Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

The microRNA inhibitor CDR132L in patients with reduced left ventricular ejection fraction after myocardial infarction: a randomized phase 2 trial.

Name: Kaimen Rigor review — The microRNA inhibitor CDR132L in patients with reduced left ventricular ejection fraction after myocardial infarction: a randomized phase 2 trial.
Item: The microRNA inhibitor CDR132L in patients with reduced left ventricular ejection fraction after myocardial infarction: a randomized phase 2 trial.
Rating: 39
Author: Alpha1

Bauersachs J, Solomon SD, Anker SD, Antorrena-Miranda I, de Boer RA, Filippatos G, Friede T, Hauke W, Ponikowski P, Vardeny O, Altschul R, Gamborg M, Vinther K, Thum T

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$Kaimen Rigor review — 1★ (Critical), 2 critical, 2 high issues for “The microRNA inhibitor CDR132L in patients with reduced left ventricular ejection fraction after myocardial infarction: a randomized phase 2 trial.”$

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This rigor review was examined and confirmed by Alpha1 Editorial · August 15, 2026

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The microRNA inhibitor CDR132L in patients with reduced left ventricular ejection fraction after myocardial infarction: a randomized phase 2 trial.

Bauersachs J, Solomon SD, Anker SD, Antorrena-Miranda I, de Boer RA, Filippatos G, Friede T, Hauke W, Ponikowski P, Vardeny O, Altschul R, Gamborg M, Vinther K, Thum T

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DOI

10.1038/s41591-026-04408-4

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

The microRNA inhibitor CDR132L in patients with reduced left ventricular ejection fraction after myocardial infarction: a randomized phase 2 trial.

Bauersachs J, Solomon SD, Anker SD, Antorrena-Miranda I, de Boer RA, Filippatos G, Friede T, Hauke W, Ponikowski P, Vardeny O, Altschul R, Gamborg M, Vinther K, Thum T

Paper source

The microRNA inhibitor CDR132L in patients with reduced left ventricular ejection fraction after myocardial infarction: a randomized phase 2 trial.

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Links back to this Kaimen Rigor review.

Alpha1 Editorial

This rigor review was examined and confirmed by Alpha1 Editorial · August 15, 2026

Kaimen Rigor review

Kaimen Rigor reviewed

1 / 5

Critical — a demonstrable failure

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

StatisticsImpossible or misreported statistic ×3−3★
IntegrityIntegrity concern ×3−1.5★
StatisticsPrinted percentage does not match its own count (capped) ×13−0.25★

A demonstrable critical failure caps the rating at the minimum, regardless of the deductions above.

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Not verified in this report

The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 12 reported means were read, and their group size is not stated where the values are printed. These checks need the count the mean was averaged over, so none was performed.

Biggest issues3 demonstrable

01Printed percentage does not match its own countdemonstrable
criticalArithmeticrecomputedFull detail
4% is unattainable for n=4 (nearest: 0, 25%)
“Class III/IV | 4 (4)”
Table 1Find in source
02Printed percentage does not match its own countdemonstrable
criticalArithmeticrecomputedFull detail
7% is unattainable for n=7 (nearest: 0, 14%)
“Class III | 7 (7)”
Table 1Find in source
03Printed percentage does not match its own countdemonstrable
criticalArithmeticrecomputedFull detail
4% is unattainable for n=4 (nearest: 0, 25%)
“Class III | 4 (4)”
Table 1Find in source
04Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
12% is unattainable for n=11 (nearest: 9, 18%)
“Female | 11 (12)”
Table 1Find in source
05Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
16% is unattainable for n=15 (nearest: 13, 20%)
“Female | 15 (16)”
Table 1Find in source
06Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
10% is unattainable for n=9 (nearest: 0, 11%)
“Female | 9 (10)”
Table 1Find in source

11 further findings of this severity or below — every one is in the sections below, filed under its error type.

Findings by category

301ArithmeticNumerical inconsistencies 102OverreachOverstated conclusions 103AuthenticityData authenticity concerns 04DisclosureNone found 05AvailabilityNone found 06Copyedit2 minor suggestions

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. Both reviewers found all eight rigor dimensions adequate, with strong methodology, ethical compliance, and proportional conclusions. Minor reporting gaps (e.g., race/ethnicity, exact p-values in abstract) and a few internal consistency issues in the safety population description are noted but do not undermine the overall rigor.

Both reviewers classified the study as interventional, which was adopted. The evaluation covered all eight dimensions; several sub-criteria were not applicable (e.g., animal housing, cell line authentication) for this human trial. The statistics verification component checked only a subset of tests (those with test statistics/df or effect estimates with CIs); 16 of 19 recomputations were inconsistent, but this is likely due to rounding or unverifiable threshold-only p-values, and no decision errors were found. The integrity component flagged a retrospective registration concern and minor internal contradictions in the safety population description.

Numerical inconsistencies

3 findings · worst critical

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.

Summary statistic impossible for the stated N (GRIM/GRIMMER)Recomputed
Printed percentage does not match its own countRecomputed
Internal contradictions in the reported numbersAssessed

Recomputed 1 test: 1 consistent, 0 inconsistent; 1 via agent-written checks. 3 reported summary statistics mathematically impossible for the stated N (PERCENT). 13 printed percentages that do not match their own count.

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

8 major claims checked against the paper's own evidence: 1 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.

Data authenticity concerns

1 finding · worst medium

An adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.

Other integrity concernAssessed

3 integrity concerns flagged (0 high).

Reporting gaps

None found

Required detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.

Checked — nothing surfaced.

Eight Dimensions8 pass

The introduction cites prior research on miR-132's role in cardiac remodeling and preclinical studies of CDR132L, acknowledging both strengths and limitations. The rationale linking miR-132 inhibition to potential therapeutic benefit is logically presented, and the study builds on a phase 1b trial. Limitations of prior work, such as the need for human data, are implicitly addressed by the phase 2 design.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The paper establishes a strong scientific premise with extensive prior work and a clear rationale for targeting miR-132.

Evidence

paraphrase[Introduction, paragraphs 2-4]

“Inhibition of miR-132 in preclinical models halts and can partially reverse pathological remodeling, resulting in improved systolic and diastolic function.”

“Current pharmacological approaches predominantly target neurohormonal activation and hemodynamic load, but few interventions directly modulate the molecular and structural maladaptations of the myocardium.”

Introduction ¶1Find in source

paraphrase[Introduction, paragraph 4]

“In a first-in-human phase 1b trial (NCT04045405), CDR132L was well tolerated at doses up to 10 mg kg−1, exhibited linear pharmacokinetics and achieved durable target engagement with dose-dependent reductions in circulating miR-132.”

PASSReviewer 2· 90% conf

The paper establishes a strong scientific premise by citing prior research on miR-132 and CDR132L, and provides a logical rationale for the study.

Evidence

paraphrase[Introduction, paragraph 2-3]

“Inhibition of miR-132 in preclinical models halts and can partially reverse pathological remodeling, resulting in improved systolic and diastolic function.”

paraphrase[Introduction, paragraph 3]

“On this basis, the HF-REVERT trial was designed as an international, multicenter, randomized, double-blind, placebo-controlled phase 2 study to evaluate the efficacy and safety of CDR132L in patients with LV systolic dysfunction early after acute MI.”

paraphrase[Discussion, paragraph 4]

“Although correlations between plasma and cardiac tissue miR-132 levels have been demonstrated in preclinical models, this relationship has not been established in humans.”

Randomization was centralized using a computer-generated schedule stratified by age and infarction location. Blinding was double-blind with a blinded core laboratory. A priori sample size calculation with power estimates is provided. Inclusion/exclusion criteria are detailed, and the mITT population is prespecified as primary. Missing data handling (LOCF, MMRM) is described. The trial is registered (NCT05350969).

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The trial design is rigorous with adequate randomization, blinding, power analysis, and prespecified analysis populations.

Evidence

“Patients were randomized centrally using a computer-generated schedule stratified by age group (<60 years, ≥60 years) and location of infarction (anterior, non-anterior).”

MethodsFind in source

“Investigators, patients, core laboratory personnel and the sponsor remained blinded until all patients had completed month 6.”

MethodsFind in source

paraphrase[Methods, Sample size determination]

“a sample size of 90 patients per group provided 96.0% power to detect a 5-percentage-point difference between 10 mg kg−1 and placebo (step 1) and 84.3% power to detect a 4-percentage-point difference between 5 mg kg−1 and placebo (step 2), within a hierarchical testing procedure.”

PASSReviewer 2· 95% conf

The trial design is rigorous with clear randomization, blinding, power analysis, and prespecified analysis populations.

Evidence

“Patients were randomized centrally using a computer-generated schedule stratified by age group (<60 years, ≥60 years) and location of infarction (anterior, non-anterior).”

MethodsFind in source

“Investigators, patients, core laboratory personnel and the sponsor remained blinded until all patients had completed month 6.”

MethodsFind in source

paraphrase[Methods, Sample size determination]

Sex at birth is reported (13% women), age is reported, and extensive baseline clinical characteristics are provided in Table 1. Since both sexes are enrolled, sex justification is not applicable. Demographics include age, sex, and clinical measures; race/ethnicity is not reported but is not required for this trial.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Biological variables are well reported for a human trial, including sex, age, and clinical characteristics.

Evidence

“In the mITT population, the median age was 61.0 years (range, 35–80), and 13% were women based on sex at birth; gender data were not collected.”

ResultsFind in source

“Median age a , years (min, max) | 61.0 (35, 80) | 62.0 (37, 79) | 62.0 (36, 79) | 61.0 (35, 80)”

Table 1Find in source

PASSReviewer 2· 90% conf

Biological variables are well reported for a human trial, including sex, age, and clinical characteristics.

Evidence

“In the mITT population, the median age was 61.0 years (range, 35–80), and 13% were women based on sex at birth; gender data were not collected.”

ResultsFind in source

“Median age a , years (min, max) | 61.0 (35, 80) | 62.0 (37, 79) | 62.0 (36, 79) | 61.0 (35, 80)”

Table 1Find in source

paraphrase[Table 1]

“Sex at birth, n (%) | Male | 83 (88) | 81 (84) | 81 (90) | 245 (88) | Female | 11 (12) | 15 (16) | 9 (10) | 35 (13)”

The paper states that the protocol was approved by an independent ethics committee or IRB at each site, and that all patients provided written informed consent. It also cites compliance with ICH GCP and the Declaration of Helsinki. The trial is registered.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Ethical approvals and consent are adequately documented.

Evidence

“The study protocol, all study protocol amendments, written study participant information, informed consent form, Investigator’s Brochure and any other relevant documents were reviewed and approved by an independent ethics committee or institutional review board at each study site.”

EthicsFind in source

“All patients provided written informed consent.”

MethodsFind in source

EthicsFind in source

PASSReviewer 2· 95% conf

Ethical approvals and consent are adequately documented.

Evidence

EthicsFind in source

“All patients provided written informed consent.”

MethodsFind in source

“This study was conducted in accordance with the study protocol and all approved amendments; the International Council for Harmonisation (ICH) Guideline for Good Clinical Practice E6(R2); the ethical principles of the Declaration of Helsinki; the Council for International Organizations of Medical Sciences, International Ethical Guidelines; all applicable local laws and regulations; and ICH requirements for archiving and retention of essential documents.”

EthicsFind in source

CDR132L is identified as a synthetic LNA-based antisense oligonucleotide, and the miRNA assay kit is specified (CardiorHealth miR-132 Plasma PCR Kit). The drug is named with manufacturer (Cardior Pharmaceuticals) and dose regimen. Software (SAS 9.4) is identified. No antibodies or cell lines are used.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational product and key reagents are adequately identified.

Evidence

“CDR132L is a synthetic, locked nucleic acid (LNA)-based antisense oligonucleotide specifically designed and optimized to inhibit miR-132.”

Introduction ¶4Find in source

“Plasma miR-132 levels were quantified at Biotype GmbH using the CardiorHealth miR-132 Plasma PCR Kit (Cardior Pharmaceuticals GmbH) in accordance with the manufacturer’s instructions.”

MethodsFind in source

“All analyses performed used SAS version 9.4 software.”

Statistical analysisFind in source

PASSReviewer 2· 90% conf

Key resources, including the investigational drug and assay kits, are adequately identified.

Evidence

“CDR132L is a synthetic, locked nucleic acid (LNA)-based antisense oligonucleotide specifically designed and optimized to inhibit miR-132.”

Introduction ¶3Find in source

“Plasma miR-132 levels were quantified at Biotype GmbH using the CardiorHealth miR-132 Plasma PCR Kit (Cardior Pharmaceuticals GmbH) in accordance with the manufacturer’s instructions.”

MethodsFind in source

“All analyses performed used SAS version 9.4 software.”

Statistical analysisFind in source

The primary analysis uses ANCOVA with a one-sided test at alpha 0.025. Tests are named, and effect sizes with 95% CIs are reported. P-values are reported as exact values (e.g., P = 0.37). Software is identified. Data presentation includes per-group n and dispersion. Mathematical plausibility checks were not performed due to continuous outcomes and large N.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical methods are appropriate and well described, with effect sizes and confidence intervals reported.

Evidence

“The primary analysis used an analysis of covariance (ANCOVA) model that included treatment as a fixed effect and baseline LVESVI as a covariate.”

Statistical analysisFind in source

paraphrase[Results, Primary and secondary endpoints]

“The resulting placebo-adjusted least squares mean (LSM) differences were −1.11% (s.e.m. 3.37; F-test P = 0.37) for 5 mg kg−1 and −2.14% (s.e.m. 3.27; F-test P = 0.26) for 10 mg kg−1.”

“LSM difference, CDR132L versus placebo (95% CI; one-sided P value) | 0.87 (−1.41, 3.15; P = 0.227)”

Table 2Find in source

PASSReviewer 2· 90% conf

Statistical methods are appropriate and well-described, with effect sizes and confidence intervals reported.

Evidence

“The primary analysis used an analysis of covariance (ANCOVA) model that included treatment as a fixed effect and baseline LVESVI as a covariate.”

Statistical analysisFind in source

paraphrase[Results, Primary and secondary endpoints]

“The resulting placebo-adjusted least squares mean (LSM) differences were −1.11% (s.e.m. 3.37; F-test P = 0.37) for 5 mg kg−1 and −2.14% (s.e.m. 3.27; F-test P = 0.26) for 10 mg kg−1.”

“LSM difference, CDR132L versus placebo (95% CI; one-sided P value) | 0.87 (−1.41, 3.15; P = 0.227)”

Table 2Find in source

The data availability statement provides a concrete mechanism for requesting access via Novo Nordisk's trial data platform, with conditions and timeframe. Since the data are patient-level and identifiable, repository deposit and accession numbers are not applicable. No custom code was used beyond standard SAS, so code sharing is not applicable.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Data availability is adequately described with a concrete access route.

Evidence

“Researchers can request access to clinical trial data by submitting a research proposal for review and approval by Novo Nordisk and an internal independent review panel.”

Data availabilityFind in source

“Requests are considered after the research is concluded or completed and the main results have been published.”

Data availabilityFind in source

PASSReviewer 2· 90% conf

Data availability is adequately described with a concrete access route.

Evidence

“Researchers can request access to clinical trial data by submitting a research proposal for review and approval by Novo Nordisk and an internal independent review panel. Requests are considered after the research is concluded or completed and the main results have been published.”

Data availabilityFind in source

The trial is registered (NCT05350969). Methods are detailed enough for replication. All outcomes are reported, including negative results. Limitations are thoroughly discussed. Conclusions are appropriately cautious, emphasizing the exploratory nature of subgroup findings. Funding and COI statements are provided.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Reporting is transparent with trial registration, detailed methods, and proportional conclusions.

Evidence

“ClinicalTrials.gov: NCT05350969”

AbstractFind in source

“Several additional factors may have influenced the ability to detect a significant treatment effect in the overall study population.”

Discussion ¶3Find in source

“The subgroup findings are exploratory and hypothesis generating only.”

DiscussionFind in source

PASSReviewer 2· 95% conf

Reporting is transparent with trial registration, detailed methods, and balanced conclusions.

Evidence

“ClinicalTrials.gov: NCT05350969”

AbstractFind in source

“Several additional factors may have influenced the ability to detect a significant treatment effect in the overall study population.”

Discussion ¶4Find in source

“The subgroup findings are exploratory and hypothesis generating only.”

DiscussionFind in source

Registered (4 IDs: ClinicalTrials.gov). Reporting guideline cited: CONSORT.

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 12 references by DOI: 12 verified.

1 data/code link checked; 1 live.

Copyediting

2 minor

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

No major wording or formatting errors. 2 minor suggestions below.

2 copyedit issues flagged: mostly consistency, clarity.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust and well-reported; an informed reader should weigh the minor internal consistency issues in the safety population description and the retrospective registration of the phase 1b trial (NCT04045405) as caveats. No erratum is clearly warranted, but the authors should consider clarifying the safety population discrepancy and providing exact p-values for primary endpoints in the abstract for completeness.

1.
CRITICALstatistics
Correct or explain the statistically impossible value: PERCENT: 4% is unattainable for n=4 (nearest: 0, 25%)
Demonstrable critical failure — blocks the verdict from passing.
2.
CRITICALstatistics
Correct or explain the statistically impossible value: PERCENT: 7% is unattainable for n=7 (nearest: 0, 14%)
Demonstrable critical failure — blocks the verdict from passing.
3.
HIGHreporting
Clarify the safety population description in the Methods/Results: state explicitly that one patient randomized to 10 mg/kg received placebo and is counted in the placebo arm for safety, making the safety population group sizes differ from mITT (94, 95, 91 vs 94, 96, 90).
The current text says the safety population is identical to mITT, which contradicts the reported group assignments and could confuse readers.
4.
HIGHreporting
Add a note in the Discussion or Methods acknowledging that the phase 1b trial (NCT04045405) was registered retrospectively (first submitted 2019-07-23 after study start 2019-06-21), and discuss any implications for the current trial's interpretation.
Retrospective registration of the prior trial is a transparency concern that informed readers should weigh.
5.
MEDIUMreporting
Report exact p-values for the primary endpoint in the Abstract, not just in the Results section.
The abstract currently omits exact p-values, which are important for readers assessing the primary outcome.
6.
MEDIUMreporting
Add a statement in the Methods about whether the trial was reported according to CONSORT guidelines, and include a completed CONSORT checklist as supplementary material.
Explicit adherence to CONSORT improves transparency and reproducibility.
7.
MEDIUMreporting
Report the number of patients screened and reasons for exclusion at each stage in the CONSORT diagram more explicitly.
The current text mentions 427 screened but does not detail exclusion reasons, which is a standard CONSORT requirement.
8.
MEDIUMstatistics
Provide results of the sensitivity analysis using multiple imputation for the primary endpoint, as mentioned in the Methods.
Reporting the results of prespecified sensitivity analyses strengthens the statistical robustness assessment.
9.
MEDIUMreporting
Report exact p-values for subgroup analyses in the text or tables, as forest plots may not provide exact values.
Exact p-values allow readers to assess the strength of subgroup findings.
10.
MEDIUMreporting
Add a statement about the availability of the statistical analysis plan in a public repository (e.g., ClinicalTrials.gov or a preprint server).
Public availability of the SAP enhances transparency and reproducibility.
11.
MEDIUMreporting
Discuss the potential impact of open-label pharmacy staff on blinding, and whether any unblinding risks were mitigated.
The pharmacy staff were not blinded, which is a potential source of bias that should be addressed.
12.
LOWreporting
Report race/ethnicity in baseline demographics to enhance generalizability.
Race/ethnicity is not currently reported, which limits assessment of generalizability.
13.
LOWreporting
Provide more detail on the randomization schedule generation (e.g., block size) in the Methods.
Details on block size and generation method improve reproducibility of the randomization process.
14.
LOWreporting
Report the intraclass correlation coefficient for core lab echocardiography readings to assess reproducibility.
ICC values would help readers assess the reliability of the primary endpoint measurements.
15.
LOWdata code
Provide more details on the data request review process, such as a template or timeline for approval.
More transparency on data access procedures would facilitate data sharing.
16.
LOWcopyedit
Move the sentence about the ESC Heart Failure Congress presentation from the Abstract to the end or remove it, as it is not a standard abstract element.
The congress presentation sentence is unusual in an abstract and may distract from the scientific content.
17.
LOWcopyedit
Clarify in the Results that the ITT population is the same as the randomized population (n=294) for conciseness.
The current definition is clear but could be more concise and standard.

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Read alongside

The microRNA inhibitor CDR132L in patients with reduced left ventricular ejection fraction after myocardial infarction: a randomized phase 2 trial.

Bauersachs J, Solomon SD, Anker SD, Antorrena-Miranda I, de Boer RA, Filippatos G, Friede T, Hauke W, Ponikowski P, Vardeny O, Altschul R, Gamborg M, Vinther K, Thum T

Read full text (PMC)

DOI

10.1038/s41591-026-04408-4

Share this Kaimen Rigor review

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Record fingerprint

d5257df818b4142084e524bc604a3a2211963f3d7f1b74f63576fa4682910f9a

Verify via API

Issued Aug 15, 2026Engine 7.39.0

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

Kaimen Rigor review

Kaimen Rigor reviewed

1 / 5

Critical — a demonstrable failure

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

StatisticsImpossible or misreported statistic ×3−3★
IntegrityIntegrity concern ×3−1.5★
StatisticsPrinted percentage does not match its own count (capped) ×13−0.25★

A demonstrable critical failure caps the rating at the minimum, regardless of the deductions above.

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Not verified in this report

The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 12 reported means were read, and their group size is not stated where the values are printed. These checks need the count the mean was averaged over, so none was performed.

Biggest issues3 demonstrable

01Printed percentage does not match its own countdemonstrable
criticalArithmeticrecomputedFull detail
4% is unattainable for n=4 (nearest: 0, 25%)
“Class III/IV | 4 (4)”
Table 1Find in source
02Printed percentage does not match its own countdemonstrable
criticalArithmeticrecomputedFull detail
7% is unattainable for n=7 (nearest: 0, 14%)
“Class III | 7 (7)”
Table 1Find in source
03Printed percentage does not match its own countdemonstrable
criticalArithmeticrecomputedFull detail
4% is unattainable for n=4 (nearest: 0, 25%)
“Class III | 4 (4)”
Table 1Find in source
04Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
12% is unattainable for n=11 (nearest: 9, 18%)
“Female | 11 (12)”
Table 1Find in source
05Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
16% is unattainable for n=15 (nearest: 13, 20%)
“Female | 15 (16)”
Table 1Find in source
06Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
10% is unattainable for n=9 (nearest: 0, 11%)
“Female | 9 (10)”
Table 1Find in source

11 further findings of this severity or below — every one is in the sections below, filed under its error type.

Findings by category

301ArithmeticNumerical inconsistencies 102OverreachOverstated conclusions 103AuthenticityData authenticity concerns 04DisclosureNone found 05AvailabilityNone found 06Copyedit2 minor suggestions

Numerical inconsistencies

3 findings · worst critical

Summary statistic impossible for the stated N (GRIM/GRIMMER)Recomputed
Printed percentage does not match its own countRecomputed
Internal contradictions in the reported numbersAssessed

Overstated conclusions

1 finding · worst low

Conclusions only partially backed by the presented evidenceAssessed

8 major claims checked against the paper's own evidence: 1 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.

Data authenticity concerns

1 finding · worst medium

Other integrity concernAssessed

3 integrity concerns flagged (0 high).

Reporting gaps

None found

Checked — nothing surfaced.

Eight Dimensions8 pass

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The paper establishes a strong scientific premise with extensive prior work and a clear rationale for targeting miR-132.

Evidence

paraphrase[Introduction, paragraphs 2-4]

“Inhibition of miR-132 in preclinical models halts and can partially reverse pathological remodeling, resulting in improved systolic and diastolic function.”

Introduction ¶1Find in source

paraphrase[Introduction, paragraph 4]

PASSReviewer 2· 90% conf

The paper establishes a strong scientific premise by citing prior research on miR-132 and CDR132L, and provides a logical rationale for the study.

Evidence

paraphrase[Introduction, paragraph 2-3]

“Inhibition of miR-132 in preclinical models halts and can partially reverse pathological remodeling, resulting in improved systolic and diastolic function.”

paraphrase[Introduction, paragraph 3]

paraphrase[Discussion, paragraph 4]

“Although correlations between plasma and cardiac tissue miR-132 levels have been demonstrated in preclinical models, this relationship has not been established in humans.”

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The trial design is rigorous with adequate randomization, blinding, power analysis, and prespecified analysis populations.

Evidence

“Patients were randomized centrally using a computer-generated schedule stratified by age group (<60 years, ≥60 years) and location of infarction (anterior, non-anterior).”

MethodsFind in source

“Investigators, patients, core laboratory personnel and the sponsor remained blinded until all patients had completed month 6.”

MethodsFind in source

paraphrase[Methods, Sample size determination]

PASSReviewer 2· 95% conf

The trial design is rigorous with clear randomization, blinding, power analysis, and prespecified analysis populations.

Evidence

“Patients were randomized centrally using a computer-generated schedule stratified by age group (<60 years, ≥60 years) and location of infarction (anterior, non-anterior).”

MethodsFind in source

“Investigators, patients, core laboratory personnel and the sponsor remained blinded until all patients had completed month 6.”

MethodsFind in source

paraphrase[Methods, Sample size determination]

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Biological variables are well reported for a human trial, including sex, age, and clinical characteristics.

Evidence

“In the mITT population, the median age was 61.0 years (range, 35–80), and 13% were women based on sex at birth; gender data were not collected.”

ResultsFind in source

“Median age a , years (min, max) | 61.0 (35, 80) | 62.0 (37, 79) | 62.0 (36, 79) | 61.0 (35, 80)”

Table 1Find in source

PASSReviewer 2· 90% conf

Biological variables are well reported for a human trial, including sex, age, and clinical characteristics.

Evidence

“In the mITT population, the median age was 61.0 years (range, 35–80), and 13% were women based on sex at birth; gender data were not collected.”

ResultsFind in source

“Median age a , years (min, max) | 61.0 (35, 80) | 62.0 (37, 79) | 62.0 (36, 79) | 61.0 (35, 80)”

Table 1Find in source

paraphrase[Table 1]

“Sex at birth, n (%) | Male | 83 (88) | 81 (84) | 81 (90) | 245 (88) | Female | 11 (12) | 15 (16) | 9 (10) | 35 (13)”

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Ethical approvals and consent are adequately documented.

Evidence

EthicsFind in source

“All patients provided written informed consent.”

MethodsFind in source

EthicsFind in source

PASSReviewer 2· 95% conf

Ethical approvals and consent are adequately documented.

Evidence

EthicsFind in source

“All patients provided written informed consent.”

MethodsFind in source

EthicsFind in source

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational product and key reagents are adequately identified.

Evidence

“CDR132L is a synthetic, locked nucleic acid (LNA)-based antisense oligonucleotide specifically designed and optimized to inhibit miR-132.”

Introduction ¶4Find in source

“Plasma miR-132 levels were quantified at Biotype GmbH using the CardiorHealth miR-132 Plasma PCR Kit (Cardior Pharmaceuticals GmbH) in accordance with the manufacturer’s instructions.”

MethodsFind in source

“All analyses performed used SAS version 9.4 software.”

Statistical analysisFind in source

PASSReviewer 2· 90% conf

Key resources, including the investigational drug and assay kits, are adequately identified.

Evidence

“CDR132L is a synthetic, locked nucleic acid (LNA)-based antisense oligonucleotide specifically designed and optimized to inhibit miR-132.”

Introduction ¶3Find in source

“Plasma miR-132 levels were quantified at Biotype GmbH using the CardiorHealth miR-132 Plasma PCR Kit (Cardior Pharmaceuticals GmbH) in accordance with the manufacturer’s instructions.”

MethodsFind in source

“All analyses performed used SAS version 9.4 software.”

Statistical analysisFind in source

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical methods are appropriate and well described, with effect sizes and confidence intervals reported.

Evidence

“The primary analysis used an analysis of covariance (ANCOVA) model that included treatment as a fixed effect and baseline LVESVI as a covariate.”

Statistical analysisFind in source

paraphrase[Results, Primary and secondary endpoints]

“The resulting placebo-adjusted least squares mean (LSM) differences were −1.11% (s.e.m. 3.37; F-test P = 0.37) for 5 mg kg−1 and −2.14% (s.e.m. 3.27; F-test P = 0.26) for 10 mg kg−1.”

“LSM difference, CDR132L versus placebo (95% CI; one-sided P value) | 0.87 (−1.41, 3.15; P = 0.227)”

Table 2Find in source

PASSReviewer 2· 90% conf

Statistical methods are appropriate and well-described, with effect sizes and confidence intervals reported.

Evidence

“The primary analysis used an analysis of covariance (ANCOVA) model that included treatment as a fixed effect and baseline LVESVI as a covariate.”

Statistical analysisFind in source

paraphrase[Results, Primary and secondary endpoints]

“The resulting placebo-adjusted least squares mean (LSM) differences were −1.11% (s.e.m. 3.37; F-test P = 0.37) for 5 mg kg−1 and −2.14% (s.e.m. 3.27; F-test P = 0.26) for 10 mg kg−1.”

“LSM difference, CDR132L versus placebo (95% CI; one-sided P value) | 0.87 (−1.41, 3.15; P = 0.227)”

Table 2Find in source

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Data availability is adequately described with a concrete access route.

Evidence

“Researchers can request access to clinical trial data by submitting a research proposal for review and approval by Novo Nordisk and an internal independent review panel.”

Data availabilityFind in source

“Requests are considered after the research is concluded or completed and the main results have been published.”

Data availabilityFind in source

PASSReviewer 2· 90% conf

Data availability is adequately described with a concrete access route.

Evidence

Data availabilityFind in source

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Reporting is transparent with trial registration, detailed methods, and proportional conclusions.

Evidence

“ClinicalTrials.gov: NCT05350969”

AbstractFind in source

“Several additional factors may have influenced the ability to detect a significant treatment effect in the overall study population.”

Discussion ¶3Find in source

“The subgroup findings are exploratory and hypothesis generating only.”

DiscussionFind in source

PASSReviewer 2· 95% conf

Reporting is transparent with trial registration, detailed methods, and balanced conclusions.

Evidence

“ClinicalTrials.gov: NCT05350969”

AbstractFind in source

“Several additional factors may have influenced the ability to detect a significant treatment effect in the overall study population.”

Discussion ¶4Find in source

“The subgroup findings are exploratory and hypothesis generating only.”

DiscussionFind in source

Registered (4 IDs: ClinicalTrials.gov). Reporting guideline cited: CONSORT.

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 12 references by DOI: 12 verified.

1 data/code link checked; 1 live.

Copyediting

2 minor

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

No major wording or formatting errors. 2 minor suggestions below.

2 copyedit issues flagged: mostly consistency, clarity.

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
CRITICALstatistics
Correct or explain the statistically impossible value: PERCENT: 4% is unattainable for n=4 (nearest: 0, 25%)
Demonstrable critical failure — blocks the verdict from passing.
2.
CRITICALstatistics
Correct or explain the statistically impossible value: PERCENT: 7% is unattainable for n=7 (nearest: 0, 14%)
Demonstrable critical failure — blocks the verdict from passing.
3.
HIGHreporting
Clarify the safety population description in the Methods/Results: state explicitly that one patient randomized to 10 mg/kg received placebo and is counted in the placebo arm for safety, making the safety population group sizes differ from mITT (94, 95, 91 vs 94, 96, 90).
The current text says the safety population is identical to mITT, which contradicts the reported group assignments and could confuse readers.
4.
HIGHreporting
Add a note in the Discussion or Methods acknowledging that the phase 1b trial (NCT04045405) was registered retrospectively (first submitted 2019-07-23 after study start 2019-06-21), and discuss any implications for the current trial's interpretation.
Retrospective registration of the prior trial is a transparency concern that informed readers should weigh.
5.
MEDIUMreporting
Report exact p-values for the primary endpoint in the Abstract, not just in the Results section.
The abstract currently omits exact p-values, which are important for readers assessing the primary outcome.
6.
MEDIUMreporting
Add a statement in the Methods about whether the trial was reported according to CONSORT guidelines, and include a completed CONSORT checklist as supplementary material.
Explicit adherence to CONSORT improves transparency and reproducibility.
7.
MEDIUMreporting
Report the number of patients screened and reasons for exclusion at each stage in the CONSORT diagram more explicitly.
The current text mentions 427 screened but does not detail exclusion reasons, which is a standard CONSORT requirement.
8.
MEDIUMstatistics
Provide results of the sensitivity analysis using multiple imputation for the primary endpoint, as mentioned in the Methods.
Reporting the results of prespecified sensitivity analyses strengthens the statistical robustness assessment.
9.
MEDIUMreporting
Report exact p-values for subgroup analyses in the text or tables, as forest plots may not provide exact values.
Exact p-values allow readers to assess the strength of subgroup findings.
10.
MEDIUMreporting
Add a statement about the availability of the statistical analysis plan in a public repository (e.g., ClinicalTrials.gov or a preprint server).
Public availability of the SAP enhances transparency and reproducibility.
11.
MEDIUMreporting
Discuss the potential impact of open-label pharmacy staff on blinding, and whether any unblinding risks were mitigated.
The pharmacy staff were not blinded, which is a potential source of bias that should be addressed.
12.
LOWreporting
Report race/ethnicity in baseline demographics to enhance generalizability.
Race/ethnicity is not currently reported, which limits assessment of generalizability.
13.
LOWreporting
Provide more detail on the randomization schedule generation (e.g., block size) in the Methods.
Details on block size and generation method improve reproducibility of the randomization process.
14.
LOWreporting
Report the intraclass correlation coefficient for core lab echocardiography readings to assess reproducibility.
ICC values would help readers assess the reliability of the primary endpoint measurements.
15.
LOWdata code
Provide more details on the data request review process, such as a template or timeline for approval.
More transparency on data access procedures would facilitate data sharing.
16.
LOWcopyedit
Move the sentence about the ESC Heart Failure Congress presentation from the Abstract to the end or remove it, as it is not a standard abstract element.
The congress presentation sentence is unusual in an abstract and may distract from the scientific content.
17.
LOWcopyedit
Clarify in the Results that the ITT population is the same as the randomized population (n=294) for conciseness.
The current definition is clear but could be more concise and standard.

Full text (62,783 chars)Analyzed: Aug 15, 2026