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Kaimen Rigor review

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

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

DOI: 10.1038/s41591-025-04090-y
Record issued: 2026-08-10
Engine: 7.29.0
Exported: 2026-09-22

Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/ae081de6-4d40-4fdd-b13e-56b8a1423d57 is authoritative.

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.

Agent-written checks— recomputed from reported CIs / ratios by code the agent wrote

CONSISTENTreported p = .015 · recomputed p = .014Reviewer 1
Primary outcome: difference in arterial inflammation (mean TBR_max) between groups at end of treatment.
“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).”
Find in source
Taken as given: The estimate (-0.171) is the difference in means between groups.; The 95% CI is two-sided and symmetric (standard for linear regression).; The CI is on the same scale as the estimate (not log-transformed).; The p-value is derived from the t-distribution approximation to the Wald test.
Method: pCI function from the sandbox, which computes the two-sided p-value from the estimate and its 95% CI assuming a normal approximation. The result should match the reported p-value of 0.015.
How we recomputed it: pCI(-0.171, -0.308, -0.034, 0)
CONSISTENTreported p = .009 · recomputed p = .008Reviewers 1, 2
Secondary analysis: difference in arterial inflammation in active segments (TBR_max > 2 at baseline).
“Arterial inflammation in the low-dose IL-2 group was −0.185 (8.3%) lower compared to placebo, at the end of the treatment period (P = 0.009).”
Find in source
Taken as given: The estimate (-0.185) is the difference in means between groups.; The 95% CI is two-sided and symmetric.; The p-value is derived from the t-distribution approximation.
Method: pCI function; result should approximate 0.009.
How we recomputed it: pCI(-0.185, -0.323, -0.048, 0)
CONSISTENTreported p = .015 · recomputed p = .014Reviewer 2
Primary outcome: difference in arterial inflammation (index vessel) at end of treatment
“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).”
Find in source
Taken as given: The reported 95% CI is a two-sided confidence interval for the mean difference.; The estimate -0.171 is the difference between groups (IL-2 minus placebo).; The CI is based on a normal approximation or t-distribution.
Method: Two-sided p-value from the point estimate and 95% CI using the normal approximation.
How we recomputed it: pCI(-0.171, -0.308, -0.034, 0)
CONSISTENTreported p = .015 · recomputed p = .014Reviewer 3
Primary outcome: difference in arterial inflammation (mean TBR_max) between low-dose IL-2 and placebo at end of treatment.
“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)”
Find in source
Taken as given: The 95% CI is two-sided and symmetric on the difference scale (log=0).; The estimate and CI are for the same contrast (low-dose IL-2 minus placebo).; Gaussian approximation is adequate for n≈60 (the paper states CIs/P follow a t-distribution; for df≈58 the t and normal quantiles are nearly identical).
Method: Two-sided p reconstructed from estimate and 95% CI: SE=(high-low)/(2*1.96); z=estimate/SE; p=2*(1-normalCdf(|z|)).
How we recomputed it: pCI(-0.171,-0.308,-0.034,0)
CONSISTENTreported p = .009 · recomputed p = .008Reviewer 3
Secondary outcome: difference in arterial inflammation in active (inflamed) segments at end of treatment.
“the difference between the two groups was greater, with an 8.3% difference in arterial inflammation between the low-dose IL-2 group and the placebo group (−0.185, 95% CI −0.323 to −0.048, P = 0.009)”
Find in source
Taken as given: The 95% CI is two-sided and symmetric on the difference scale (log=0).; The estimate and CI refer to the same active-segment contrast.; Gaussian approximation is adequate for n≈60.
Method: Two-sided p reconstructed from estimate and 95% CI as above.
How we recomputed it: pCI(-0.185,-0.323,-0.048,0)
CONSISTENTreported p = .086 · recomputed p = .093Reviewer 3
Secondary outcome: baseline-adjusted change in arterial inflammation in the index vessel between groups.
“the difference in change from baseline between the groups (Extended Data Table ) showed a trend toward a reduction in arterial inflammation in the low-dose IL-2 group compared to placebo, but did not reach statistical significance (−0.103, 95% CI −0.22 to 0.02, P = 0.086)”
Find in source
Taken as given: The 95% CI is two-sided and symmetric on the difference scale (log=0).; The estimate and CI refer to the baseline-adjusted change contrast.; Gaussian approximation is adequate for n≈60.
Method: Two-sided p reconstructed from estimate and 95% CI as above.
How we recomputed it: pCI(-0.103,-0.22,0.02,0)

mediuminternal contradiction
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

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.

partialReviewer 1
Low-dose IL-2 may reduce MACE recurrence (from IVORY-FINALE).
The IVORY-FINALE data show no MACE in the IL-2 arm vs. 3 patients with MACE in placebo at 2 years, but the sample is small (55 patients) and the study is not powered for clinical outcomes. The authors appropriately call for larger trials.
Evidence: Results, IVORY-FINALE: 4 MACE in 3 patients (11%) in placebo, 0 in IL-2 arm. Figure 4 shows MACE-free survival curves.
“At 2 years of follow-up, 4 chronologically distinct MACE occurred in 3 (11%) patients in the placebo group. No MACEs occurred in the low-dose IL-2 arm.”
ResultsFind in source
partialReviewer 2
Low-dose IL-2 may reduce major adverse cardiovascular events (MACE) at 2 years.
The IVORY-FINALE data show no MACE in the IL-2 group versus 3 events in placebo, but the study is not powered for clinical outcomes, and the paper correctly calls for larger trials.
Evidence: At 2-year follow-up, 4 MACE occurred in 3 patients in placebo, none in IL-2. The paper states 'larger trials powered to assess the effect of low-dose IL-2 on clinical outcomes are needed.'
“At 2 years of follow-up, 4 chronologically distinct MACE occurred in 3 (11%) patients in the placebo group. No MACEs occurred in the low-dose IL-2 arm.”
ResultsFind in source
partialReviewer 3
Low-dose IL-2 may have a potential benefit on MACE recurrence.
The MACE data come from a small, non-powered observational follow-up (3 events in placebo, 0 in IL-2) and the claim is appropriately hedged as 'potential', so it is only partially supported by the presented evidence.
Evidence: IVORY-FINALE: at 2 years, 4 MACE in 3 (11%) placebo patients, none in IL-2; 55 of 60 patients followed.
“At 2 years of follow-up, 4 chronologically distinct MACE occurred in 3 (11%) patients in the placebo group. No MACEs occurred in the low-dose IL-2 arm.”
DiscussionFind in source
supportedReviewer 1
Low-dose IL-2 safely increases Treg cell levels in patients with ACS.
The paper provides clear evidence of Treg increase (percentage and absolute counts) at multiple time points with robust statistical significance and no safety signals that would override this finding.
Evidence: Figure 3 and Extended Data Figure 2 show significant increases in Treg cells (as % of CD4+ and absolute counts) in the IL-2 arm compared to placebo at all post-baseline visits. Safety data (Table 2) show no serious adverse events or increased infections.
At all treatment visits after baseline, there was a significant increase from baseline in T reg cells in the low-dose IL-2 group compared to placebo... After 4 days of treatment in the induction phase, a 57% increase in T reg cells from baseline was observed compared to an 0.6% increase in placebo (Δ = 56.73%, 95% CI 43.42–70.04).
Resultsreviewer’s wording
supportedReviewer 1
Low-dose IL-2 reduces arterial inflammation as measured by [18F]FDG PET-CT.
The primary outcome showed a statistically significant reduction in arterial inflammation (mean TBR_max) in the index vessel, meeting the pre-specified endpoint.
Evidence: Primary outcome: difference of -0.171 (95% CI -0.308 to -0.034, P=0.015) in index vessel at end of treatment.
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).
Resultsreviewer’s wording
supportedReviewer 1
Low-dose IL-2 is safe and well tolerated in patients with ACS.
Safety data show no severe adverse events, similar infection rates, and low discontinuation (3%) in the IL-2 arm. Injection site reactions were common but mild.
Evidence: Table 2: no severe AEs, infection rates 9% vs 13%, one withdrawal due to rash. IVORY-FINALE: no MACE in IL-2 arm at 2 years.
“Treatment with low-dose IL-2 across 8 weeks was safe and well tolerated in patients with ACSs. Drug discontinuation rates were low (3%, n = 1) with IL-2 therapy. Infection rates were similar in both treatment arms (9% in low-dose IL-2 versus 13% in placebo) and they were all classified as mild.”
ResultsFind in source
supportedReviewers 1, 2
The anti-inflammatory effect of low-dose IL-2 is greater in more inflamed segments.
Secondary analyses of active segments (TBR_max>2) and most diseased segments show larger effect sizes (8.3% and 9.3% reduction), consistent with the hypothesis.
Evidence: Figure 2b: active segment analysis shows -0.185 (8.3% lower, P=0.009). Most diseased segment analysis: -0.213 (9.3% lower, P=0.010).
When areas of the index vessel with a TBR max > 2 at baseline (active segments) were analyzed... the difference between the two groups was greater, with an 8.3% difference in arterial inflammation between the low-dose IL-2 group and the placebo group (−0.185, 95% CI −0.323 to −0.048, P = 0.009).
Resultsreviewer’s wording
supportedReviewer 2
Low-dose IL-2 reduces arterial inflammation compared to placebo in patients with ACS.
The primary outcome shows a statistically significant reduction in arterial inflammation (TBRmax) in the IL-2 group compared to placebo.
Evidence: Primary outcome: mean TBRmax index vessel was lower (−0.171, 95% CI −0.308 to −0.034, P=0.015) in the IL-2 group.
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).
Resultsreviewer’s wording
supportedReviewer 2
Low-dose IL-2 increases circulating Treg cells in patients with ACS.
The paper reports significant increases in Treg cells at multiple time points compared to placebo.
Evidence: Figure 3 shows Treg increases at all post-baseline visits; at V7, Δ=56.73% (95% CI 43.42–70.04) and P=1.1×10^(-10).
“After 4 days of treatment in the induction phase, a 57% increase in T reg cells from baseline was observed compared to an 0.6% increase in placebo (Δ = 56.73%, 95% CI 43.42–70.04).”
ResultsFind in source
supportedReviewer 2
Low-dose IL-2 is safe and well-tolerated in patients with ACS.
The safety data show no serious adverse events related to IL-2, low discontinuation rates, and similar infection rates between groups.
Evidence: Table 2 shows no SAEs in the IL-2 group, 1 in placebo. Injection site reactions were common but mild. No deaths. Infection rates similar.
One serious AE (SAE) occurred in a patient in the placebo arm... No MACEs occurred in the low-dose IL-2 arm.
Resultsreviewer’s wording
supportedReviewer 3
Treatment with low-dose IL-2 over 8 weeks reduced arterial inflammation in patients with ACS and residual inflammation compared to placebo.
The primary outcome (difference in mean TBR_max of the index vessel) was met with a statistically significant effect, so the headline efficacy claim is backed by the presented analysis.
Evidence: Primary outcome: arterial inflammation −0.171 lower in the IL-2 group (95% CI −0.308 to −0.034, P = 0.015).
“At the end of treatment, 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).”
AbstractFind in source
supportedReviewer 3
Low-dose IL-2 increased regulatory T cell levels compared to placebo.
The Treg increases were large, consistent across treatment visits, and statistically significant.
Evidence: 57% increase vs 0.6% in placebo after 4 days (P<0.0001); 34% higher at maintenance (95% CI 27.58-40.45); significant at all visits after baseline.
“At all treatment visits after baseline, there was a significant increase from baseline in T reg cells in the low-dose IL-2 group compared to placebo”
ResultsFind in source

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).

highother
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
mediumother
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
lowother
The URL for IVORY-FINALE registration appears to reference a different trial (NCT03690193) and has a typo in the query parameter.
“IVORY-FINALE (ClinicalTrials.gov registration: NCT06427694 (http://clinicaltrials.gov/ct2/show/NCT03690193?term=NCT06437694) )”
MethodsFind in source

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.

ClinicalTrials.gov

ClinicalTrials.gov

ClinicalTrials.gov

ClinicalTrials.gov

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).

NO DOI
Antiinflammatory therapy with canakinumab for atherosclerotic disease.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Efficacy and safety of low-dose colchicine after myocardial infarction.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Colchicine in patients with chronic coronary disease.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Targeting cardiovascular inflammation: next steps in clinical translation.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Colchicine in acute myocardial infarction.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Low-dose colchicine for secondary prevention of cardiovascular disease.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Targeting the immune system in atherosclerosis: JACC state-of-the-art review.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
The regulation and differentiation of regulatory T cells and their dysfunction in autoimmune diseases.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Principles of regulatory T cell function.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Altered status of CD4+ CD25+ regulatory T cells in patients with acute coronary syndromes.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Increased PTPN22 expression and defective CREB activation impair regulatory T-cell differentiation in non-ST-segment elevation acute coronary syndromes.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Natural regulatory T cells control the development of atherosclerosis in mice.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Role of naturally occurring CD4+ CD25+ regulatory T cells in experimental atherosclerosis.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Regulatory T cells prevent plaque disruption in apolipoprotein E-knockout mice.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Cytokine therapy with interleukin-2/anti-interleukin-2 monoclonal antibody complexes expands CD4+CD25+Foxp3+ regulatory T cells and attenuates development and progression of atherosclerosis.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Foxp3+ CD4+ T cells improve healing after myocardial infarction by modulating monocyte/macrophage differentiation.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Regulatory T lymphocytes attenuate myocardial infarction-induced ventricular remodeling in mice.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Regulatory T-cell response to low-dose interleukin-2 in ischemic heart disease.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Atherosclerosis inflammation imaging with 18 F-FDG PET: carotid, iliac, and femoral uptake reproducibility, quantification methods, and recommendations.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
18Fluorodeoxyglucose positron emission tomography imaging of atherosclerotic plaque inflammation is highly reproducible: implications for atherosclerosis therapy trials.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Position paper of the Cardiovascular Committee of the European Association of Nuclear Medicine (EANM) on PET imaging of atherosclerosis.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
FDG-PET/CT (A) imaging in large vessel vasculitis and polymyalgia rheumatica: joint procedural recommendation of the EANM, SNMMI, and the PET Interest Group (PIG), and endorsed by the ASNC.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
18F-FDG PET/CT identifies patients at risk for future vascular events in an otherwise asymptomatic cohort with neoplastic disease.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Arterial wall uptake of fluorodeoxyglucose on PET imaging in stable cancer disease patients indicates higher risk for cardiovascular events.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Measurement of arterial activity on routine FDG PET/CT images improves prediction of risk of future CV events.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
PET imaging of inflammation in atherosclerosis.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Effect of treatment for 12 weeks with rilapladib, a lipoprotein-associated phospholipase A2 inhibitor, on arterial inflammation as assessed with 18 F-fluorodeoxyglucose-positron emission tomography imaging.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Intensive statin therapy in acute coronary syndromes and stable coronary heart disease: a comparative meta-analysis of randomised controlled trials.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Meta-analysis of time-related benefits of statin therapy in patients with acute coronary syndrome undergoing percutaneous coronary intervention.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Inflammation and the pathogenesis of atherosclerosis.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Intensification of statin therapy results in a rapid reduction in atherosclerotic inflammation: results of a multicenter fluorodeoxyglucose-positron emission tomography/computed tomography feasibility study.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
PCSK9 antibody alirocumab attenuates arterial wall inflammation without changes in circulating inflammatory markers.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
High-intensity statin therapy yields better outcomes in acute coronary syndrome patients: a meta-analysis involving 26,497 patients.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
The effects of 3-month atorvastatin therapy on arterial inflammation, calcification, abdominal adipose tissue and circulating biomarkers.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Simvastatin attenuates plaque inflammation: evaluation by fluorodeoxyglucose positron emission tomography.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Low-dose interleukin-2 induces clonal expansion of BACH2-repressed effector regulatory T cells following acute coronary syndrome.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Low-dose IL-2 enhances the generation of IL-10-producing immunoregulatory B cells.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Innate lymphoid cells promote recovery of ventricular function after myocardial infarction.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Low-dose daily interleukin-2 immunotherapy: accelerating immune restoration and expanding HIV-specific T-cell immunity without toxicity.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Low-dose IL-2 reduces lymphocyte apoptosis and increases naive CD4 cells in HIV-1 patients treated with HAART.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Interleukin-2 and regulatory T cells in graft-versus-host disease.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
The universal effects of low-dose interleukin-2 across 13 autoimmune diseases in a basket clinical trial.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Low-dose interleukin-2 treatment selectively modulates CD4 + T cell subsets in patients with systemic lupus erythematosus.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Vascular inflammation in subclinical atherosclerosis detected by hybrid PET/MRI.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Bone marrow activation in response to metabolic syndrome and early atherosclerosis.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Low-dose interleukin 2 for the reduction of vascular inflammation in acute coronary syndromes (IVORY): protocol and study rationale for a randomised, double-blind, placebo-controlled, phase II clinical trial.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Anti-tumor necrosis factor-α therapy reduces aortic inflammation and stiffness in patients with rheumatoid arthritis.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Imaging atherosclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emission tomography.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).

4 data/code links checked; 4 live.

datahttps://clinicaltrials.gov/study/NCT04241601LIVEHTTP 200
Resolves, but the content could not be matched to the paper.
datahttp://clinicaltrials.gov/ct2/show/NCT03690193?term=NCT06437694LIVEHTTP 200
Resolves, but the content could not be matched to the paper.
datahttp://www.sealedenvelope.comLIVEHTTP 200
Resolves, but the content could not be matched to the paper.
datahttp://BioRender.comLIVEHTTP 200
Resolves, but the content could not be matched to the paper.

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.

MAJORconsistencyMethods, Study design and oversight (IVORY-FINALE registration)
“IVORY-FINALE (ClinicalTrials.gov registration: NCT06427694 (http://clinicaltrials.gov/ct2/show/NCT03690193?term=NCT06437694))”
→ Replace the hyperlink with one that resolves to the record for NCT06427694.
The URL term and CT2 ID do not match the stated registration number; this could misdirect a reader to the wrong trial record.
MINORotherAbstract, line 1
“32 2 624 624–632”
→ Remove extraneous numbers; likely a page-number artifact.
Appears to be a formatting error from the journal layout.
MINORotherResults, Secondary efficacy analyses
“95% C1 −30.97 to −17.45”
→ Change 'C1' to 'CI'.
Typographical error; should be 'CI' for confidence interval.
MINORconsistencyMethods, Statistical analysis
“The statistical package used was R.”
→ Add version number, e.g., 'R version 4.3.0'.
Version is important for reproducibility.
MINORclarityResults, Primary efficacy analyses
“The difference in change from baseline between the groups (Extended Data Table ) showed a trend toward a reduction in arterial inflammation in the low-dose IL-2 group compared to placebo, but did not reach statistical significance (−0.103, 95% CI −0.22 to 0.02, P = 0.086).”
→ Consider rephrasing to clarify that this is the change-from-baseline difference, not the end-of-treatment comparison.
The text is technically correct but could be clearer.
MINORconsistencyAbstract, sex ratios
“placebo = 29 (F-to-M = 6:23); low-dose IL-2 = 31 (F-to-M = 3:28)”
→ Change to 'placebo = 29 (F-to-M = 7:24); low-dose IL-2 = 31 (F-to-M = 3:29)' to match Table 1.
The reported sex ratios in the abstract do not match the numbers in Table 1.
MINORotherResults, Effects on circulating immune cells
“95% C1 −30.97 to −17.45”
→ Change 'C1' to 'CI'.
Typographical error: 'C1' should be 'CI'.
MINORconsistencyIVORY-FINALE registration URL
“http://clinicaltrials.gov/ct2/show/NCT03690193?term=NCT06437694”
→ Correct to 'https://clinicaltrials.gov/study/NCT06427694' or the appropriate URL for NCT06427694.
The URL appears to contain a wrong identifier (NCT03690193) and a typo in the term parameter.
MINORclarityResults, Primary efficacy analyses
“This is equivalent to the effect observed with high-dose statin therapy (when compared to low-dose statin therapy), which reduces MACEs in ACSs – .”
→ Add a citation for the reference about high-dose statin effect.
The sentence ends with a dash and space before the period, and the reference is missing.
MINORtypoResults, Effects on circulating immune cells (T follicular helper cells)
“95% C1 −30.97 to −17.45”
→ Change 'C1' to 'CI'.
Confidence interval abbreviated as C1.
MINORconsistencyAbstract vs. Fig. 2 legend
“P = 0.015 (abstract) ... P = 0.0149 (Fig. 2 legend)”
→ Use one consistent level of precision for the primary-outcome p-value.
Both values are consistent, but the abstract and figure report different rounding of the same p-value.

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

RigorReviewer 1

RigorReviewer 2

RigorReviewer 3

RigorPre-Submission Reviewer

CopyeditAgent Scribe

CitationsCitation Integrity

StatisticsStatistics Consistency

ReproducibilityLink verification (liveness + content)· no model (rule-based)

PreregistrationDeterministic check· no model (rule-based)

The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”

How stars are deducted

Reporting — 8 dimensionseach dimension that fully fails−½★
each dimension partially met−¼★
Statistics · Integrity · Claimseach serious problem−1★
each medium problem−½★
Citationseach retracted or unverifiable reference−¼★
Copyeditonly when the manuscript needs a full edit−½★

The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.

The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.

The eight reporting dimensions

Scientific PremisePrior work, rationale, and how it addresses gaps.

Study Design & RigorRandomization, blinding, power, controls, replication.

Biological VariablesSex, age, species/strain, housing, demographics.

Ethical ApprovalsIRB/IACUC approval, informed consent, regulatory compliance.

Key ResourcesAntibodies, cell lines, organisms, software — identified with persistent IDs.

Statistical ReportingNamed tests, exact p-values, effect sizes, plausible summary stats.

Data & Code AvailabilityAvailability statements, repositories, accession numbers, shared code.

Reporting TransparencyMethods, registration, guidelines, outcomes, limitations, funding/COI.

Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.

This Kaimen Rigor review is model-assisted and is not a substitute for formal expert review. It complements human evaluation by surfacing potential methodological concerns — verify each finding against the source.

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

DOI

10.1038/s41591-025-04090-y

Record issued

2026-08-10

Engine

7.29.0

Exported

2026-09-22