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
- 2026-08-15
- Engine
- 7.39.0
- 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/1a39f6c8-fca9-48b1-a488-7148e4c286c2 is authoritative.
How this rating was calculated
- IntegrityIntegrity concern ×4−2★
- CitationsCitations & links (capped) ×5−1★
- ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
- ClaimsTreatment effect not shown to be clinically meaningful−0.5★
- ReportingData & code availability partially met−0.25★
Citations & links are capped at −1★ combined, however many are flagged.
- The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 4 reported means were read, and their group size is not stated where the values are printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.
- 01Efficacy rests on an unvalidated surrogate endpoint
The primary efficacy endpoint is arterial inflammation measured by [18F]FDG PET-CT (mean TBR max), which is a surrogate imaging biomarker. The paper does not provide evidence of target engagement at the tested dose (e.g., PK/PD or dose-exposure relationship) nor does it cite validated evidence linking this surrogate to clinical outcomes in the context of this trial. Although the paper mentions that vascular FDG uptake is related to future cardiovascular risk, it does not establish a validated surrogate-to-clinical-outcome link for this specific intervention.
“The primary outcome was the difference in arterial inflammation in the index vessel ... on follow-up imaging between the two groups ... At the end of treatment, arterial inflammation was −0.171 (−7.7%) lower in the low-dose IL-2 group compared to the placebo…”
- 02Treatment effect not shown to be clinically meaningful
The primary reported effect is a 7.7% reduction in arterial inflammation (mean TBR max) compared to placebo. This is a small fraction of the reference value and is not anchored to a clinically meaningful threshold. The paper compares this to effects of statins, but does not establish a minimal clinically important difference for this surrogate. The effect size is presented as statistically significant but lacks explicit clinical meaningfulness.
“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).”
- 03Other integrity concern
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 - 04Other integrity concern
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
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.
The paper is a well-designed and transparently reported phase 2 randomized controlled trial with rigorous methodology, clear ethical approvals, and appropriate statistical analysis. The main weakness is the vague data availability statement, and there are minor copyediting issues including an unresolvable trial registration number and inconsistent p-value rounding.
Both reviewers classified the study as interventional and agreed on all dimension statuses; no substantive divergence. The statistics verification covered only 2 tests (those with test statistics/df or effect+CI), so the statistical analysis is not fully verified; the citation check flagged 5 references not found in registries, and the integrity check raised a high-severity concern about an unresolvable trial registration number.
Numerical inconsistencies
1 finding · worst lowValues that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.
- Internal contradictions in the reported numbersAssessed
Recomputed 2 tests: 2 consistent, 0 inconsistent; 2 via agent-written checks.
- CONSISTENTreported p = .015 · recomputed p = .014Reviewer 2Primary outcome p-value from estimate and CI
“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).”
Taken as given: The estimate is the difference in means.; The CI is a 95% confidence interval.; The test is two-sided.Method: Recomputed two-sided p-value from the reported estimate and 95% CI using the normal approximation.How we recomputed it: pCI(-0.171, -0.308, -0.034, 0) - CONSISTENTreported p = .009 · recomputed p = .008Reviewer 2Secondary outcome p-value from estimate and CI
“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).”
Taken as given: The estimate is the difference in means.; The CI is a 95% confidence interval.; The test is two-sided.Method: Recomputed two-sided p-value from the reported estimate and 95% CI using the normal approximation.How we recomputed it: pCI(-0.185, -0.323, -0.048, 0)
- lowinternal contradictionThe IVORY-FINALE registration number in the text (NCT06427694) does not match the URL (NCT03690193 or NCT06437694). This is likely a typographical error.
“IVORY-FINALE (ClinicalTrials.gov registration: NCT06427694 (http://clinicaltrials.gov/ct2/show/NCT03690193?term=NCT06437694) )”
MethodsFind in source - lowinternal contradictionThe abstract reports P=0.015 for the primary outcome, while the figure legend reports P=0.0149. This is a minor inconsistency in rounding.
P = 0.015 (abstract); P = 0.0149 (figure legend)
Figure 2Areviewer’s wording
Overstated conclusions
3 findings · worst highConclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.
- Efficacy rests on an unvalidated surrogate endpointAssessed
- Treatment effect not shown to be clinically meaningfulAssessed
- Conclusions only partially backed by the presented evidenceAssessed
8 major claims checked against the paper's own evidence: 2 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.
- partialReviewer 1Low-dose IL-2 reduces arterial inflammation through Treg cell enhancement.The paper shows both Treg increase and inflammation reduction, but does not establish a causal link between them.Evidence: Treg cells increased and inflammation decreased, but no mediation analysis is presented.
“We hypothesized that the anti-inflammatory effect of low-dose IL-2 was a result of enhanced T reg cell numbers and function”
DiscussionFind in source - partialReviewer 2Low-dose IL-2 may reduce MACE recurrence.The IVORY-FINALE data show no MACE in the IL-2 arm vs 3 in placebo, but the study is not powered for clinical outcomes and follow-up is only 2 years.Evidence: At 2 years, 3 MACE in placebo, 0 in IL-2 arm.
“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 - supportedReviewers 1, 2Low-dose IL-2 reduces arterial inflammation compared to placebo in patients with ACS.The primary outcome showed a statistically significant reduction in arterial inflammation (P=0.015), supporting the claim.Evidence: Primary outcome: difference in mean TBRmax -0.171 (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 1Low-dose IL-2 increases Treg cell levels compared to placebo.Treg cells were significantly increased at all post-baseline visits, with highly significant p-values.Evidence: Treg cell percentage changes from baseline were significantly higher in the IL-2 group at all visits (e.g., V7 P=1.1e-10).
“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 - supportedReviewer 1Low-dose IL-2 treatment appeared to be safe, with no major adverse cardiovascular events at 2-year follow-up.No MACEs occurred in the IL-2 group, and adverse events were mostly mild injection site reactions.Evidence: IVORY-FINALE: 0 MACEs in IL-2 group vs 3 in placebo; safety data in Table 2.
“Low-dose IL-2 treatment appeared to be safe, with no major adverse cardiovascular events at the 2-year follow-up, compared to three patients with such events in the placebo group.”
AbstractFind in source - supportedReviewers 1, 2The anti-inflammatory effect of low-dose IL-2 is greater in more inflamed segments.Secondary analyses showed larger reductions in active and most diseased segments, supporting the claim.Evidence: Active segments: -8.3% (P=0.009); most diseased segments: -9.3% (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
Resultsreviewer’s wording - supportedReviewer 2Low-dose IL-2 increases Treg cell levels.Treg cells were significantly increased at all post-baseline visits, with exact p-values reported.Evidence: Treg cell increases of 57% after induction and 34% at maintenance, with p-values <0.0001.
“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 2Low-dose IL-2 is safe in ACS patients.Safety data show no SAEs in the IL-2 arm and no MACE at 2 years, supporting the claim of safety.Evidence: No SAEs in IL-2 arm; no MACE at 2 years in IL-2 arm vs 3 in placebo.
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
Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.
- INADEQUATESurrogate endpointThe primary efficacy endpoint is arterial inflammation measured by [18F]FDG PET-CT (mean TBR max), which is a surrogate imaging biomarker. The paper does not provide evidence of target engagement at the tested dose (e.g., PK/PD or dose-exposure relationship) nor does it cite validated evidence linking this surrogate to clinical outcomes in the context of this trial. Although the paper mentions that vascular FDG uptake is related to future cardiovascular risk, it does not establish a validated surrogate-to-clinical-outcome link for this specific intervention.
“The primary outcome was the difference in arterial inflammation in the index vessel ... on follow-up imaging between the two groups ... 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).”
- INADEQUATEEffect sizeThe primary reported effect is a 7.7% reduction in arterial inflammation (mean TBR max) compared to placebo. This is a small fraction of the reference value and is not anchored to a clinically meaningful threshold. The paper compares this to effects of statins, but does not establish a minimal clinically important difference for this surrogate. The effect size is presented as statistically significant but lacks explicit clinical meaningfulness.
“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).”
Data authenticity concerns
1 finding · worst mediumAn 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).
- highotherThe 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 - mediumotherTrial 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
Reporting gaps
1 finding · worst mediumRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
- Data/code availability incompleteAssessed
The introduction cites prior studies on Treg cells in ACS, low-dose IL-2 effects, and the unmet need for anti-inflammatory therapies. The hypothesis follows logically from the cited evidence. Limitations of prior work are implicitly addressed by the trial design, though not explicitly framed as addressing prior limitations.
“Studies have demonstrated that T reg cell numbers are reduced and their function impaired in ACSs”
“we hypothesized that low-dose IL-2 would reduce arterial inflammation compared to placebo in patients presenting with ACSs who have residual inflammation”
“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 .”
Randomization method (permuted block, stratified) and unit (patient) are described. Blinding is comprehensive for patients, investigators, and outcome assessors. Power analysis is provided with effect size, alpha, and power. Inclusion/exclusion criteria are pre-specified. Outlier handling is addressed via the full analysis population and pre-specified analysis plan. Controls are appropriate (placebo). Independent replication is not applicable for a single pivotal trial.
“Permutated block randomization was used, with random block sizes of 2, 4 and 6. Randomization was stratified by ST-segment elevation status.”
“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.”
“Assuming an s.d. of 0.24, 24 patients per arm, testing at a two-sided 5% significance level, provided 80% power.”
“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.”
“Assuming an s.d. of 0.24, 24 patients per arm, testing at a two-sided 5% significance level, provided 80% power.”
Sex is reported for both groups, and the single-sex restriction (postmenopausal/perimenopausal women) is justified by safety concerns. Age, BMI, and health status are reported. Demographics include ethnicity and comorbidities. Species/strain and housing are not applicable for a human trial.
“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.”
“Median age (range), years | 55 (39–75) | 56.5 (34–73)”
The trial received favorable ethical opinion from a named ethics committee (Yorkshire and Humber—Sheffield) with protocol number, and regulatory approval from MHRA. Written informed consent was obtained. Compliance with Declaration of Helsinki and ICH-GCP is stated. The follow-up study also has its own ethics approval.
“The trial received favorable ethical opinion from the Yorkshire and Humber—Sheffield ethics committee (19/YH/0171)”
“Written informed consent was obtained from all patients before carrying out any study procedures for both IVORY and IVORY-FINALE.”
“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 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).”
“Written informed consent was obtained from all patients before carrying out any study procedures for both IVORY and IVORY-FINALE.”
“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 (IL-2) is described with dose and regimen. Antibodies are identified with vendor, catalog numbers, and clones. Statistical software (R) and packages are named. Cell lines and mycoplasma testing are not applicable.
“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) or placebo for 8 weeks”
“The statistical package used was R. For the MMRM the ‘gls’ function from the ‘nlme’ package was used.”
“CD196 phycoerythrin (PE) (20 μl in 100 μl of blood; BD Pharmingen, cat. no. 551773, clone 11A9)”
“randomized in a 1:1 ratio to receive subcutaneous low-dose IL-2 (1.5 × 10 6 IU) or placebo for 8 weeks.”
“The statistical package used was R. For the MMRM the ‘gls’ function from the ‘nlme’ package was used.”
Tests are named (linear regression, MMRM, Mann-Whitney U). Assumptions are handled by design (pre-specified models). Exact p-values are reported for primary and key secondary outcomes. Effect sizes with 95% CIs are reported throughout. Software is identified. Data presentation includes individual data points and error bars defined. Mathematical plausibility checks were not possible for most continuous outcomes, but no inconsistencies were found.
“linear regression models were used to estimate the treatment effect”
“−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)”
“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).”
“the mean TBR max in the index vessel was lower (−0.171, 95% CI −0.308 to −0.034, P = 0.015)”
The data availability statement says deidentified participant data are available upon reasonable request, but does not specify a platform, data access committee, or timeframe. This is reported_but_inadequate. Repository deposit and accession numbers are not applicable for patient-level data. Code sharing is not applicable as no bespoke code is mentioned.
“Deidentified participant data generated during the trial are available upon reasonable request from academic researchers or clinical researchers affiliated with recognized institutions.”
“Deidentified participant data generated during the trial are available upon reasonable request from academic researchers or clinical researchers affiliated with recognized institutions.”
The trial is registered (NCT04241601). A reporting summary is mentioned. All outcomes are reported, including null results. Limitations are discussed. Conclusions are proportional, noting the need for larger validation. Funding and COI are stated.
“ClinicalTrials.gov registration: NCT04241601”
“This phase 2 study has some limitations.”
“The clinical benefit of low-dose IL-2 requires validation in larger studies.”
“ClinicalTrials.gov registration: NCT04241601”
“We also thank our funders: Medical Research Council, UK (grant no. MR/N028015/1 to Z.M.).”
Registered (4 IDs: ClinicalTrials.gov). No reporting guideline cited.
Broken references and links
1 finding · worst lowReferences 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.
- References not resolvable to a published paperRecomputed
Checked 49 references by DOI: 44 verified — 5 DOI unresolved.
- UNRESOLVED10.2967/jnumed.107.049239Atherosclerosis inflammation imaging with 18 F-FDG PET: carotid, iliac, and femoral uptake reproducibility, quantification methods, and recommendationsCited DOI does not resolve to any Crossref record.
- UNRESOLVED10.1007/bf03005308Arterial wall uptake of fluorodeoxyglucose on PET imaging in stable cancer disease patients indicates higher risk for cardiovascular eventsCited DOI does not resolve to any Crossref record.
- UNRESOLVED10.1186/s12944-020-01306-1High-intensity statin therapy yields better outcomes in acute coronary syndrome patients: a meta-analysis involving 26,497 patientsCited DOI does not resolve to any Crossref record.
- UNRESOLVED10.1038/s44161-025-00620-8Low-dose interleukin-2 induces clonal expansion of BACH2-repressed effector regulatory T cells following acute coronary syndromeCited DOI does not resolve to any Crossref record.
- UNRESOLVED10.1038/s41467-023-37723-6Low-dose IL-2 enhances the generation of IL-10-producing immunoregulatory B cellsCited DOI does not resolve to any Crossref record.
2 data/code links checked; 2 live.
- datahttps://clinicaltrials.gov/study/NCT04241601LIVEHTTP 200Resolves, but the content could not be matched to the paper.
- datahttp://clinicaltrials.gov/ct2/show/NCT03690193?term=NCT06437694LIVEHTTP 200Resolves, but the content could not be matched to the paper.
Copyediting
8 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 8 minor suggestions below.
8 copyedit issues flagged: mostly consistency, typo, clarity.
- MINORtypoAbstract“F-to-M = 6:23”→ Consider using 'female-to-male ratio' consistently.Abbreviation used without definition in abstract.
- MINORconsistencyResults, Primary efficacy analyses“P = 0.015”→ Ensure consistent reporting of p-values (e.g., 0.015 vs 0.0149).Abstract reports P=0.015, figure legend reports P=0.0149.
- MINORtypoResults, Secondary efficacy analyses“95% C1 −30.97 to −17.45”→ Change 'C1' to 'CI'.Typographical error in confidence interval abbreviation.
- MINORconsistencyMethods, Study design and oversight“NCT06427694 (http://clinicaltrials.gov/ct2/show/NCT03690193?term=NCT06437694)”→ Verify the correct URL for the IVORY-FINALE registration.URL appears to contain a different trial number.
- MINORtypoAbstract“F-to-M”→ F-to-M ratioAbbreviation not defined at first use.
- MINORconsistencyResults, Secondary efficacy analyses“95% C1”→ 95% CITypo in confidence interval abbreviation.
- MINORconsistencyResults, Primary efficacy analyses“P = 0.0149”→ P = 0.015Inconsistent rounding of p-value compared to abstract.
- MINORclarityMethods, Study design and oversight“IVORY-FINALE (ClinicalTrials.gov registration: NCT06427694 (http://clinicaltrials.gov/ct2/show/NCT03690193?term=NCT06437694) )”→ Correct the URL to match the registration number.URL appears to be for a different trial.
The published work is methodologically robust, but an informed reader should weigh the unresolvable trial registration number (NCT06437694) and the retrospective registration of the main trial (NCT03690193), which undermine the prospective registration claim. The vague data availability statement and minor copyediting issues (p-value rounding, URL mismatch) are lower-level concerns that would warrant a correction or clarification.
- 1.HIGHreportingCorrect the trial registration number for IVORY-FINALE in the Methods (currently NCT06427694) and ensure the URL matches; verify the registration exists on ClinicalTrials.gov.The integrity check found that NCT06437694 has no record, and the URL points to a different trial (NCT03690193), which is a serious reporting error that undermines the registration claim.
- 2.HIGHreportingClarify the prospective vs. retrospective registration status of the main trial (NCT03690193) in the Methods, noting the first submission date (2018-08-01) relative to the study start date (2013-12-03).The integrity check indicates the trial was registered after the study began, which is a transparency concern that should be acknowledged.
- 3.HIGHdata codeSpecify a concrete data access mechanism in the Data Availability section (e.g., a data access committee, a platform like Vivli, or a named repository) and a timeframe for responding to requests.The current 'available upon reasonable request' statement is vague and does not meet the standard for actionable data sharing.
- 4.HIGHreportingVerify and correct the 5 references flagged as not found in registries (e.g., 'Atherosclerosis inflammation imaging with 18F-FDG PET...', 'Arterial wall uptake of fluorodeoxyglucose...', 'High-intensity statin therapy...', 'Low-dose interleukin-2 induces clonal expansion...', 'Low-dose IL-2 enhances the generation...') to ensure they are real and correctly cited.References that cannot be found in any registry may be fabricated or contain errors, which is a serious integrity concern.
- 5.HIGHstatisticsReconcile the p-value for the primary outcome across the Abstract (P=0.015) and the figure legend (P=0.0149) to a single consistent value.Inconsistent rounding of the primary outcome p-value is a minor but visible inconsistency that could confuse readers.
- 6.MEDIUMcopyeditFix the typo '95% C1' to '95% CI' in the Results, Secondary efficacy analyses.The confidence interval abbreviation is misspelled, which is a simple copyediting error.
- 7.MEDIUMcopyeditDefine the abbreviation 'F-to-M' at first use in the Abstract (e.g., 'female-to-male ratio').The abbreviation is used without definition, which reduces clarity for readers.
- 8.MEDIUMreportingAdd an explicit statement in the Methods or Reporting Summary that the trial was reported according to CONSORT guidelines and provide the checklist as supplementary material.Explicit adherence to a reporting guideline improves transparency and reproducibility.
- 9.MEDIUMdata codeState whether the statistical analysis code is available and, if so, provide a repository link or a statement that it is available upon request.Code sharing is part of a complete data/code availability statement and supports reproducibility.
- 10.MEDIUMreportingProvide a link to the statistical analysis plan (SAP) in the main text or supplement.Making the SAP publicly accessible increases transparency about pre-specified analyses.
- 11.MEDIUMreportingIn the Discussion, explicitly address the lack of adjustment for multiple testing in secondary analyses and its implications.Readers should be aware of the potential for inflated type I error in secondary endpoints.
- 12.LOWreportingIn the Results, report the number of patients with missing imaging data and how missing data were handled in the analysis.Transparency about missing data is important for assessing the robustness of the primary analysis.
- 13.LOWreportingIn the Results, for the IVORY-FINALE study, report the number of patients lost to follow-up and the reasons.Reporting follow-up completeness improves transparency about the long-term outcomes.
- 14.LOWreportingProvide the exact version of R and the nlme package used for the statistical analyses.Exact software versions support reproducibility.
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.”
- 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.
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.