Trial of Selective Early Treatment of Patent Ductus Arteriosus with Ibuprofen.
Gupta S, Subhedar NV, Bell JL, Field D, Bowler U, Hutchison E, Johnson S, Kelsall W, Pepperell J, Roberts T, Sinha S, Stanbury K, Wyllie J, Hardy P, Juszczak E, Baby-OSCAR Collaborative Group
- DOI
- 10.1056/NEJMoa2305582
- Record issued
- 2026-08-16
- 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/02967399-cced-4a7b-8328-31dde2b4061d is authoritative.
How this rating was calculated
- ReportingData & code availability partially met−0.25★
- The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 8 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.
- No data or code availability links were detected to verify.
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 multicenter RCT with rigorous randomization, blinding, and statistical methods. The main weaknesses are the absence of a data availability statement and the lack of explicit ethics committee identification, both of which are reporting gaps rather than substantive flaws.
Both reviewers classified the study as interventional, and no divergence was noted. The evaluation covered all eight dimensions; several sub-criteria were not applicable (e.g., animal-related, cell line, housing). The statistics verification covered only 2 tests, so the statistical analysis is not fully verified.
Numerical inconsistencies
None foundValues 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.
Checked — nothing surfaced.
Recomputed 2 tests: 2 consistent, 0 inconsistent; 2 via agent-written checks.
- CONSISTENTreported p = .100 · recomputed p = .095Reviewers 1, 2Primary outcome risk ratio p-value from adjusted analysis
“adjusted risk ratio [aRR], 1.09; 95% CI, 0.98 to 1.20; p=0.10”
Taken as given: The risk ratio is 1.09 with 95% CI 0.98 to 1.20.; The CI is two-sided at 95%.; The p-value is two-tailed.Method: Recomputed p-value from the reported risk ratio and 95% CI using the normal approximation for the log risk ratio.How we recomputed it: pCI(1.09, 0.98, 1.20, 1) - CONSISTENTreported p = .130 · recomputed p = .133Reviewer 2Death risk ratio p-value from adjusted analysis
“Death occurred in 44 of 323 infants (13.6%) assigned to ibuprofen and 33 of 321 infants (10.3%) assigned to placebo (aRR, 1.32; 95% CI, 0.92 to 1.90).”
Taken as given: The CI is a 95% confidence interval for the risk ratio.; The p-value is two-sided.Method: Recomputed p-value from the reported risk ratio and 95% CI using the normal approximation for the log risk ratio.How we recomputed it: pCI(1.32, 0.92, 1.90, 1)
Overstated conclusions
None foundConclusions 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.
Checked — nothing surfaced.
6 major claims checked against the paper's own evidence: all adequately supported.
- supportedReviewers 1, 2Early treatment with ibuprofen was not associated with an improvement in the composite outcome of death or moderate or severe BPD at 36 weeks’ post-menstrual age compared to placebo.The primary outcome result (aRR 1.09, 95% CI 0.98-1.20, p=0.10) directly supports the claim of no improvement.Evidence: Primary outcome: 220/318 (69.2%) vs 202/318 (63.5%), aRR 1.09 (0.98-1.20), p=0.10.
“Early treatment with ibuprofen was not associated with an improvement in the composite outcome of death or moderate or severe BPD at 36 weeks’ post-menstrual age compared to placebo.”
AbstractFind in source - supportedReviewer 1There were two severe adverse events that were possibly related to ibuprofen.The safety section reports two serious adverse events assessed as possibly related to ibuprofen.Evidence: Safety section: 'There were two serious adverse events that were assessed as possibly related to ibuprofen.'
“There were two severe adverse events that were possibly related to ibuprofen.”
ResultsFind in source - supportedReviewers 1, 2A single early course of ibuprofen resulted in a closed or small PDA in only 55.5% of infants randomized to ibuprofen.The result is directly reported in the outcomes section.Evidence: Outcomes: 'A closed or small PDA (diameter <1.5 mm) at around 3 weeks of age was present in 176 of 317 patients (55.5%) in the ibuprofen group.'
“A single early course of ibuprofen resulted in a closed or small PDA (confirmed by echocardiography at 3 weeks of age) in only 55.5% of infants randomized to ibuprofen.”
ResultsFind in source - supportedReviewer 2There were no apparent between-group differences in death or moderate or severe BPD.Secondary outcomes for death and BPD show no statistically significant differences, supporting the claim.Evidence: Death: 44/323 (13.6%) vs 33/321 (10.3%), aRR 1.32, 95% CI 0.92-1.90; BPD: 176/274 (64.2%) vs 169/285 (59.3%), aRR 1.09, 95% CI 0.96-1.23.
“There were no apparent between-group differences in death or moderate or severe BPD.”
Discussion ¶1Find in source - supportedReviewer 2The rate of open-label medical therapy for patients with a symptomatic PDA in this trial appeared lower than that reported in other similar trials and occurred almost twice as frequently in the placebo group compared to the ibuprofen group.The reported rates (13.3% vs 25.5%) support the claim.Evidence: 43 infants (13.3%) assigned to ibuprofen and 82 infants (25.5%) in the placebo group required open-label medical treatment.
“A total of 43 infants (13.3%) assigned to ibuprofen and 82 infants (25.5%) in the placebo group required open-label medical treatment for symptoms attributable to a PDA (); 9 infants (2.8%) assigned to ibuprofen and 31 infants (9.6%) assigned to placebo required surgical treatment ().”
ResultsFind in source - supportedReviewer 2We found no evidence that ibuprofen resulted in excess serious complications.The safety data show only two serious adverse events possibly related to ibuprofen, supporting the claim.Evidence: There were two serious adverse events that were assessed as possibly related to ibuprofen.
“There were two serious adverse events that were assessed as possibly related to ibuprofen.”
ResultsFind in source
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
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 research on PDA management, including prophylaxis and symptomatic treatment, and notes limitations such as unnecessary treatment and lack of outcome improvement. The hypothesis follows logically from the cited evidence that large PDAs are associated with worse outcomes and that selective early treatment may avoid unnecessary treatment.
“Prophylaxis with indomethacin or ibuprofen in the first 12 to 24 hours of life is reported to reduce severe intraventricular hemorrhage and pulmonary hemorrhage, but without an improvement in survival without neurosensory impairment at 18 months.”
“We hypothesized that early (up to 72 hours) selective treatment of patients who have a PDA that is 1.5 mm diameter or larger with unrestricted flow, identified using bedside echocardiography, with ibuprofen compared to placebo, would reduce mortality and improve short-term outcomes such as BPD.”
“However, utilizing a prophylactic approach, most infants will receive treatment unnecessarily since PDAs can close spontaneously.”
“Prophylaxis with indomethacin or ibuprofen in the first 12 to 24 hours of life is reported to reduce severe intraventricular hemorrhage and pulmonary hemorrhage, but without an improvement in survival without neurosensory impairment at 18 months.”
“We hypothesized that early (up to 72 hours) selective treatment of patients who have a PDA that is 1.5 mm diameter or larger with unrestricted flow, identified using bedside echocardiography, with ibuprofen compared to placebo, would reduce mortality and improve short-term outcomes such as BPD.”
“However, utilizing a prophylactic approach, most infants will receive treatment unnecessarily since PDAs can close spontaneously.”
The trial is a multicenter, randomized, double-blind, placebo-controlled design with a web-based randomization system using minimization to balance key factors. Blinding of clinicians, families, and outcome assessors is described. A sample size calculation was performed, though the target was not reached. Inclusion/exclusion criteria are pre-specified, and the analysis population (ITT) and missing data handling are defined. The trial is registered and follows a published protocol.
“Dynamic assignment to treatment group was performed via a secure web-based randomization system that was created and hosted by the NPEU Clinical Trials Unit with 24/7 telephone back-up, ensuring concealment of group assignment.”
“Treatment assignment was blinded from the clinicians, the infant’s family and individuals who assessed outcomes.”
“A sample size of 730 infants would be required to detect a clinically important absolute risk reduction of 12% with 90% power and a type I error of 5% from a control group event rate of 60% to a treatment group event rate of 48%, assuming 1% of infants were lost to follow-up.”
“Dynamic assignment to treatment group was performed via a secure web-based randomization system that was created and hosted by the NPEU Clinical Trials Unit with 24/7 telephone back-up, ensuring concealment of group assignment.”
“Treatment assignment was blinded from the clinicians, the infant’s family and individuals who assessed outcomes.”
“A sample size of 730 infants would be required to detect a clinically important absolute risk reduction of 12% with 90% power and a type I error of 5% from a control group event rate of 60% to a treatment group event rate of 48%, assuming 1% of infants were lost to follow-up.”
The study reports sex, gestational age, birth weight, and maternal demographics in baseline characteristics. Since both sexes are enrolled, sex justification is not applicable. Age and health status are captured via gestational age and postnatal age. Species/strain and housing conditions are not applicable for a human trial.
“Gestational age— weeks | 26.1±1.5 | 26.1±1.6”
“Male | 180 (55.6) | 175 (54.3)”
“Gestational age— weeks | 26.1±1.5 | 26.1±1.6”
The paper states that written informed consent was obtained from parents. Although the specific ethics committee name is not mentioned in the text, the trial was conducted in the UK with a published protocol and funded by NIHR, implying ethical approval. The trial is registered with ISRCTN. Regulatory compliance is implied by adherence to Good Manufacturing Practice and the Declaration of Helsinki (not explicitly stated but standard).
“After written informed consent was obtained from parents, infants born between 23 weeks+0 days to 28 weeks+6 days’ gestation, less than 72 hours old and confirmed by echocardiography to have a large PDA, were considered eligible.”
“Baby-OSCAR ISRCTN Registry number, ISRCTN84264977”
“A multicenter, randomized, double-blind, placebo-controlled trial was conducted in 32 neonatal intensive care units in the United Kingdom following a published protocol (available online with the full text of this article at NEJM.org).”
“After written informed consent was obtained from parents, infants born between 23 weeks+0 days to 28 weeks+6 days’ gestation, less than 72 hours old and confirmed by echocardiography to have a large PDA, were considered eligible.”
“A multicenter, randomized, double-blind, placebo-controlled trial was conducted in 32 neonatal intensive care units in the United Kingdom following a published protocol (available online with the full text of this article at NEJM.org).”
“(Funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme; Baby-OSCAR ISRCTN Registry number, ISRCTN84264977)”
The trial intervention is identified as ibuprofen sodium with dosing regimen, and placebo is described as 0.9% sodium chloride. Statistical software (Stata/SE version 15) is identified. No other biological or chemical resources are used, so other sub-criteria are not applicable.
“Ibuprofen was administered parenterally as loading dose of 10 mg per kilogram followed by two doses of 5 mg per kilogram at least 24 hours apart.”
“The statistical software Stata/SE version 15 was used for all analyses.”
“Ibuprofen was administered parenterally as loading dose of 10 mg per kilogram followed by two doses of 5 mg per kilogram at least 24 hours apart.”
“The matched placebo was supplied as a clear sterile solution of 0.9% sodium chloride.”
“The statistical software Stata/SE version 15 was used for all analyses.”
The primary analysis uses mixed effects Poisson regression with robust variance, adjusted for minimization factors. Exact p-values are reported for the primary outcome (p=0.10). Effect sizes are reported with 95% CIs. Software is identified. Data presentation includes per-group n and percentages. Model assumptions were checked. The paper acknowledges no multiplicity adjustment for secondary outcomes.
“Binary outcomes were analyzed using mixed effects Poisson regression with a robust variance estimator with risk ratios and 95% confidence intervals presented.”
“adjusted risk ratio [aRR], 1.09; 95% CI, 0.98 to 1.20; p=0.10”
“Binary outcomes were analyzed using mixed effects Poisson regression with a robust variance estimator with risk ratios and 95% confidence intervals presented.”
“adjusted risk ratio [aRR], 1.09; 95% CI, 0.98 to 1.20; p=0.10”
The paper does not include a data availability statement. It mentions supplementary material available online, but no repository or data access procedure is described. Since this is a clinical trial, a data availability statement is expected. The lack of a statement is a reporting gap.
“following a published protocol (available online with the full text of this article at NEJM.org)”
The trial is registered with ISRCTN. Methods are detailed enough for replication. Limitations are explicitly discussed, including open-label treatment and under-recruitment. Conclusions are proportional to the results, noting no improvement in the primary outcome. Funding and COI are disclosed.
“Baby-OSCAR ISRCTN Registry number, ISRCTN84264977”
“Our study has limitations. Despite adopting strict criteria to restrict its use, 29.8% of babies in the placebo arm received open-label medical therapy, the likely impact of which would have been to increase the PDA closure rate in this group and make it more difficult to demonstrate between-group differences in clinical outcomes.”
“This study was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme (11/92/15).”
“Baby-OSCAR ISRCTN Registry number, ISRCTN84264977”
“Our study has limitations. Despite adopting strict criteria to restrict its use, 29.8% of babies in the placebo arm received open-label medical therapy, the likely impact of which would have been to increase the PDA closure rate in this group and make it more difficult to demonstrate between-group differences in clinical outcomes.”
“This study was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme (11/92/15).”
Registered (1 ID: ISRCTN). No reporting guideline cited.
Broken references and links
None found · partly checkedReferences 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.
Nothing surfaced — but not everything feeding this category ran (missing: data/code link verification), so read this as a partial clean bill.
Checked 29 references by DOI: 29 verified.
Every extracted reference resolved against Crossref/OpenAlex with no retraction flags.
Copyediting
2 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 2 minor suggestions below.
2 copyedit issues flagged: mostly typo, consistency.
- MINORtypoAbstract, Results“adjusted risk ratio [aRR], 1.09; 95% confidence interval (CI), 0.98 to 1.20; p=0.10”→ Ensure consistent use of brackets and spacing.Minor formatting inconsistency.
- MINORconsistencyTable 1“Mother’s ethnicity— no. (%)”→ Use consistent em-dash spacing.Minor formatting.
The published work is robust and methodologically sound, but readers should weigh the absence of a data availability statement and the lack of explicit ethics committee details. These are reporting gaps that could warrant a correction or clarification from the authors, but they do not undermine the validity of the findings.
- 1.HIGHdata codeAdd a data availability statement to the manuscript (e.g., in the Methods or a dedicated section) specifying how de-identified data can be accessed, such as through a data access committee or a public repository.The absence of a data availability statement is a reporting gap that undermines transparency and reproducibility for a clinical trial.
- 2.HIGHethicsIn the Methods section, explicitly name the ethics committee that approved the trial and provide the approval number.The current paper implies ethical approval but does not name the committee, which is a reporting gap that should be corrected for full transparency.
- 3.MEDIUMreportingAdd an explicit statement of adherence to CONSORT reporting guidelines in the Methods or Acknowledgments.Explicitly stating CONSORT adherence enhances transparency and is expected for a randomized trial.
- 4.MEDIUMethicsState compliance with the Declaration of Helsinki or other ethical standards explicitly in the Methods.Explicit ethical standards compliance is a standard expectation for human research and is currently only implied.
- 5.MEDIUMdata codeProvide a link to the full statistical analysis plan or protocol in the data availability statement or as a supplementary file.Making the analysis plan accessible supports reproducibility and allows readers to verify pre-specified analyses.
- 6.LOWdata codeConsider depositing the statistical analysis code in a public repository to enhance reproducibility.Sharing analysis code is a best practice that facilitates independent verification of results.
- 7.LOWcopyeditFix minor formatting inconsistencies in the Abstract (e.g., consistent use of brackets and spacing in 'adjusted risk ratio [aRR]').Minor formatting issues can be polished for a cleaner presentation.
- 8.LOWcopyeditEnsure consistent em-dash spacing in Table 1 (e.g., 'Mother’s ethnicity— no. (%)').Consistent formatting improves readability and professionalism.
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.