”

Table 1Find in source

“Weight, mean (s.d.) (kg) | 93.2 (14.9) | 98.8 (14.4)”

Table 1Find in source

paraphrase[Table 1]

“Race, n (%) | White | 40 (78.4) | 38 (74.5)”

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The trial was approved by a named central IRB (Advarra) and site IRBs, and adhered to the Declaration of Helsinki and GCP. Informed consent is mentioned.

Evidence

MethodsFind in source

“After a 4-week screening period and written informed consent, site personnel administered an initial dose of tirzepatide 2.5 mg plus apitegromab or placebo (day 1).”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethical approvals are clearly documented: named IRB approval, informed consent, and compliance with Declaration of Helsinki and GCP.

Evidence

“The trial protocol was approved by Advarra, a central institutional review board (IRB), as well as IRBs at participating sites”

MethodsFind in source

“After a 4-week screening period and written informed consent”

MethodsFind in source

“adhered to the Declaration of Helsinki and Good Clinical Practice guidelines”

MethodsFind in source

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational product (apitegromab) and comparator (tirzepatide) are identified with dose and regimen. DEXA scanners are named. Statistical software is identified.

Evidence

paraphrase[Abstract]

“adults with overweight or obesity (n = 102) were randomized 1:1 to receive tirzepatide plus apitegromab (10 mg kg−1) or tirzepatide plus placebo.”

“Analyses were conducted using SAS version 9.4 software.”

Statistical analysisFind in source

PASSReviewer 2· 85% conf

The investigational product (apitegromab) and comparator (tirzepatide) are identified with dose and regimen; statistical software is identified.

Evidence

“randomized 1:1 to receive tirzepatide plus apitegromab (10 mg kg −1 ) or tirzepatide plus placebo”

AbstractFind in source

“Analyses were conducted using SAS version 9.4 software.”

Statistical analysisFind in source

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedINADEQUATE

mathematical plausibilityPASS

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Evidence

Statistical analysisFind in source

ResultsFind in source

“Change in lean mass (kg) (80% CI) (primary endpoint) | −1.6 (−2.3, −0.8) | −3.5 (−4.1, −2.8) | 1.9 (1.2, 2.7) | 0.0014”

Table 2Find in source

PASSReviewer 2· 90% conf

Statistical methods are appropriate and well-described: linear regression models, exact p-values, effect sizes with CIs, and software identified.

Evidence

Statistical analysisFind in source

“preserving 1.9 kg (1.2−2.7, least square means (80% confidence interval (CI))) of lean mass compared to placebo (nominal, P = 0.0014)”

ResultsFind in source

“Change in lean mass (kg) (80% CI) (primary endpoint) | −1.6 (−2.3, −0.8) | −3.5 (−4.1, −2.8) | 1.9 (1.2, 2.7) | 0.0014”

Table 2Find in source

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositN/A

data availability statementINADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 85% conf

Evidence

“Scholar Rock, Inc. is committed to sharing deidentified clinical trial data with external investigators upon reasonable request.”

Data availabilityFind in source

WARNReviewer 2· 80% conf

A data availability statement is present but vague, lacking a concrete access mechanism or timeframe beyond 'reasonable request'.

Evidence

“Scholar Rock, Inc. is committed to sharing deidentified clinical trial data with external investigators upon reasonable request.”

Data availabilityFind in source

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineINADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Evidence

“ClinicalTrials.gov identifier: NCT06445075”

AbstractFind in source

Discussion ¶4Find in source

“This work was supported by Scholar Rock, Inc. The funders had a role in the design and conduct of the trial; collection, management and analysis of the data; and the review of the manuscript.”

FundingFind in source

PASSReviewer 2· 90% conf

The manuscript is transparent: trial registration, detailed methods, limitations, and funding/COI statements are provided.

Evidence

“ClinicalTrials.gov identifier: NCT06445075”

AbstractFind in source

“Several limitations should be considered when interpreting these results.”

DiscussionFind in source

“This work was supported by Scholar Rock, Inc.”

FundingFind in source

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

Broken references and links

None found

References checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.

Checked — nothing surfaced.

Checked 20 references by DOI: 19 verified — 1 no DOI (shown, not verified).

3 data/code links checked; 3 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 consistency, clarity, punctuation.

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHreporting
In the Data availability section, specify a managed-access platform (e.g., Vivli or YODA) or a detailed data-sharing agreement process with a timeline for approval, to move from 'reasonable request' to a concrete mechanism.
The current statement is vague and does not meet the standard for a concrete data-sharing mechanism, which is a common reviewer concern.
2.
HIGHreporting
In the Methods or Reporting Summary, explicitly name the reporting guideline followed (e.g., CONSORT) and consider adding a CONSORT flow diagram.
Explicitly naming the reporting guideline strengthens transparency and is expected for clinical trials.
3.
HIGHstatistics
In the Statistical analysis section, add a statement on how outliers were handled and whether model assumptions (e.g., linearity, normality of residuals) were checked.
Both reviewers flagged outlier handling and assumptions as reported_but_inadequate; addressing these improves statistical rigor.
4.
MEDIUMreporting
Reconcile the primary endpoint p-value in the Abstract (P = 0.001) with the Results/Table 2 (P = 0.0014) to ensure consistency.
The integrity check flagged this internal contradiction; it is a minor rounding issue but should be corrected for accuracy.
5.
MEDIUMreporting
In the Methods, clarify the statement about semaglutide not being administered due to lack of drug availability, as semaglutide was not part of the trial design.
The integrity check noted this odd statement may be a leftover from a protocol amendment; clarifying avoids confusion.
6.
MEDIUMdata code
Add a statement about code availability, even if it is 'not applicable' because standard software was used.
The code_sharing sub-criterion is not reported; a brief statement addresses this gap.
7.
MEDIUMreporting
In the Discussion, expand on the unconventional use of 80% CIs and the 0.20 significance level, and their implications for interpretability.
Reviewer 2 suggested this; it helps readers understand the statistical choices.
8.
LOWcopyedit
Use 'least squares mean' consistently throughout the manuscript (Abstract and Results).
The copyedit pass flagged inconsistent terminology between 'least square mean' and 'least squares mean'.
9.
LOWcopyedit
Rephrase the primary endpoint sentence in Results for clarity: 'apitegromab preserved 1.9 kg (80% CI 1.2–2.7) more lean mass than placebo (nominal P = 0.0014)'.
The current phrasing is awkward and could be clearer.
10.
LOWcopyedit
In Table 3, ensure footnote 'c' is defined and use en dashes consistently for ranges and minus signs.
The copyedit pass flagged a missing footnote marker and inconsistent dash usage.

Full text (40,615 chars)Analyzed: Aug 15, 2026