Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Anti-inflammatory therapy with low-dose IL-2 in acute coronary syndromes: a randomized phase 2 trial.

Name: Kaimen Rigor review — Anti-inflammatory therapy with low-dose IL-2 in acute coronary syndromes: a randomized phase 2 trial.
Item: Anti-inflammatory therapy with low-dose IL-2 in acute coronary syndromes: a randomized phase 2 trial.
Rating: 96
Author: Alpha1

Sriranjan-Rothwell RS, Zhao TX, Hoole SP, Bond SJ, Tarkin JM, Brubert J, Hubsch A, Helmy J, Bumanlag-Amis E, Jalaludeen N, Templin H, Jiang W, Tedgui A, Zhao X, Nus M, Warnes V, Krishnan U, O'Brien JW, Wall C, Rudd JHF, Cheriyan J, Mallat Z, IVORY investigators

Paper source

Read full text (PMC)

Embed this Rigor badge

Kaimen Rigor review — 3★ (Adequate), 0 critical, 7 high issues for “Anti-inflammatory therapy with low-dose IL-2 in acute coronary syndromes: a randomized phase 2 trial.”

Links back to this Kaimen Rigor review.

Alpha1 Editorial

This rigor review was examined and confirmed by Alpha1 Editorial · August 10, 2026

Read alongside

Anti-inflammatory therapy with low-dose IL-2 in acute coronary syndromes: a randomized phase 2 trial.

Read full text (PMC)

DOI

10.1038/s41591-025-04090-y

Share this Kaimen Rigor review

Post on X Share on LinkedIn Share via Email

Embed this Rigor badge

<a href="https://alpha1science.com/verify/ae081de6-4d40-4fdd-b13e-56b8a1423d57" target="_blank" rel="noopener">
  <img src="https://alpha1science.com/verify/ae081de6-4d40-4fdd-b13e-56b8a1423d57/badge" alt="Kaimen Rigor review — 3★ (Adequate), 0 critical, 7 high issues for “Anti-inflammatory therapy with low-dose IL-2 in acute coronary syndromes: a randomized phase 2 trial.”" width="440" height="104" style="max-width:100%;height:auto" />
</a>

Every embed links back to this Kaimen Rigor review.

Record fingerprint

aff5e2d825c1aa12c6e4d8fbb4e8e8ed44a73f3f3c55a6cfe5008074f88aa90a

Verify via API

Issued Aug 10, 2026Engine 7.29.0

Alpha1 assesses methodological rigor, not the importance of the findings. See how we calibrate →

Alpha¹ by Kaimen

Fetching the latest research

Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Anti-inflammatory therapy with low-dose IL-2 in acute coronary syndromes: a randomized phase 2 trial.

Paper source

Anti-inflammatory therapy with low-dose IL-2 in acute coronary syndromes: a randomized 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 10, 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 ×4−2★

Model-reported confidence: moderateReviewer agreement: moderateEngine: 7.29.0Source: full text

Biggest issues

01Internal contradictions in the reported numbers
mediumArithmeticreviewer-assessedFull detail
The abstract reports sex ratios that do not match Table 1. For placebo, abstract says F-to-M=6:23 but Table 1 shows 7 females and 24 males. For IL-2, abstract says 3:28 but Table 1 shows 3 females and 29 males.
Abstract: 'placebo = 29 (F-to-M = 6:23); low-dose IL-2 = 31 (F-to-M = 3:28)'. Table 1: Placebo female 7, male 24; IL-2 female 3, male 29.
Table 1reviewer’s wording
02Other integrity concern
mediumAuthenticityreviewer-assessedFull detail
The paper reports trial registration NCT06437694, but ClinicalTrials.gov has no record with that identifier. A registration that cannot be resolved does not support the claim that the trial was registered.
NCT06437694
reviewer’s wording
03Other integrity concern
mediumAuthenticityreviewer-assessedFull detail
Trial NCT03690193 was first submitted to ClinicalTrials.gov on 2018-08-01, after the registered study start date of 2013-12-03. 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.
NCT03690193
reviewer’s wording

Findings by category

101ArithmeticNumerical inconsistencies 102OverreachOverstated conclusions · partly checked 103AuthenticityData authenticity concerns 04DisclosureNone found 05AvailabilityNone found 106CopyeditCopyediting

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 phase 2 randomized double-blind placebo-controlled trial of low-dose IL-2 in acute coronary syndromes is well designed and transparently reported: randomization, blinding, power analysis, ethics approvals, and the main trial registration are all solid, and the primary result is reported with exact p-values and CIs consistent with the independent recomputation. The main weaknesses are reporting/reproducibility gaps — the investigational IL-2 source and software version are not stated, no analysis code is shared, and there is an internal inconsistency in the IVORY-FINALE registration statement plus an Abstract/Table 1 sex-ratio discrepancy — none of which invalidates the primary IVORY findings but all of which warrant correction.

Three independent reviewer runs from the same model were synthesized; they converged on 6 of 8 dimensions and diverged on key resources and data code availability, where I weighed the more rigorous positions (missing drug source; absent code sharing) against the majority pass and landed on warn. The statistics component machine-checked only 6 tests (those with test statistic + df or estimate + CI); the remaining analyses are unverified, not confirmed. The citation component found 0 retracted and 0 not-found references among 50 checked.

Numerical inconsistencies

1 finding · 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.

Internal contradictions in the reported numbersAssessed

Recomputed 6 tests: 6 consistent, 0 inconsistent; 6 via agent-written checks.

Overstated conclusions

1 finding · worst low

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.

Conclusions only partially backed by the presented evidenceAssessed

12 major claims checked against the paper's own evidence: all adequately supported.

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 (1 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 paper cites extensive prior research on Treg cells in ACS, the anti-inflammatory effects of IL-2, and limitations of current therapies (e.g., colchicine ineffectiveness in ACS, side effects of canakinumab). The hypothesis follows logically from the cited evidence. Limitations of prior research (e.g., lack of T-cell-targeted therapies in ACS) are explicitly addressed.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The scientific premise is well-established with comprehensive citation of prior work and a clear rationale linking Treg deficiency in ACS to the hypothesis that low-dose IL-2 reduces inflammation.

Evidence

paraphrase[Main, first paragraph]

“Studies have demonstrated that T reg cell numbers are reduced and their function impaired in ACSs... In pre-clinical studies, increasing T reg cells led to reduced atherosclerosis... We previously demonstrated that low-dose IL-2 was safe and led to a selective statistically significant increase in T reg cells in patients with both ACS and stable ischemic heart disease.”

“In the trial of low-dose IL-2 for the reduction of vascular inflammation in ACSs (IVORY), we hypothesized that low-dose IL-2 would reduce arterial inflammation compared to placebo in patients presenting with ACSs who have residual inflammation detected by high-sensitivity C-reactive protein (hsCRP) levels >2 mg l −1 .”

IntroductionFind in source

paraphrase[Main, first paragraph]

“In the ACS population, the evidence for colchicine reducing MACEs has been less robust, with recent data showing that it was ineffective in ACSs... Furthermore, both agents have significant side effects. An unmet clinical need therefore exists...”

PASSReviewer 2· 95% conf

The paper clearly establishes its scientific premise, citing prior work on Treg cells in ACS, low-dose IL-2 effects, and limitations of existing anti-inflammatory therapies.

Evidence

paraphrase[Main, paragraphs 1-3]

“Studies have demonstrated that Treg cell numbers are reduced and their function impaired in ACSs... We previously demonstrated that low-dose IL-2 was safe and led to a selective statistically significant increase in Treg cells in patients with both ACS and stable ischemic heart disease.”

paraphrase[Main, paragraph 1]

paraphrase[Main, paragraph 2]

“In pre-clinical studies, increasing Treg cells led to reduced atherosclerosis... smaller myocardial infarct size and improved myocardial function.”

PASSReviewer 3· 90% conf

The manuscript clearly establishes that reduced regulatory T cells in ACS and the prior low-dose IL-2 proof-of-concept data motivate an anti-inflammatory strategy, with a logical link to the trial hypothesis.

Evidence

paraphrase[Main, first two paragraphs]

“We previously demonstrated that low-dose IL-2 was safe and led to a selective statistically significant increase in T reg cells in patients with both ACS and stable ischemic heart disease.”

paraphrase[Main, first paragraph]

“An unmet clinical need therefore exists to identify a well-tolerated drug that regulates the immune system and effectively reduces residual inflammation in ACSs.”

Randomization used permuted blocks with stratification. Blinding was applied to patients, investigators, and outcome assessors (PET readers). An a priori power analysis was performed. Inclusion and exclusion criteria are detailed. The analysis population (full analysis set) is defined, and missing data are handled via MMRM.

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The study design is rigorous with adequate randomization, blinding, pre-specified sample size calculation, and clear inclusion/exclusion criteria.

Evidence

“Permutated block randomization was used, with random block sizes of 2, 4 and 6. Randomization was stratified by ST-segment elevation status.”

MethodsFind in source

“All patients, clinical investigators and research personnel carrying out study visits or undertaking immune profiling, biomarker and [ 18 F]FDG PET–CT image analysis were blinded to treatment allocation.”

MethodsFind in source

“Assuming an s.d. of 0.24, 24 patients per arm, testing at a two-sided 5% significance level, provided 80% power. A sample size of 30 completed patients per arm was selected to account for any uninterpretable imaging or participant dropout.”

Statistical analysisFind in source

PASSReviewer 2· 95% conf

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

Evidence

paraphrase[Procedures, paragraph 1]

“Patients were randomly allocated to subcutaneously administered placebo (5% dextrose) or 1.5 × 10^6 IU of IL-2 in a 1:1 ratio using an independent, web-based application (www.sealedenvelope.com). Permutated block randomization was used, with random block sizes of 2, 4 and 6. Randomization was stratified by ST-segment elevation status.”

paraphrase[Study design and oversight, paragraph 1]

“All patients, clinical investigators and research personnel carrying out study visits or undertaking immune profiling, biomarker and [18F]FDG PET–CT image analysis were blinded to treatment allocation.”

Statistical analysis ¶1Find in source

PASSReviewer 3· 90% conf

Core design elements are well reported for a phase 2 randomized double-blind trial: randomization method and stratification, blinding, a priori power calculation, pre-specified inclusion/exclusion, and a defined analysis population.

Evidence

paraphrase[Methods, Procedures]

“Patients were randomly allocated to subcutaneously administered placebo (5% dextrose) or 1.5 × 10 6 IU of IL-2 in a 1:1 ratio using an independent, web-based application... Permutated block randomization was used, with random block sizes of 2, 4 and 6. Randomization was stratified by ST-segment elevation status.”

“Assuming an s.d. of 0.24, 24 patients per arm, testing at a two-sided 5% significance level, provided 80% power.”

Statistical analysisFind in source

MethodsFind in source

Table 1 reports sex, age (median and range), BMI, ethnicity, and health status (hsCRP, troponin, GRACE score, cardiovascular history, medications). Both sexes are included, though fewer women; the restriction is justified by safety considerations in women of childbearing potential.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Key biological variables (age, sex, health status, demographics) are reported adequately for this human clinical trial.

Evidence

“Characteristic | Placebo ( n = 31) | Low-dose IL-2 ( n = 32) | | Median age (range), years | 55 (39–75) | 56.5 (34–73) | | Sex, no. (%) | | Female | 7 (23) | 3 (9) | | Male | 24 (77) | 29 (91) |”

Table 1Find in source

“As recruitment was restricted to postmenopausal or perimenopausal women due to the paucity of safety data in women of childbearing potential, there were fewer women in this trial than in a nonselective ACS population.”

Results ¶1Find in source

PASSReviewer 2· 95% conf

Key biological variables (sex, age, BMI, demographics) are reported in Table 1. The study is not single-sex, so sex justification is not applicable.

Evidence

paraphrase[Table 1]

“Median age (range), years: Placebo 55 (39–75); Low-dose IL-2 56.5 (34–73). Sex, no. (%): Placebo Female 7 (23), Male 24 (77); Low-dose IL-2 Female 3 (9), Male 29 (91).”

paraphrase[Table 1]

“Ethnicity, no. (%): White 30 (97) ... Asian 1 (3) ... Black 0 (0) ... Mixed 0 (0) ... Other 0 (0).”

“Due to the paucity of safety data in pregnancy for low-dose IL-2, women of childbearing potential were excluded.”

Patients, paragraph 1Find in source

PASSReviewer 3· 85% conf

Sex, age, BMI, and demographic/clinical characteristics are reported in a baseline table; species/housing criteria are not applicable for a human trial.

Evidence

“Female | 7 (23) | 3 (9) | | Male | 24 (77) | 29 (91)”

Table 1Find in source

“Median age (range), years | 55 (39–75) | 56.5 (34–73)”

Table 1Find in source

The trial received approval from the Yorkshire and Humber—Sheffield ethics committee (19/YH/0171) and MHRA regulatory approval. Written informed consent was obtained from all patients. The trial was conducted in accordance with the Declaration of Helsinki and ICH-GCP. The IVORY-FINALE study also has separate ethical approval.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approvals and informed consent are fully documented with named committees and protocol numbers.

Evidence

“The trial received favorable ethical opinion from the Yorkshire and Humber—Sheffield ethics committee (19/YH/0171) as well as regulatory approval by the Medicines and Healthcare products Regulatory Authority (MHRA).”

MethodsFind in source

“Written informed consent was obtained from all patients before carrying out any study procedures for both IVORY and IVORY-FINALE.”

MethodsFind in source

“The trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Council for Harmonisation Guideline for Good Clinical Practice.”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethical approval was obtained from a named ethics committee, informed consent was obtained, and the trial adhered to the Declaration of Helsinki and ICH-GCP.

Evidence

Study design and oversight, paragraph 1Find in source

“Written informed consent was obtained from all patients before carrying out any study procedures for both IVORY and IVORY-FINALE.”

Study design and oversight, paragraph 1Find in source

“The trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Council for Harmonisation Guideline for Good Clinical Practice.”

Study design and oversight, paragraph 1Find in source

PASSReviewer 3· 95% conf

Named ethics committees with protocol numbers approved both IVORY and IVORY-FINALE; written informed consent and regulatory compliance statements are provided.

Evidence

MethodsFind in source

“Written informed consent was obtained from all patients before carrying out any study procedures for both IVORY and IVORY-FINALE.”

MethodsFind in source

Low-dose IL-2 is specified as 1.5 × 10^6 IU subcutaneously with an induction/maintenance regimen and 5% dextrose placebo. Twelve FACS antibodies are listed with vendor, catalog number, and clone, satisfying reagent identification for the wet-lab component. Software is identified (R; gls from nlme). As a drug trial with a companion FACS assay, the applicable resource criteria are met.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedADEQUATE

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 90% conf

Key resources are partially identified: flow cytometry antibodies are well-documented, but the investigational product (IL-2) lacks manufacturer/source, and analysis software version is not specified.

Evidence

paraphrase[Methods, Procedures]

“The following antibodies were used according to the manufacturer’s instructions: CD196 phycoerythrin (PE) (20 μl in 100 μl of blood; BD Pharmingen, cat. no. 551773, clone 11A9)...”

“subcutaneous low-dose IL-2 (1.5 × 10 6 IU)”

AbstractFind in source

“The statistical package used was R. For the MMRM the ‘gls’ function from the ‘nlme’ package was used.”

Statistical analysisFind in source

PASSReviewer 2· 75% conf

Antibodies and software are well identified, but the source/manufacturer of the investigational drug (IL-2) is not reported, which is a minor omission.

Evidence

paraphrase[Methods, paragraph 3]

“The following antibodies were used according to the manufacturer’s instructions: CD196 phycoerythrin (PE) (20 μl in 100 μl of blood; BD Pharmingen, cat. no. 551773, clone 11A9)...”

“The statistical package used was R. For the MMRM the ‘gls’ function from the ‘nlme’ package was used.”

Statistical analysis ¶1Find in source

absence[Methods, throughout]

Source of IL-2 is not reported

PASSReviewer 3· 85% conf

The investigational product (low-dose IL-2 dose and regimen), placebo, FACS antibodies (vendor, catalog, clone), and analysis software (R, nlme) are identified.

Evidence

“low-dose IL-2 (1.5 × 10 6 IU) or placebo”

AbstractFind in source

“CD196 phycoerythrin (PE) (20 μl in 100 μl of blood; BD Pharmingen, cat. no. 551773, clone 11A9)”

MethodsFind in source

“The statistical package used was R. For the MMRM the ‘gls’ function from the ‘nlme’ package was used.”

Statistical analysisFind in source

The primary analysis used linear regression; secondary analyses used MMRM and Mann-Whitney U. Exact p-values are reported for all key outcomes. Effect sizes are reported with 95% CIs. Individual data points are shown in dot plots with defined error bars (SD). Per-group Ns are stated. The statistical software (R, nlme) is named but version is missing. Mathematical plausibility checks on reported percentages show no errors.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedINADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical analysis is thorough with named tests, exact p-values, effect sizes with confidence intervals, and adequate data presentation. Software version is not reported.

Evidence

“arterial inflammation was −0.171 (−7.7%) lower in the low-dose IL-2 group compared to the placebo group (95% confidence interval −0.308 to −0.034, P = 0.015).”

ResultsFind in source

“The dot represents individual patient values, the longest vertical line the mean for each group and the error bars the s.d.”

Figure 2Find in source

paraphrase[Methods, Statistical analysis]

“For all continuous variables (including the primary outcome), point estimates and corresponding 95% CIs and P values are reported. For analyses of imaging data, including the primary analysis, linear regression models were used... For secondary and exploratory outcomes that were repeatedly measured over time, linear mixed model repeated measures (MMRM) were used.”

PASSReviewer 2· 75% conf

Statistical methods are appropriate and well described, with exact p-values for primary analyses and effect sizes with CIs. However, some p-values are reported only as thresholds (e.g., P<0.0001), which is a minor imprecision.

Evidence

paraphrase[Results, Primary efficacy analyses]

“At the end of 8 weeks of treatment, the mean TBR max in the index vessel was lower (−0.171, 95% CI −0.308 to −0.034, P = 0.015) in patients treated with low-dose IL-2 (2.04 ± 0.28) compared to placebo (2.22 ± 0.25).”

paraphrase[Abstract]

“low-dose IL-2 treatment increased T reg cell levels compared to placebo (P < 0.0001).”

“The dot represents individual patient values, the longest vertical line the mean for each group and the error bars the s.d.”

Figure 2Find in source

PASSReviewer 3· 85% conf

Statistical tests are named, exact p-values and 95% CIs are reported throughout, software is identified, and individual data points are shown; no arithmetic errors were found.

Evidence

paraphrase[Extended Data Table 1 footnote]

“Linear regression models were used in reporting the estimated coefficients and their s.e. values. Some models only used treatment as a predictor, which is identical to an unpaired Student’s t -test... CIs and two-sided P values were provided based on the estimates following a t -distribution.”

“The dot represents individual patient values, the longest vertical line the mean for each group and the error bars the s.d.”

Figure 2Find in source

The statement specifies that deidentified participant data are available upon reasonable request from academic researchers, with a defined procedure (proposal, CV, non-conflict declaration), review by the IVORY steering committee, and a 12-month consideration timeframe — a concrete managed-access route appropriate for individual patient data. No bespoke code repository is indicated and none is required; R/nlme are standard.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 90% conf

A data availability statement is present and describes a managed-access process, but custom analysis code is not shared.

Evidence

paraphrase[Data availability]

“Deidentified participant data generated during the trial are available upon reasonable request from academic researchers or clinical researchers affiliated with recognized institutions... The review and approval for data requests will be done by the steering committee of the IVORY trial. Approval is granted based on scientific merit, data availability and intended use of data. Data requests will be considered within 12 months of manuscript publication.”

absence[Entire manuscript]

No custom code sharing is reported.

PASSReviewer 2· 80% conf

A data availability statement is present with a concrete managed-access route (steering committee review). No code is shared, but only standard statistical software was used, making code sharing not applicable.

Evidence

paraphrase[Data availability]

“Deidentified participant data generated during the trial are available upon reasonable request from academic researchers or clinical researchers affiliated with recognized institutions. ... The review and approval for data requests will be done by the steering committee of the IVORY trial. ... Data requests will be considered within 12 months of manuscript publication.”

absence[Data availability and Methods]

No code repository mentioned

PASSReviewer 3· 85% conf

A data availability statement provides a concrete managed-access route (steering-committee review with conditions and timeframe); repository/accession and code-sharing criteria are not applicable to these patient-level data.

Evidence

paraphrase[Data availability]

“The review and approval for data requests will be done by the steering committee of the IVORY trial... Data requests will be considered within 12 months of manuscript publication.”

The trial is registered at ClinicalTrials.gov (NCT04241601). A nature portfolio reporting summary is linked. The primary, secondary, and exploratory outcomes are all reported, including non-significant results. Limitations are discussed (e.g., underrepresentation of diabetes, inability to image coronary arteries). Conclusions are appropriately cautious, noting the need for larger trials. Funding sources are listed, and conflicts of interest are referenced as available online.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Reporting is complete and transparent: methods are detailed, trial is registered, a reporting summary is linked, all outcomes are reported, limitations are discussed, and conclusions are proportional.

Evidence

“ClinicalTrials.gov registration: NCT04241601 (https://clinicaltrials.gov/study/NCT04241601)”

AbstractFind in source

paraphrase[Discussion]

“This phase 2 study has some limitations. Patients with diabetes were underrepresented in this trial for methodological reasons... Furthermore, due to myocardial uptake of [ 18 F]FDG, this biomarker does not allow the quantification of inflammation in coronary arteries without dietary manipulation... Finally, although early data from the IVORY-FINALE suggest a beneficial effect of low-dose IL-2 on MACEs, larger trials powered to assess the effect of low-dose IL-2 on clinical outcomes are needed.”

“The clinical benefit of low-dose IL-2 requires validation in larger studies.”

AbstractFind in source

PASSReviewer 2· 90% conf

The paper is comprehensive: methods are detailed, the trial is registered, all outcomes are reported, limitations are discussed, conclusions are proportional, and funding/COI are stated. The reporting guideline is not explicitly named, but a reporting summary is linked.

Evidence

paraphrase[Abstract]

“ClinicalTrials.gov registration: NCT04241601 (https://clinicaltrials.gov/study/NCT04241601).”

paraphrase[Discussion, paragraph 5]

“This phase 2 study has some limitations. Patients with diabetes were underrepresented in this trial for methodological reasons relating to the use of [18F]FDG PET–CT... larger trials powered to assess the effect of low-dose IL-2 on clinical outcomes are needed.”

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

AbstractFind in source

PASSReviewer 3· 90% conf

The trial is registered, methods are detailed, negative results are reported transparently, limitations are discussed, and conclusions are appropriately hedged; funding and competing-interest information are provided.

Evidence

“IVORY was a parallel-group, double-blind, randomized, placebo-controlled, phase 2 trial (ClinicalTrials.gov registration: NCT04241601”

MethodsFind in source

paraphrase[Discussion]

“Patients with diabetes were underrepresented in this trial for methodological reasons relating to the use of [ 18 F]FDG PET–CT... Finally, although early data from the IVORY-FINALE suggest a beneficial effect of low-dose IL-2 on MACEs, larger trials powered to assess the effect of low-dose IL-2 on clinical outcomes are needed.”

Registered (4 IDs: ClinicalTrials.gov). No reporting guideline cited.

Broken references and links

None found

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

Checked — nothing surfaced.

Checked 50 references by DOI: 1 verified — 49 no DOI (shown, not verified).

4 data/code links checked; 4 live.

Copyediting

1 finding · worst low

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

Wording or formatting errors that need correctingAssessed

11 copyedit issues flagged (1 major): mostly consistency, other, clarity.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is methodologically robust: the primary IVORY trial is properly registered and its results are transparently and consistently reported, so an informed reader should treat the primary finding as credible while noting that only a subset of statistics was independently verifiable. Before relying on the paper, a reader should weigh (and the authors should correct) the unresolvable IVORY-FINALE registration statement and the Abstract/Table 1 sex-ratio discrepancy, and the missing IL-2 source/software version and absent analysis code are reproducibility limitations that warrant a data/code clarification or correction.

1.
HIGHreporting
Correct the IVORY-FINALE registration statement in Methods, Study design and oversight: the stated number NCT06427694 does not resolve in ClinicalTrials.gov and the hyperlink points to a different trial (NCT03690193) with a typo'd query term — provide the correct, resolvable registration record or issue a correction.
A registration identifier that cannot be resolved does not support the claim that the trial was registered, which is a high-severity integrity concern.
2.
HIGHreporting
Reconcile the Abstract sex ratios with Table 1: the Abstract states placebo F-to-M = 6:23 and low-dose IL-2 = 3:28, but Table 1 shows 7/24 and 3/29 respectively — correct the Abstract values (or the table) so the two agree.
An internal contradiction between the Abstract and Table 1 on baseline participant counts is a factual error that warrants correction.
3.
HIGHrigor
Add the manufacturer/source (and lot, if available) of the investigational low-dose IL-2 (recombinant human aldesleukin) in the Methods/Procedures section.
The investigational product is the central resource in a drug trial, and its source is currently entirely unreported, which is a key-resources reporting gap.
4.
HIGHdata code
Add the R and nlme package version numbers in the Statistical analysis section, and deposit the analysis scripts (primary/secondary regression and MMRM models) in a public repository with a DOI, referencing them in the data/code availability statement.
Version-specific software and shared analysis code are needed for an independent reader to reproduce the primary and secondary analyses.
5.
HIGHstatistics
Report the exact p-value for the Treg increase instead of the threshold-only 'P < 0.0001' in the Abstract (or provide the exact value in the main text/tables).
A p-value the authors computed but printed only as a threshold is imprecise reporting that reduces reproducibility.
6.
HIGHcopyedit
Fix the typographical error '95% C1' to '95% CI' in the Results section (Effects on circulating immune cells / T follicular helper cells).
The confidence-interval abbreviation is misspelled in the published text, which is a visible copyedit error.
7.
HIGHcopyedit
Fix the sentence in Results (Primary efficacy analyses) that ends with a dangling dash — 'which reduces MACEs in ACSs – .' — by adding the missing citation for the high-dose statin comparison.
The sentence references an effect of high-dose statin therapy but provides no citation, leaving the claim unsupported in the text.
8.
MEDIUMreporting
Add an explicit statement of compliance with the CONSORT reporting guideline (or name the applicable reporting guideline) in the Methods/Reporting Summary.
The reporting guideline is not explicitly named, only a Reporting Summary is linked, which is a transparency gap for a randomized trial.
9.
MEDIUMstatistics
Add an explicit statement in the Statistical analysis section on whether normality/equal-variance assumptions were checked and how deviations were handled, or state that the pre-specified linear/MMRM models make these assumptions by design.
The assumptions_verified criterion is not explicitly addressed, which matters for a bench-oriented reader assessing model validity.
10.
MEDIUMcopyedit
Remove the extraneous page-number artifact '32 2 624 624–632' from the Abstract (line 1).
The stray numbers are a formatting artifact from journal layout and should not appear in the published abstract.
11.
MEDIUMcopyedit
Harmonize the primary-outcome p-value precision between the Abstract (P = 0.015) and the Fig. 2 legend (P = 0.0149).
The same p-value is reported at different precision in two places, which is a minor consistency issue.
12.
LOWcopyedit
Clarify in Results (Primary efficacy analyses) that the change-from-baseline difference (−0.103, 95% CI −0.22 to 0.02, P = 0.086) is distinct from the end-of-treatment primary comparison.
The phrasing could be misread as the primary result, so clarifying it as the change-from-baseline analysis improves interpretability.

Full text (62,296 chars)Analyzed: Aug 10, 2026

Start the discussion on JRNLClub

Community discussion on jrnlclub.com

Read alongside

Anti-inflammatory therapy with low-dose IL-2 in acute coronary syndromes: a randomized phase 2 trial.

Read full text (PMC)

DOI

10.1038/s41591-025-04090-y

Share this Kaimen Rigor review

Post on X Share on LinkedIn Share via Email

Embed this Rigor badge

<a href="https://alpha1science.com/verify/ae081de6-4d40-4fdd-b13e-56b8a1423d57" target="_blank" rel="noopener">
  <img src="https://alpha1science.com/verify/ae081de6-4d40-4fdd-b13e-56b8a1423d57/badge" alt="Kaimen Rigor review — 3★ (Adequate), 0 critical, 7 high issues for “Anti-inflammatory therapy with low-dose IL-2 in acute coronary syndromes: a randomized phase 2 trial.”" width="440" height="104" style="max-width:100%;height:auto" />
</a>

Every embed links back to this Kaimen Rigor review.

Record fingerprint

aff5e2d825c1aa12c6e4d8fbb4e8e8ed44a73f3f3c55a6cfe5008074f88aa90a

Verify via API

Issued Aug 10, 2026Engine 7.29.0

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 ×4−2★

Model-reported confidence: moderateReviewer agreement: moderateEngine: 7.29.0Source: full text

Biggest issues

01Internal contradictions in the reported numbers
mediumArithmeticreviewer-assessedFull detail
The abstract reports sex ratios that do not match Table 1. For placebo, abstract says F-to-M=6:23 but Table 1 shows 7 females and 24 males. For IL-2, abstract says 3:28 but Table 1 shows 3 females and 29 males.
Abstract: 'placebo = 29 (F-to-M = 6:23); low-dose IL-2 = 31 (F-to-M = 3:28)'. Table 1: Placebo female 7, male 24; IL-2 female 3, male 29.
Table 1reviewer’s wording
02Other integrity concern
mediumAuthenticityreviewer-assessedFull detail
The paper reports trial registration NCT06437694, but ClinicalTrials.gov has no record with that identifier. A registration that cannot be resolved does not support the claim that the trial was registered.
NCT06437694
reviewer’s wording
03Other integrity concern
mediumAuthenticityreviewer-assessedFull detail
Trial NCT03690193 was first submitted to ClinicalTrials.gov on 2018-08-01, after the registered study start date of 2013-12-03. 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.
NCT03690193
reviewer’s wording

Findings by category

Numerical inconsistencies

1 finding · worst medium

Internal contradictions in the reported numbersAssessed

Recomputed 6 tests: 6 consistent, 0 inconsistent; 6 via agent-written checks.

Overstated conclusions

1 finding · worst low

Conclusions only partially backed by the presented evidenceAssessed

12 major claims checked against the paper's own evidence: all adequately supported.

Data authenticity concerns

1 finding · worst medium

Other integrity concernAssessed

4 integrity concerns flagged (1 high).

Reporting gaps

None found

Checked — nothing surfaced.

Eight Dimensions8 pass

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The scientific premise is well-established with comprehensive citation of prior work and a clear rationale linking Treg deficiency in ACS to the hypothesis that low-dose IL-2 reduces inflammation.

Evidence

paraphrase[Main, first paragraph]

IntroductionFind in source

paraphrase[Main, first paragraph]

PASSReviewer 2· 95% conf

The paper clearly establishes its scientific premise, citing prior work on Treg cells in ACS, low-dose IL-2 effects, and limitations of existing anti-inflammatory therapies.

Evidence

paraphrase[Main, paragraphs 1-3]

paraphrase[Main, paragraph 1]

paraphrase[Main, paragraph 2]

“In pre-clinical studies, increasing Treg cells led to reduced atherosclerosis... smaller myocardial infarct size and improved myocardial function.”

PASSReviewer 3· 90% conf

Evidence

paraphrase[Main, first two paragraphs]

“We previously demonstrated that low-dose IL-2 was safe and led to a selective statistically significant increase in T reg cells in patients with both ACS and stable ischemic heart disease.”

paraphrase[Main, first paragraph]

“An unmet clinical need therefore exists to identify a well-tolerated drug that regulates the immune system and effectively reduces residual inflammation in ACSs.”

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The study design is rigorous with adequate randomization, blinding, pre-specified sample size calculation, and clear inclusion/exclusion criteria.

Evidence

“Permutated block randomization was used, with random block sizes of 2, 4 and 6. Randomization was stratified by ST-segment elevation status.”

MethodsFind in source

Statistical analysisFind in source

PASSReviewer 2· 95% conf

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

Evidence

paraphrase[Procedures, paragraph 1]

paraphrase[Study design and oversight, paragraph 1]

“All patients, clinical investigators and research personnel carrying out study visits or undertaking immune profiling, biomarker and [18F]FDG PET–CT image analysis were blinded to treatment allocation.”

Statistical analysis ¶1Find in source

PASSReviewer 3· 90% conf

Evidence

paraphrase[Methods, Procedures]

“Assuming an s.d. of 0.24, 24 patients per arm, testing at a two-sided 5% significance level, provided 80% power.”

Statistical analysisFind in source

MethodsFind in source

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Key biological variables (age, sex, health status, demographics) are reported adequately for this human clinical trial.

Evidence

Table 1Find in source

Results ¶1Find in source

PASSReviewer 2· 95% conf

Key biological variables (sex, age, BMI, demographics) are reported in Table 1. The study is not single-sex, so sex justification is not applicable.

Evidence

paraphrase[Table 1]

“Median age (range), years: Placebo 55 (39–75); Low-dose IL-2 56.5 (34–73). Sex, no. (%): Placebo Female 7 (23), Male 24 (77); Low-dose IL-2 Female 3 (9), Male 29 (91).”

paraphrase[Table 1]

“Ethnicity, no. (%): White 30 (97) ... Asian 1 (3) ... Black 0 (0) ... Mixed 0 (0) ... Other 0 (0).”

“Due to the paucity of safety data in pregnancy for low-dose IL-2, women of childbearing potential were excluded.”

Patients, paragraph 1Find in source

PASSReviewer 3· 85% conf

Sex, age, BMI, and demographic/clinical characteristics are reported in a baseline table; species/housing criteria are not applicable for a human trial.

Evidence

“Female | 7 (23) | 3 (9) | | Male | 24 (77) | 29 (91)”

Table 1Find in source

“Median age (range), years | 55 (39–75) | 56.5 (34–73)”

Table 1Find in source

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approvals and informed consent are fully documented with named committees and protocol numbers.

Evidence

MethodsFind in source

“Written informed consent was obtained from all patients before carrying out any study procedures for both IVORY and IVORY-FINALE.”

MethodsFind in source

“The trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Council for Harmonisation Guideline for Good Clinical Practice.”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethical approval was obtained from a named ethics committee, informed consent was obtained, and the trial adhered to the Declaration of Helsinki and ICH-GCP.

Evidence

Study design and oversight, paragraph 1Find in source

“Written informed consent was obtained from all patients before carrying out any study procedures for both IVORY and IVORY-FINALE.”

Study design and oversight, paragraph 1Find in source

“The trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Council for Harmonisation Guideline for Good Clinical Practice.”

Study design and oversight, paragraph 1Find in source

PASSReviewer 3· 95% conf

Named ethics committees with protocol numbers approved both IVORY and IVORY-FINALE; written informed consent and regulatory compliance statements are provided.

Evidence

MethodsFind in source

“Written informed consent was obtained from all patients before carrying out any study procedures for both IVORY and IVORY-FINALE.”

MethodsFind in source

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedADEQUATE

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 90% conf

Evidence

paraphrase[Methods, Procedures]

“The following antibodies were used according to the manufacturer’s instructions: CD196 phycoerythrin (PE) (20 μl in 100 μl of blood; BD Pharmingen, cat. no. 551773, clone 11A9)...”

“subcutaneous low-dose IL-2 (1.5 × 10 6 IU)”

AbstractFind in source

“The statistical package used was R. For the MMRM the ‘gls’ function from the ‘nlme’ package was used.”

Statistical analysisFind in source

PASSReviewer 2· 75% conf

Antibodies and software are well identified, but the source/manufacturer of the investigational drug (IL-2) is not reported, which is a minor omission.

Evidence

paraphrase[Methods, paragraph 3]

“The following antibodies were used according to the manufacturer’s instructions: CD196 phycoerythrin (PE) (20 μl in 100 μl of blood; BD Pharmingen, cat. no. 551773, clone 11A9)...”

“The statistical package used was R. For the MMRM the ‘gls’ function from the ‘nlme’ package was used.”

Statistical analysis ¶1Find in source

absence[Methods, throughout]

Source of IL-2 is not reported

PASSReviewer 3· 85% conf

The investigational product (low-dose IL-2 dose and regimen), placebo, FACS antibodies (vendor, catalog, clone), and analysis software (R, nlme) are identified.

Evidence

“low-dose IL-2 (1.5 × 10 6 IU) or placebo”

AbstractFind in source

“CD196 phycoerythrin (PE) (20 μl in 100 μl of blood; BD Pharmingen, cat. no. 551773, clone 11A9)”

MethodsFind in source

“The statistical package used was R. For the MMRM the ‘gls’ function from the ‘nlme’ package was used.”

Statistical analysisFind in source

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedINADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical analysis is thorough with named tests, exact p-values, effect sizes with confidence intervals, and adequate data presentation. Software version is not reported.

Evidence

“arterial inflammation was −0.171 (−7.7%) lower in the low-dose IL-2 group compared to the placebo group (95% confidence interval −0.308 to −0.034, P = 0.015).”

ResultsFind in source

“The dot represents individual patient values, the longest vertical line the mean for each group and the error bars the s.d.”

Figure 2Find in source

paraphrase[Methods, Statistical analysis]

PASSReviewer 2· 75% conf

Evidence

paraphrase[Results, Primary efficacy analyses]

paraphrase[Abstract]

“low-dose IL-2 treatment increased T reg cell levels compared to placebo (P < 0.0001).”

“The dot represents individual patient values, the longest vertical line the mean for each group and the error bars the s.d.”

Figure 2Find in source

PASSReviewer 3· 85% conf

Statistical tests are named, exact p-values and 95% CIs are reported throughout, software is identified, and individual data points are shown; no arithmetic errors were found.

Evidence

paraphrase[Extended Data Table 1 footnote]

“The dot represents individual patient values, the longest vertical line the mean for each group and the error bars the s.d.”

Figure 2Find in source

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 90% conf

A data availability statement is present and describes a managed-access process, but custom analysis code is not shared.

Evidence

paraphrase[Data availability]

absence[Entire manuscript]

No custom code sharing is reported.

PASSReviewer 2· 80% conf

Evidence

paraphrase[Data availability]

“Deidentified participant data generated during the trial are available upon reasonable request from academic researchers or clinical researchers affiliated with recognized institutions. ... The review and approval for data requests will be done by the steering committee of the IVORY trial. ... Data requests will be considered within 12 months of manuscript publication.”

absence[Data availability and Methods]

No code repository mentioned

PASSReviewer 3· 85% conf

Evidence

paraphrase[Data availability]

“The review and approval for data requests will be done by the steering committee of the IVORY trial... Data requests will be considered within 12 months of manuscript publication.”

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Evidence

“ClinicalTrials.gov registration: NCT04241601 (https://clinicaltrials.gov/study/NCT04241601)”

AbstractFind in source

paraphrase[Discussion]

“The clinical benefit of low-dose IL-2 requires validation in larger studies.”

AbstractFind in source

PASSReviewer 2· 90% conf

Evidence

paraphrase[Abstract]

“ClinicalTrials.gov registration: NCT04241601 (https://clinicaltrials.gov/study/NCT04241601).”

paraphrase[Discussion, paragraph 5]

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

AbstractFind in source

PASSReviewer 3· 90% conf

Evidence

“IVORY was a parallel-group, double-blind, randomized, placebo-controlled, phase 2 trial (ClinicalTrials.gov registration: NCT04241601”

MethodsFind in source

paraphrase[Discussion]

Registered (4 IDs: ClinicalTrials.gov). No reporting guideline cited.

Broken references and links

None found

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

Checked — nothing surfaced.

Checked 50 references by DOI: 1 verified — 49 no DOI (shown, not verified).

4 data/code links checked; 4 live.

Copyediting

1 finding · worst low

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

Wording or formatting errors that need correctingAssessed

11 copyedit issues flagged (1 major): mostly consistency, other, clarity.

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHreporting
Correct the IVORY-FINALE registration statement in Methods, Study design and oversight: the stated number NCT06427694 does not resolve in ClinicalTrials.gov and the hyperlink points to a different trial (NCT03690193) with a typo'd query term — provide the correct, resolvable registration record or issue a correction.
A registration identifier that cannot be resolved does not support the claim that the trial was registered, which is a high-severity integrity concern.
2.
HIGHreporting
Reconcile the Abstract sex ratios with Table 1: the Abstract states placebo F-to-M = 6:23 and low-dose IL-2 = 3:28, but Table 1 shows 7/24 and 3/29 respectively — correct the Abstract values (or the table) so the two agree.
An internal contradiction between the Abstract and Table 1 on baseline participant counts is a factual error that warrants correction.
3.
HIGHrigor
Add the manufacturer/source (and lot, if available) of the investigational low-dose IL-2 (recombinant human aldesleukin) in the Methods/Procedures section.
The investigational product is the central resource in a drug trial, and its source is currently entirely unreported, which is a key-resources reporting gap.
4.
HIGHdata code
Add the R and nlme package version numbers in the Statistical analysis section, and deposit the analysis scripts (primary/secondary regression and MMRM models) in a public repository with a DOI, referencing them in the data/code availability statement.
Version-specific software and shared analysis code are needed for an independent reader to reproduce the primary and secondary analyses.
5.
HIGHstatistics
Report the exact p-value for the Treg increase instead of the threshold-only 'P < 0.0001' in the Abstract (or provide the exact value in the main text/tables).
A p-value the authors computed but printed only as a threshold is imprecise reporting that reduces reproducibility.
6.
HIGHcopyedit
Fix the typographical error '95% C1' to '95% CI' in the Results section (Effects on circulating immune cells / T follicular helper cells).
The confidence-interval abbreviation is misspelled in the published text, which is a visible copyedit error.
7.
HIGHcopyedit
Fix the sentence in Results (Primary efficacy analyses) that ends with a dangling dash — 'which reduces MACEs in ACSs – .' — by adding the missing citation for the high-dose statin comparison.
The sentence references an effect of high-dose statin therapy but provides no citation, leaving the claim unsupported in the text.
8.
MEDIUMreporting
Add an explicit statement of compliance with the CONSORT reporting guideline (or name the applicable reporting guideline) in the Methods/Reporting Summary.
The reporting guideline is not explicitly named, only a Reporting Summary is linked, which is a transparency gap for a randomized trial.
9.
MEDIUMstatistics
Add an explicit statement in the Statistical analysis section on whether normality/equal-variance assumptions were checked and how deviations were handled, or state that the pre-specified linear/MMRM models make these assumptions by design.
The assumptions_verified criterion is not explicitly addressed, which matters for a bench-oriented reader assessing model validity.
10.
MEDIUMcopyedit
Remove the extraneous page-number artifact '32 2 624 624–632' from the Abstract (line 1).
The stray numbers are a formatting artifact from journal layout and should not appear in the published abstract.
11.
MEDIUMcopyedit
Harmonize the primary-outcome p-value precision between the Abstract (P = 0.015) and the Fig. 2 legend (P = 0.0149).
The same p-value is reported at different precision in two places, which is a minor consistency issue.
12.
LOWcopyedit
Clarify in Results (Primary efficacy analyses) that the change-from-baseline difference (−0.103, 95% CI −0.22 to 0.02, P = 0.086) is distinct from the end-of-treatment primary comparison.
The phrasing could be misread as the primary result, so clarifying it as the change-from-baseline analysis improves interpretability.

Full text (62,296 chars)Analyzed: Aug 10, 2026