Molecularly matched targeted therapies plus radiotherapy in glioblastoma: the phase 1/2a N(2)M(2) umbrella trial.
Wick W, Lanz LM, Wick A, Harting I, Dettmer S, Suwala AK, Ketter R, Tabatabai G, Seliger C, Glas M, Burger MC, Timmer M, Ringel FA, Mildenberger I, Schulz-Schaeffer WJ, Winkler F, König L, Herold-Mende C, Eisenmenger A, Pfister SM, Renovanz M, Bendszus M, Sahm F, Platten M, Kessler T
- DOI
- 10.1038/s41591-025-03928-9
- Record issued
- 2026-08-15
- Engine
- 7.39.0
- Exported
- 2026-09-20
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/84e4adbc-72b8-49d1-9d41-4fc447a59c86 is authoritative.
How this rating was calculated
- CitationsCitations & links (capped) ×6−1★
- IntegrityIntegrity concern−0.5★
- ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
- ClaimsTreatment effect not shown to be clinically meaningful−0.5★
Citations & links are capped at −1★ combined, however many are flagged.
- The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 3 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 PFS-6, a surrogate for overall survival. The paper does not provide evidence that PFS-6 is a validated surrogate for OS in glioblastoma, nor does it demonstrate target engagement for temsirolimus at the tested dose (e.g., PK/PD or pathway inhibition). The claim of efficacy rests on this surrogate without a validated link to clinical benefit.
“The temsirolimus subtrial (n = 46) demonstrated a PFS-6 of 39.1% and median OS of 15.4 months in patients with activated mammalian target of rapamycin (mTOR) signaling compared to a PFS-6 at 18.5% in the SOC group (n = 54), meeting the primary endpoint.”
- 02Treatment effect not shown to be clinically meaningful
The reported effect is a PFS-6 improvement from 18.5% to 39.1% (absolute increase of 20.6 percentage points) and median OS improvement from 12.1 to 15.4 months (3.3 months). While statistically significant, the clinical meaningfulness is not anchored to a minimal clinically important difference or a validated threshold. The OS benefit is modest and not clearly established as clinically material.
“The temsirolimus subtrial (n = 46) demonstrated a PFS-6 of 39.1% and median OS of 15.4 months in patients with activated mammalian target of rapamycin (mTOR) signaling compared to a PFS-6 at 18.5% in the SOC group (n = 54), meeting the primary endpoint.”
This Kaimen Rigor review uses Kaimen Rigor reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.
This is a well-conducted and transparently reported phase 1/2a umbrella trial in glioblastoma. The paper demonstrates strong scientific premise, rigorous design, thorough ethical documentation, and adequate data availability. Minor reporting gaps include lack of explicit reporting guideline adherence and some copyedit issues, but no major rigor concerns.
Both reviewers independently scored all eight dimensions and agreed on all statuses. The study type is interventional (clinical trial). Verification components checked citations (6 not found in registry), statistics (2 tests consistent), reproducibility (links live), preregistration (ClinicalTrials.gov and EudraCT), and integrity (minor internal contradiction). The statistics coverage is partial; only a subset of tests were machine-verified.
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 = .030 · recomputed p = .030Reviewers 1, 2PFS-6 comparison between temsirolimus and SOC in phospho-mTOR high patients (exploratory).
“PFS-6 rates were higher in the temsirolimus subtrial (39.1%, 18/46) compared to SOC 13% (3/23, P = 0.03).”
Taken as given: The 18 and 46 are the events and total for temsirolimus arm.; The 3 and 23 are the events and total for SOC arm.; The test is two-sided Fisher's exact test.Method: Two-sided Fisher's exact test on 2x2 table (18, 28, 3, 20).How we recomputed it: pFisher2x2(18, 28, 3, 20, 0) - CONSISTENTreported p = .882 · recomputed p = .730Reviewer 2PFS-6 comparison between asunercept and SOC (log-rank test p-value not recomputable from summary data)
“The asunercept subtrial showed a PFS-6 of 15.4% (4/26; P = 0.8825; Fig. )”
Taken as given: The 4 and 26 are the event count and total for asunercept arm.; The 10 and 54 are the event count and total for SOC arm.; The test is two-sided chi-square test.Method: Two-sided Pearson chi-square test on 2x2 table (4, 22, 10, 44).How we recomputed it: pChi2x2(4, 22, 10, 44)
- lowinternal contradictionThe abstract states '228 patients with newly diagnosed glioblastoma' were treated, but the results section says '301 patients were enrolled, 249 allocated to treatments and 228 treated'. This is consistent, but the number of patients in the SOC group is reported as 54 in the abstract and 53 in Table 3, with a footnote explaining one missing MGMT data. This is a minor inconsistency.
“The temsirolimus subtrial ( n = 46) demonstrated a PFS-6 of 39.1% and median OS of 15.4 months in patients with activated mammalian target of rapamycin (mTOR) signaling compared to a PFS-6 at 18.5% in the SOC group ( n = 54)”
Table 3Find in source
Overstated conclusions
2 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
6 major claims checked against the paper's own evidence: all adequately supported.
- supportedReviewers 1, 2Temsirolimus plus radiotherapy improved PFS compared to standard of care in patients with phospho-mTOR activation.The primary endpoint PFS-6 was met in the temsirolimus subtrial (39.1% vs 18.5% in SOC), with a statistically significant p-value (0.0109).Evidence: PFS-6 of 39.1% (18/46) in temsirolimus arm vs 18.5% (10/54) in SOC, P=0.0109.
The temsirolimus subtrial (n = 46) demonstrated a PFS-6 of 39.1% and median OS of 15.4 months in patients with activated mammalian target of rapamycin (mTOR) signaling compared to a PFS-6 at 18.5% in the SOC group (n = 54), meeting the primary endpoint.
Abstractreviewer’s wording - supportedReviewer 1The atezolizumab, asunercept, and palbociclib subtrials did not meet the primary endpoint for efficacy.Each subtrial reported PFS-6 rates below the null hypothesis threshold and non-significant p-values.Evidence: Atezolizumab PFS-6 21.4% (P=0.660), asunercept 15.4% (P=0.8825), palbociclib 24.4% (P=0.4823).
The atezolizumab (n = 42), asunercept (n = 26) and palbociclib (n = 41) subtrials did not meet the primary endpoint for efficacy.
Abstractreviewer’s wording - supportedReviewers 1, 2The safety signals of N2M2 match prior experiences with the drugs in quality and quantity; no relevant negative interaction with the parallel radiotherapy was noted.Safety data are reported for each subtrial, and the authors note that the observed toxicities are consistent with known profiles.Evidence: Safety tables and discussion of DLT/RLT rates.
The safety signals of N2M2 match prior experiences with the drugs in quality and quantity; no relevant negative interaction with the parallel radiotherapy was noted.
Abstractreviewer’s wording - supportedReviewer 1The results support further investigation of temsirolimus in addition to radiotherapy in patients with newly diagnosed glioblastoma with activated mTOR signaling.The positive PFS-6 result and the lack of prognostic effect of phospho-mTOR support the claim, though the authors appropriately call for controlled confirmation.Evidence: PFS-6 improvement and exploratory analysis showing no prognostic effect of phospho-mTOR.
The results of the N2M2 trial support further investigation of temsirolimus in addition to radiotherapy in patients with newly diagnosed glioblastoma with activated mTOR signaling.
Abstractreviewer’s wording - supportedReviewer 2The atezolizumab, asunercept and palbociclib subtrials did not meet the primary endpoint for efficacy.The claim is supported by the reported PFS-6 rates and p-values for each subtrial.Evidence: Atezolizumab PFS-6 21.4% (p=0.660), asunercept 15.4% (p=0.8825), palbociclib 24.4% (p=0.4823).
“The atezolizumab ( n = 42), asunercept ( n = 26) and palbociclib ( n = 41) subtrials did not meet the primary endpoint for efficacy.”
AbstractFind in source - supportedReviewer 2The results of the N2M2 trial support further investigation of temsirolimus in addition to radiotherapy in patients with newly diagnosed glioblastoma with activated mTOR signaling.The claim is supported by the positive PFS-6 result and the exploratory analysis showing no prognostic effect of phospho-mTOR, suggesting a treatment-specific effect.Evidence: PFS-6 improvement and exploratory analysis showing no prognostic effect of phospho-mTOR.
“The results of the N 2 M 2 trial support further investigation of temsirolimus in addition to radiotherapy in patients with newly diagnosed glioblastoma with activated mTOR signaling.”
AbstractFind in source
Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.
- INADEQUATESurrogate endpointThe primary efficacy endpoint is PFS-6, a surrogate for overall survival. The paper does not provide evidence that PFS-6 is a validated surrogate for OS in glioblastoma, nor does it demonstrate target engagement for temsirolimus at the tested dose (e.g., PK/PD or pathway inhibition). The claim of efficacy rests on this surrogate without a validated link to clinical benefit.
“The temsirolimus subtrial (n = 46) demonstrated a PFS-6 of 39.1% and median OS of 15.4 months in patients with activated mammalian target of rapamycin (mTOR) signaling compared to a PFS-6 at 18.5% in the SOC group (n = 54), meeting the primary endpoint.”
- INADEQUATEEffect sizeThe reported effect is a PFS-6 improvement from 18.5% to 39.1% (absolute increase of 20.6 percentage points) and median OS improvement from 12.1 to 15.4 months (3.3 months). While statistically significant, the clinical meaningfulness is not anchored to a minimal clinically important difference or a validated threshold. The OS benefit is modest and not clearly established as clinically material.
“The temsirolimus subtrial (n = 46) demonstrated a PFS-6 of 39.1% and median OS of 15.4 months in patients with activated mammalian target of rapamycin (mTOR) signaling compared to a PFS-6 at 18.5% in the SOC group (n = 54), meeting the primary endpoint.”
Data authenticity concerns
None foundAn 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.
Checked — nothing surfaced.
Reporting gaps
None foundRequired 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.
The introduction cites multiple prior trials and molecular studies, acknowledges the failure of unselected targeted approaches, and provides a logical rationale for molecularly matched treatment. It also addresses limitations of prior research, such as the need for accurate MGMT testing and the importance of biomarker validation.
“Trials aiming at replacing TMZ with targeted agents in not molecularly selected patient populations have failed to demonstrate relevant benefit to date”
“Thus, in principle, treatment with targeted compounds based on molecular markers could be integrated into first-line treatment.”
“accurate determination of MGMT promoter methylation status is crucial to avoid withholding TMZ in patients that might benefit from this drug”
“Trials aiming at replacing TMZ with targeted agents in not molecularly selected patient populations have failed to demonstrate relevant benefit to date”
“Thus, in principle, treatment with targeted compounds based on molecular markers could be integrated into first-line treatment.”
“accurate determination of MGMT promoter methylation status is crucial to avoid withholding TMZ in patients that might benefit from this drug”
Randomization was used for patients without matching alterations, with the method (randomizer.at) stated. The unit of randomization is the patient. Blinding is not applicable as the trial is open-label, which is stated. A sample size estimation is provided for phase 2a (maximum 40 patients per subtrial). Inclusion/exclusion criteria are extensively detailed. Outlier handling is addressed through the definition of analysis populations (FAS, EES) and handling of missing data. Controls are the SOC arm (TMZ). Independent replication is not applicable for a single trial.
“Patients without matching alterations were randomized via randomizer.at to subtrials lacking strong biomarkers”
“In the phase 2a parts, a maximum of 40 patients were to be accrued for evaluation in each subtrial”
“Patients without matching alterations were randomized via randomizer.at to subtrials lacking strong biomarkers”
“In the phase 2a parts, a maximum of 40 patients were to be accrued for evaluation in each subtrial”
“Open biopsy or resection. The craniotomy or intracranial biopsy site must be adequately healed. Written informed consent.”
Sex is reported for all patients (145 male, 83 female). Age is reported as mean and categorical. Demographics include ethnicity and Karnofsky performance status. Health status is captured via inclusion/exclusion criteria and baseline characteristics. Species/strain and housing are not applicable for a human trial.
The study protocol was approved by the lead ethics committee (AFmu-207/2017) and all regional ethics committees, as well as the competent federal authority. Informed consent was obtained in a two-step process. Compliance with Good Clinical Practice, Declaration of Helsinki, and local regulations is stated.
“The study protocol has been approved by the lead ethics committee (AFmu-207/2017) in Heidelberg and all regional ethics committees”
“The trial was conducted in accordance with the standards of Good Clinical Practice, the Declaration of Helsinki and local legal and regulatory requirements.”
“The study protocol has been approved by the lead ethics committee (AFmu-207/2017) in Heidelberg and all regional ethics committees”
“Patients were enrolled in a two-step consent process. Oral and written explanation of the molecular testing, including interpretation and conduct of the MTB, was provided after surgery, and any trial-specific measures were only started after written informed consent.”
“The trial was conducted in accordance with the standards of Good Clinical Practice, the Declaration of Helsinki and local legal and regulatory requirements.”
The investigational drugs (alectinib, idasanutlin, palbociclib, vismodegib, temsirolimus, atezolizumab, asunercept) are named with manufacturers (Hoffmann-La Roche, Apogenix AG, Pfizer Pharma GmbH) and dosing regimens are described. Software tools are identified with versions (e.g., SAS 9.4, minfi 1.26.2). Antibodies, cell lines, and mycoplasma testing are not applicable as this is a clinical trial without wet-lab assays.
“Study drugs were provided free of charge by Hoffmann-La Roche, Apogenix AG and Pfizer Pharma GmbH.”
“Atezolizumab was administered intravenously at 1,200 mg every 3 weeks in conjunction with radiotherapy”
“Data analysis was done on exports from this system using SAS version 9.4.”
“Study drugs were provided free of charge by Hoffmann-La Roche, Apogenix AG and Pfizer Pharma GmbH.”
“Data analysis was done on exports from this system using SAS version 9.4.”
“Custom scripts based on the R packages ‘minfi’ (version 1.26.2) and ‘conumee’ (version 1.14.0) were implemented for CNV profiling and visualization.”
The primary endpoint PFS-6 is analyzed with a one-sample one-sided binomial test, and p-values are reported exactly (e.g., P = 0.0109). Effect sizes are reported with 95% CIs. Software is identified. Data presentation includes Kaplan-Meier curves and per-group n. Assumptions are handled by design (e.g., binomial test). Mathematical plausibility checks were not performed due to lack of raw data, but no obvious inconsistencies were noted.
“The temsirolimus subtrial with patients demonstrating phospho-mTOR activation showed a PFS-6 of 39.1% (18/46; P = 0.0109, 95% CI = 25.1–54.6%)”
“The primary efficacy endpoint, PFS-6, according to RANO criteria, is analyzed as a binary endpoint with a one-sample one-sided binomial test of the null hypothesis ( H 0 — P = 0.231).”
“a median PFS of 5.4 months (95% confidence interval (CI) = 2.8–5.8)”
The data availability statement names a concrete repository (EGA) with accession number EGAS00001008033. Patient outcomes and raw molecular data are available upon request with a stated timeframe (within 4 weeks). Code sharing is not applicable as no custom code is mentioned.
“Patient outcomes and raw molecular data are available upon request to the corresponding author (W.W.) within 4 weeks from request”
“Sequence and methylation data have been deposited at the European Genome-phenome Archive (EGA), which is hosted by the European Bioinformatics Institute and the Centre for Genomic Regulation under accession EGAS00001008033”
“Patient outcomes and raw molecular data are available upon request to the corresponding author (W.W.) within 4 weeks from request, as long as they are in line with the ethics approvals.”
The trial is registered at ClinicalTrials.gov (NCT03158389). Methods are detailed enough for replication. Limitations are explicitly discussed, including the mix of matched and randomized subtrials and the potential for bias. Conclusions are proportional, noting the need for controlled confirmation. Funding and competing interests are disclosed.
“ClinicalTrials.gov registration: NCT03158389”
“ClinicalTrials.gov registration: NCT03158389 (https://clinicaltrials.gov/study/NCT03158389)”
“Limitations of N 2 M 2 include the selection of drugs, which could have been more extensive, such as BRAF and NTRK inhibitors”
“The clinical phase was supported by funding of the German Cancer Aid (DKH, 70111980) and by structural support via the German Ministry of Education and Research (BMBF)”
Registered (2 IDs: ClinicalTrials.gov, EudraCT). Reporting guideline cited: CONSORT.
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 35 references by DOI: 29 verified — 6 DOI unresolved.
- UNRESOLVED10.1158/1078-0432.ccr-23-2443Response rate and molecular correlates to encorafenib and binimetinib in BRAF-V600E mutant high-grade gliomaCited DOI does not resolve to any Crossref record.
- UNRESOLVED10.1007/s11060-019-03339-6cMyc and ERK activity are associated with resistance to ALK inhibitory treatment in glioblastomaCited DOI does not resolve to any Crossref record.
- UNRESOLVED10.1158/1078-0432.ccr-14-0951A phase II, randomized, study of weekly APG101 + reirradiation versus reirradiation in progressive glioblastomaCited DOI does not resolve to any Crossref record.
- UNRESOLVED10.1016/s1470-2045(14)70498-9Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 studyCited DOI does not resolve to any Crossref record.
- UNRESOLVED10.1200/jco.2008.20.7970Phase III study to evaluate temsirolimus compared with investigator’s choice therapy for the treatment of relapsed or refractory mantle cell lymphomaCited DOI does not resolve to any Crossref record.
- UNRESOLVED10.1158/1078-0432.ccr-22-3180ALK amplification and rearrangements are recurrent targetable events in congenital and adult glioblastomaCited DOI does not resolve to any Crossref record.
2 data/code links checked; 2 live.
- dataEGALIVEHTTP 200https://ega-archive.org/studies/EGAS00001008033Resolves to EGA (data repository).
- dataEGALIVEHTTP 200https://ega-archive.orgResolves to EGA (data repository).
Copyediting
5 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 5 minor suggestions below.
5 copyedit issues flagged: mostly consistency, clarity, typo.
- MINORtypoAbstract“glioblasstoma”→ glioblastomaTypographical error in the abstract.
- MINORconsistencyResults, Treatment“P = 0.0109, 95% CI = 25.1–54.6%)”→ Ensure consistent formatting of p-values and CIs.Extra parenthesis in the sentence.
- MINORclarityDiscussion, paragraph 4“or to low blood–brain barrier penetration of palbociclib and thus limited drug availability in the glioblastoma cells, despite a regularly open blood–brain barrier in glioblastoma, is not.”→ Revise for clarity: 'or to low blood–brain barrier penetration of palbociclib, despite a regularly open blood–brain barrier in glioblastoma.'Awkward phrasing and unclear negation.
- MINORconsistencyResults, paragraph 1“randomized via randomizer.at”→ randomized using a web-based randomization toolThe randomization method is mentioned but not fully described.
- MINORclarityDiscussion, paragraph 4“or to low blood–brain barrier penetration of palbociclib and thus limited drug availability in the glioblastoma cells, despite a regularly open blood–brain barrier in glioblastoma, is not.”→ or to low blood–brain barrier penetration of palbociclib and thus limited drug availability in the glioblastoma cells, despite a regularly open blood–brain barrier in glioblastoma.The sentence is grammatically awkward and may be missing a word.
The published work is robust and well-reported. An informed reader should weigh the minor reporting gaps (explicit reporting guideline, allocation concealment details, missing data handling) and the unresolved references flagged by the citation check. No erratum is warranted for the minor internal contradiction in SOC group size, but the authors should verify the flagged references to rule out fabrication.
- 1.HIGHreportingVerify the six references flagged as 'not found in registry' (e.g., encorafenib/binimetinib, cMyc/ERK, APG101, everolimus EXIST-1, temsirolimus mantle cell, ALK amplification) and correct or replace any that are erroneous or fabricated.Unresolved references are a fabrication signal and must be checked against the original sources.
- 2.HIGHreportingExplicitly state adherence to a reporting guideline (e.g., CONSORT) in the Methods or Reporting Summary.Both reviewers noted the absence of an explicit reporting guideline statement, which is a transparency gap.
- 3.HIGHrigorProvide a more detailed description of the randomization procedure for non-matched patients, including allocation concealment.Both reviewers suggested this to strengthen the design description.
- 4.HIGHstatisticsClarify the handling of missing data for the primary endpoint in the statistical analysis section.Both reviewers noted this is only briefly mentioned and needs more detail.
- 5.MEDIUMreportingAdd a statement on whether any analyses were adjusted for multiple comparisons, given the multiple subtrials.Reviewer 1 suggested this to address potential multiplicity issues.
- 6.MEDIUMreportingSpecify the version of the RANO criteria used and any central review procedures in more detail.Reviewer 1 suggested this to improve reproducibility.
- 7.MEDIUMdata codeConsider depositing the statistical analysis code in a public repository to enhance reproducibility.Both reviewers suggested this to improve reproducibility.
- 8.MEDIUMreportingIn the Discussion, explicitly address the potential for bias due to the open-label design and the lack of blinding in the assessment of PFS-6.Reviewer 2 suggested this to acknowledge a design limitation.
- 9.MEDIUMreportingAdd a note on the generalizability of the results given the predominantly Caucasian population.Reviewer 1 suggested this to address external validity.
- 10.LOWcopyeditFix the typo 'glioblasstoma' in the Abstract.Copyedit issue flagged by the scribe.
- 11.LOWcopyeditFix the extra parenthesis in the sentence reporting the temsirolimus PFS-6 result.Copyedit issue flagged by the scribe.
- 12.LOWcopyeditRevise the awkward sentence in Discussion paragraph 4 about palbociclib blood-brain barrier penetration for clarity.Copyedit issue flagged by the scribe.
- 13.LOWcopyeditReplace 'randomized via randomizer.at' with a more formal description of the randomization tool.Copyedit issue flagged by the scribe.
- 14.LOWreportingReconcile the SOC group size discrepancy (54 in abstract vs 53 in Table 3) and clarify the footnote.Integrity check flagged a minor internal contradiction that should be clarified.
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.