Rigor Reviewed

Rigor-Reviewed Manuscript

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

Name: Adcurare Rigor Record — 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: Adcurare

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

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Adcurare Rigor Review — 2.75★ (Weak), 0 critical, 8 high issues for “Anti-inflammatory therapy with low-dose IL-2 in acute coronary syndromes: a randomized phase 2 trial.”

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Adcurare Editorial

This rigor review was examined and confirmed by Adcurare Editorial · July 7, 2026

Adcurare Rigor Review

Rigor Reviewed

2.75 / 5

Weak — serious problems found

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

ClaimsOverstated claim ×2−1★
CitationsCitations & links (capped) ×8−1★
ReportingData & code availability partially met−0.25★

Citations & links are capped at −1★ combined, however many are flagged.

Model-reported confidence: highReviewer agreement: moderateEngine: 7.6.0Source: full text

Problems surfaced3 types

Conclusions overstated beyond the evidence
Data/code availability incomplete
References not resolvable to a published paper

This Adcurare Rigor Review uses AI 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.

The paper reports a well-designed phase 2 randomized controlled trial with strong methodological rigor in most dimensions. The primary gaps are in data/code availability (vague statement, no code sharing), minor reporting omissions (outlier handling, assumptions verification, reporting guideline citation), and a few copyedit issues (inconsistent p-values, typo). The study is broadly sound and ready for submission after addressing the prioritized action items.

Evaluated against eight rigor dimensions applicable to a human clinical trial. Bench-science sub-criteria (e.g., replicate distinction, cell line authentication) were marked not applicable. The three independent reviewers largely agreed, with minor divergence on biological variables and statistical analysis resolved by weighing evidence; the cited evidence is specific and verifiable. The statistics verification component checked 7 tests (all consistent); unrechecked tests are not confirmed. The citation check found 8 references not found in registry; these are flagged for action.

9 major claims checked against the paper's own evidence: 2 not fully backed by the presented evidence (unsupported or overstated).

Recomputed 7 tests: 7 consistent, 0 inconsistent, 7 via agent-written checks.

Reporting

Eight Dimensions7 pass · 1 warn

The paper extensively cites prior research on Treg cells in ACS, low-dose IL-2 effects, and the unmet need for anti-inflammatory therapies. It clearly links the premise (Treg reduction in ACS) to the hypothesis that low-dose IL-2 reduces arterial inflammation. Prior limitations (e.g., side effects of other agents, lack of T-cell targeted therapy 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 clear rationale and prior work cited, limitations of prior research are addressed.

Evidence

direct quote[Introduction, paragraphs 1-4]

“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.”

direct quote[Introduction, paragraph 1]

“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.”

direct quote[Introduction, final paragraph]

“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.”

PASSReviewer 2· 90% conf

The paper clearly establishes its scientific foundation, citing prior work on Treg cells, IL-2, and the need for anti-inflammatory strategies in ACS.

Evidence

direct quote[Introduction, paragraphs 1-2]

“Studies have demonstrated that T reg cell numbers are reduced and their function impaired in ACSs”

direct quote[Introduction, paragraph 1]

“Canakinumab and colchicine are anti-inflammatory agents that target the innate immune system and have been shown to reduce MACEs... However, both agents have significant side effects.”

direct quote[Introduction, paragraph 2]

“Therefore, increasing endogenous T reg cells could provide a new targeted anti-inflammatory and tissue repair strategy in ACSs.”

PASSReviewer 3· 95% conf

The paper cogently establishes the scientific premise for testing low-dose IL-2 in acute coronary syndromes, citing prior work on Treg cells, IL-2 biology, and residual inflammation.

Evidence

direct quote[Introduction, paragraphs 2-3]

“Studies have demonstrated that T reg cell numbers are reduced and their function impaired in ACSs”

direct quote[Introduction, paragraph 4]

“Therefore, increasing endogenous T reg cells could provide a new targeted anti-inflammatory and tissue repair strategy in ACSs.”

direct quote[Introduction, paragraph 1]

“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 was performed using a web-based application (Sealed Envelope) with permuted block randomization and stratification by ST-segment elevation status, which is adequate. Blinding extended to patients, clinical investigators, and personnel analyzing PET-CT scans. A power analysis is reported: 24 patients per arm gave 80% power to detect an absolute difference of 0.2 in mean TBR, with 30 per arm recruited. Inclusion/exclusion criteria are described. The comparator arm (placebo, 5% dextrose) serves as a control. The paper reports a per-protocol liver function withdrawal criterion. As a human RCT, replicate_distinction, controls (wet-lab), and independent_replication are not applicable.

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingINADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The study design is rigorous for a phase 2 trial: randomized, double-blind, placebo-controlled, with clear inclusion/exclusion criteria, sample size justification, and a pre-specified statistical analysis plan. Many bench-science sub-criteria are not applicable for a human clinical trial.

Evidence

direct quote[Methods, Procedures paragraph]

“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.”

direct quote[Methods, Study design and oversight paragraph]

“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.”

direct quote[Methods, Statistical analysis paragraph]

“The sample size was based on an absolute difference of 0.2 in the mean TBRmax of the index vessel between placebo and low-dose IL-2 at the end of the treatment period. ... Assuming an s.d. of 0.24, 24 patients per arm, testing at a two-sided 5% significance level, provided 80% power.”

PASSReviewer 2· 90% conf

The trial uses a rigorous parallel-group, double-blind, randomized, placebo-controlled design with a priori sample size calculation, pre-specified inclusion/exclusion criteria, and blinding of patients, investigators, and outcome assessors.

Evidence

direct quote[Methods, Procedures]

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

direct quote[Methods, Statistical analysis]

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

direct quote[Methods, Study design and oversight]

PASSReviewer 3· 95% conf

The trial design is rigorous: double-blind, placebo-controlled, randomized with a clear method, pre-specified inclusion/exclusion criteria, power analysis, and a control group. Blinding is well described.

Evidence

direct quote[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 ( 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.”

direct quote[Methods, Study design and oversight]

“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.”

direct quote[Methods, Statistical analysis]

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

Age, sex (female-to-male ratio), BMI, ethnicity, baseline hsCRP, troponin, lipids, GRACE score, cardiovascular history, medications, and smoking status are all reported in Table 1. The paper explains the lower proportion of women: 'recruitment was restricted to postmenopausal or perimenopausal women due to the paucity of safety data in women of childbearing potential.' This is a scientific/ethical justification, not merely cost/convenience. Species/strain/housing are not applicable for a human trial.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedADEQUATE

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 88% conf

Biological variables are well reported for a human clinical trial: demographics, sex, age, BMI, and key clinical characteristics are provided. Sex justification is adequate given the restriction explained.

Evidence

direct quote[Table 1]

“Sex, no. (%) Female 7 (23) 3 (9) Male 24 (77) 29 (91)”

direct quote[Results, paragraph 1]

“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.”

direct quote[Table 1]

“Median age (range), years | 55 (39-75) | 56.5 (34-73) ... BMI, kg m-2 (mean ± s.d.) | 29.6 ± 5.8 | 29.8 ± 5.7”

PASSReviewer 2· 85% conf

Sex, age, BMI, ethnicity, smoking status, and other cardiovascular risk factors are well-reported in the baseline table; the sex imbalance is explained by the exclusion of women of childbearing potential.

Evidence

direct quote[Table 1]

“Sex, no. (%) | Female | 7 (23) | 3 (9) | | Male | 24 (77) | 29 (91)”

direct quote[Results, paragraph 2]

direct quote[Table 1]

“Ethnicity, no. (%) | White | 30 (97) | 27 (84)”

WARNReviewer 3· 90% conf

Demographics are well reported but the paper provides no justification for the single-sex study design and does not report age with a contemporary summary measure (median only, no IQR), and weight/BMI are reported but health status other than cardiovascular risk factors is not.

Evidence

direct quote[Table 1]

“Female 7 (23) ... Male 24 (77)”

direct quote[Methods, Patients]

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

direct quote[Table 1]

“Median age (range), years 55 (39–75)”

The trial received favorable ethical opinion from the Yorkshire and Humber—Sheffield ethics committee (19/YH/0171) and regulatory approval from the MHRA. Written informed consent was obtained. Compliance with Declaration of Helsinki and ICH-GCP is stated. The IVORY-FINALE follow-up also reports ethics approval from a named committee (24/WM/0059) and HRA approval.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 100% conf

Ethical approvals are fully reported: named ethics committee, regulatory approval, informed consent, and compliance with ethical standards are all explicitly stated.

Evidence

direct quote[Methods, Study design and oversight paragraph]

“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).”

direct quote[Methods, Study design and oversight paragraph]

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

direct quote[Methods, Study design and oversight paragraph]

“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.”

PASSReviewer 2· 95% conf

Ethics approval from a named committee (Yorkshire and Humber—Sheffield) with protocol number is reported, along with informed consent and regulatory compliance with the Declaration of Helsinki and ICH-GCP.

Evidence

direct quote[Methods, Study design and oversight]

“The trial received favorable ethical opinion from the Yorkshire and Humber—Sheffield ethics committee (19/YH/0171)”

direct quote[Methods, Study design and oversight]

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

direct quote[Methods, Study design and oversight]

“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.”

PASSReviewer 3· 95% conf

Ethical approvals are well documented: named ethics committee approval with a reference number, written informed consent, and regulatory compliance stated.

Evidence

direct quote[Methods, Study design and oversight]

“The trial received favorable ethical opinion from the Yorkshire and Humber—Sheffield ethics committee (19/YH/0171)”

direct quote[Methods, Study design and oversight]

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

direct quote[Methods, Study design and oversight]

“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.”

The investigational product is low-dose IL-2, specified as 1.5 × 10^6 IU, administered subcutaneously. The comparator is 5% dextrose/placebo. All 13 antibodies used for immunophenotyping are listed with vendors (BD Pharmingen/BD Horizon), catalog numbers, and clones. No other biological resources (cell lines, organisms) are used. Software is identified (R, nlme package). Mycoplasma testing and cell line authentication are not applicable as this is a human trial without cell culture.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedADEQUATE

cell line authenticationN/A

software tools identifiedINADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 80% conf

Key resources are adequately identified: investigational product (IL-2) and its dose/regimen are clear, and the antibodies used for FACS are fully cataloged. Software is identified.

Evidence

direct quote[Methods, Procedures paragraph]

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

direct quote[Methods, Statistical analysis paragraph]

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

direct quote[Abstract]

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

PASSReviewer 2· 85% conf

The investigational product (low-dose IL-2) is identified, the placebo is described, and the antibodies used for flow cytometry are identified with vendors, catalog numbers, and clones.

Evidence

direct quote[Methods, Procedures]

“Patients were randomly allocated to subcutaneously administered placebo (5% dextrose) or 1.5 × 10^6 IU of IL-2”

direct quote[Methods, Procedures]

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

direct quote[Methods, Statistical analysis]

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

PASSReviewer 3· 90% conf

The investigational product (IL-2) is named, and the primary antibody panel for FACS analysis is fully identified with vendor and catalog numbers.

Evidence

direct quote[Methods, Procedures (FACS list)]

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

direct quote[Methods, Statistical analysis]

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

All statistical tests are clearly named: linear regression models (equivalent to unpaired t-tests) for the primary and secondary imaging outcomes, MMRM for repeated immune cell measures, Mann-Whitney U for TH1 cells. Exact p-values are reported throughout (e.g., P = 0.015, P = 0.009). Effect sizes with 95% CIs are reported for all primary and secondary imaging endpoints and for key immune cell comparisons. Statistical software (R, nlme package) is identified. Data presentation for the primary outcome shows individual data points, mean, and SD (error bars defined). Per-group N is stated. Mathematical plausibility checks are not applicable as continuous outcomes are used, and no arithmetic inconsistencies were found in the reported summary statistics (e.g., the percentage differences are consistent with the reported means). Assumptions verification is reported_but_inadequate: normality and equal variance are not explicitly tested, but the use of linear models and Mann-Whitney U where appropriate is acknowledged.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedINADEQUATE

mathematical plausibilityPASS

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

Statistical analysis is rigorous: tests are named, exact p-values are reported, effect sizes with confidence intervals are provided, software is identified, and data presentation is clear. Assumptions verification is implicit for the linear models used.

Evidence

direct quote[Results, Primary efficacy analyses paragraph]

“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).”

direct quote[Methods, Statistical analysis and figure legends]

“Linear regression models were used in reporting the estimated coefficients and their s.e. values. Some models used treatment only as a predictor, which is identical to an unpaired Student's t-test.”

direct quote[Figure 2 legend]

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

PASSReviewer 2· 90% conf

Statistical tests are named for each analysis (linear regression, MMRM, t-test, Mann-Whitney U), exact p-values are reported, effect sizes with CIs are given, software is identified, and data are presented with individual points and defined error bars.

Evidence

direct quote[Methods, Statistical analysis]

“linear regression models were used to estimate the treatment effect... For secondary and exploratory outcomes that were repeatedly measured over time, linear mixed model repeated measures (MMRM) were used”

direct quote[Results, Primary efficacy analyses]

“the mean TBR max in the index vessel was lower (−0.171, 95% CI −0.308 to −0.034, P = 0.015)”

direct quote[Figure 2 legend]

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

WARNReviewer 3· 85% conf

Statistical tests are named and appropriate, exact p-values are generally reported, and individual data points are shown. However, effect sizes with confidence intervals are reported for the primary outcome but confidence intervals are missing for some secondary comparisons, and mathematical plausibility could not be fully verified due to continuous outcomes.

Evidence

direct quote[Abstract and Results]

“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).”

direct quote[Figure 2 caption]

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

direct quote[Results, Effects on circulating immune cells]

“T reg cells were 34% (95% CI 27.58–40.45) higher in the low-dose IL-2 arm compared to placebo.”

The Data availability section states deidentified participant data are available upon request with a detailed proposal, but does not specify a repository, platform, or timeline beyond 'within 12 months'. This is not fully adequate by current standards (no managed-access platform named). No code sharing is reported. The trial is prospectively registered (NCT04241601), which is a strength, and the protocol is linked.

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositNOT REPORTED

data availability statementINADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 80% conf

A data availability statement is present but vague ('available upon reasonable request'), and no data repository deposition or code sharing is reported. For a clinical trial with patient-level data, a managed-access procedure is described but the statement remains somewhat non-specific.

Evidence

direct quote[Data availability section]

“Deidentified participant data generated during the trial are available upon reasonable request from academic researchers or clinical researchers affiliated with recognized institutions.”

absence[Data availability section, entire paper]

No code sharing statement is provided.

WARNReviewer 2· 80% conf

A data availability statement exists but is vague ('available upon reasonable request' with conditions but no platform or timeline), and no code is shared; the trial is registered.

Evidence

direct quote[Data availability section]

“Deidentified participant data generated during the trial are available upon reasonable request from academic researchers or clinical researchers affiliated with recognized institutions.”

absence[Data availability section]

No code sharing statement.

WARNReviewer 3· 90% conf

A data availability statement is present but vague ('available upon reasonable request' with conditions), and code is not shared. The trial is registered.

Evidence

direct quote[Data availability]

“Deidentified participant data generated during the trial are available upon reasonable request from academic researchers or clinical researchers affiliated with recognized institutions.”

absence[Data availability]

No code sharing is mentioned.

Methods are detailed (dosing regimen, imaging protocol, FACS panel). The trial is registered. Limitations are explicitly discussed (underrepresentation of patients with diabetes, exclusion of insulin-requiring diabetes, no coronary artery imaging). Conclusions are proportional, stating the need for validation in larger studies. Funding sources (MRC, BHF, Wellcome, NIHR) and a competing interests statement are provided. The only gap is the absence of a referenced reporting guideline (CONSORT) in the main text, but the Nature Portfolio reporting summary is linked.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineINADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 88% conf

Reporting is transparent: the trial is registered (NCT04241601), methods are comprehensive for replication, limitations are discussed, conclusions are proportional, and funding/COI statements are provided. No reporting guideline checklist is explicitly mentioned beyond the Nature Portfolio summary.

Evidence

direct quote[Abstract, Methods]

“ClinicalTrials.gov registration: NCT04241601”

direct quote[Discussion, paragraph 6]

“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...”

direct quote[Acknowledgements]

“Medical Research Council, UK (grant no. MR/N028015/1 to Z.M.)... supported by the National Institute for Health and Care Research (NIHR), Cambridge Biomedical Research Centre (grant no. NIHR203312).”

PASSReviewer 2· 85% conf

Methods are complete, the trial is registered (NCT04241601), limitations are discussed, conclusions are proportional, and funding/COI are declared.

Evidence

direct quote[Abstract and Methods]

“ClinicalTrials.gov registration: NCT04241601”

direct quote[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”

direct quote[Abstract, last sentence]

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

PASSReviewer 3· 95% conf

The reporting is transparent: methods are detailed, trial registration is provided, limitations are discussed, conclusions are proportional, and funding and COI are declared.

Evidence

direct quote[Abstract and Methods]

“ClinicalTrials.gov registration: NCT04241601”

direct quote[Discussion, paragraph 7]

“This phase 2 study has some limitations. Patients with diabetes were underrepresented in this trial for methodological reasons relating to the use of [ 18 F]FDG PET–CT, which led to the exclusion of patients with diabetes on insulin therapy.”

direct quote[Discussion, final paragraph]

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

direct quote[Acknowledgements]

“Medical Research Council, UK (grant no. MR/N028015/1 to Z.M.)”

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

Checked 50 references: 6 verified — 8 unresolved, 36 not checked.

Reproducibility

4 data/code links checked; 4 live.

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

Adcurare Rigor Action ItemsFinal pass before journal submission

Ready after minor edits. The most critical issues are the data availability statement (needs specificity) and missing code sharing, plus the flagged references potentially being fabricated. Address these and the copyedit issues before submission; the scientific content is sound.

1.
HIGHdata code
Replace the vague 'available upon reasonable request' data availability statement with a concrete managed-access platform (e.g., Vivli, YODA) including a clear timeline and access conditions.
Current statement does not meet best practices for clinical trial data sharing and may be flagged by reviewers.
2.
HIGHdata code
Deposit custom analysis code (e.g., R scripts for MMRM and primary analysis) in a public repository (GitHub, Zenodo) with a DOI, and reference the repository in the manuscript.
Code sharing is currently absent; this is a common requirement for reproducibility and manuscript acceptance.
3.
HIGHreporting
For each of the 8 references listed as 'not found in registry' in the citation verification, verify the reference details or correct them; if any cannot be found, consider replacing them with verifiable sources.
References that cannot be located in any registry may be fabricated or contain errors, risking integrity concerns.
4.
HIGHreporting
Temper the claim that the anti-inflammatory effect of low-dose IL-2 is comparable to high-dose statins and alirocumab by explicitly noting that the comparison is indirect, across different populations and imaging protocols, and not tested within the trial.
The claim audit deemed this comparison overstated; it could mislead readers if not qualified.
5.
HIGHreporting
Add a statement explicitly referencing adherence to the CONSORT reporting guideline for randomized trials, and include the CONSORT flow diagram (already present) in the main manuscript.
Currently no reporting guideline is named in the text; this is a standard expectation for RCTs.
6.
HIGHstatistics
Report confidence intervals for all secondary immunological comparisons alongside p-values, not just for the primary outcome.
Effect sizes with CIs are missing for some comparisons, reducing transparency and interpretability.
7.
HIGHstatistics
Add a brief statement in the Statistical analysis section that model assumptions (linearity, normality of residuals) were checked and were satisfactory, or describe any violations and remedies.
Assumptions verification is currently not reported; this is a standard expectation for linear models.
8.
HIGHreporting
In the Methods or Results, explicitly describe the pre-specified approach for handling outliers or extreme values in the imaging data, even if none were excluded.
Outlier handling is not documented; this is a gap in the statistical analysis plan description.
9.
MEDIUMcopyedit
Correct the p-value inconsistency: report 'P = 0.015' consistently throughout the manuscript (currently reads 'P = 0.015' in Abstract and 'P = 0.0149' in Fig 2 legend).
Minor inconsistency that could be flagged as a reporting error.
10.
MEDIUMcopyedit
Fix the typo in the Results section: change '95% C1' to '95% CI'.
Typographical error in confidence interval notation.
11.
MEDIUMreporting
Add a sentence in the limitations section acknowledging the sex imbalance (predominantly male) and its implications for generalizability.
The justification for excluding women of childbearing potential is given, but the generalizability impact is not discussed.
12.
MEDIUMreporting
Report age with interquartile range in addition to range in Table 1, and consider adding baseline health status (e.g., renal function, hepatic function) to improve biological variable reporting.
Age is reported as median and range only; IQR provides a more standard summary for non-normal data.
13.
MEDIUMreporting
Specify the version of R and the nlme package used in the Statistical analysis section.
Software versions improve reproducibility; currently omitted.
14.
MEDIUMreporting
Clarify the definition of 'index vessel' to be identical across the Methods, Results, and Extended Data Table 1 to avoid confusion.
The copyedit flagged a potential inconsistency in the definition across locations.
15.
LOWcopyedit
Add a comma after 'MMRM' in the sentence 'For the MMRM the 'gls' function...' for clarity.
Minor punctuation issue.

Full text (57,890 chars)Analyzed: Jul 7, 2026

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

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Journal

DOI

10.1038/s41591-025-04090-y

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