Background: The COVID-STEROID 2 trial found high probability of benefit with dexamethasone 12 mg vs. 6 mg daily among patients with COVID-19 and severe hypoxemia. There was suggestion of heterogeneity of treatment effects (HTE)between patients enrolled from Europe vs. India on the primary outcome. Whether there was HTE by geographical region for the remaining prespecified patient-important outcomes is unclear. Methods: We evaluated HTE by geographical region (Europe vs. India) for all secondary outcomes assessed in the trial with analyses adjusted for stratification variables. The results are presented as risk differences (RDs) or mean differences (MDs) with 99% confidence intervals (CIs) and P-values from interaction tests.   Results: We found HTE for mortality at day 28 (RD for Europe -8.3% (99 % CI: -17.7 to 1.0) vs. RD for India 0.1% (99% CI: -10.0 to 10.0)), mortality at day 90 (RD for Europe -7.4% (99% CI: -17.1 to 2.0) vs. RD for India -1.4% (99% CI:-12.8 to 9.8)), mortality at day 180 (RD for Europe -6.7% (99%CI:-16.4 to 2.9) vs. RD for India -1.0% (99%CI:-12.3 to 10.3)), and number of days alive without life support at day 90 (MD for Europe 6.1 days (99% CI:-1.3 to 13.4) vs. MD for India 1.7 days (99% CI:-8.4 to11.8)). For serious adverse reactions, the direction was reversed (RD for Europe -1.0% (99% CI:-7.1 to 5.2) vs. RD for India -5.3% (99% CI: -16.2 to 5.0). For HRQoL outcomes, MD in EQ-5D-5L index values was 0.08(99%CI: -0.01 to 0.16) for Europe and 0.02(99%CI:-0.10 to 0.14) for India. For EQ VAS, MD was 4.4(95%CI:-3.1 to 11.9) for Europe and 2.6(99%CI:-9.0 to 14.2) for India. P values for all tests of interaction were ≥0.12.     Conclusions: In this post hoc exploratory analysis, we found that higher dose dexamethasone may have lower beneficial effects for patients in India as compared with those in Europe without an increase in serious adverse reactions.

None for the authors. The Department of Intensive Care at Copenhagen University Hospital Rigshospitalet has received funding for other projects from The Novo Nordisk Foundation, Pfizer, Sygeforsikringen danmark, and Fresenius Kabi, and conducts contract research for AM-Pharma.

https://osf.io/6tfrk

The COVID STEROID 2 trial was funded by The Novo Nordisk Foundation and supported by Rigshospitalet’s Research Council.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This current manuscript is a secondary analysis of previously published trial data. The original trial was approved by the Institutional Ethics Committee at Apollo Main Hospital, Chennai, India. The reference number is: Apollo Main Hospital(AMH)-C-S-021/06-20

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I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

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Data are available upon reasonable request. Deidentified patient data will be made available beginning 6 months after publication of the study and ending at 2 years. All requests for data sharing must be accompanied by a formal request, a study proposal with clear statement of aims and hypotheses and a statistical analysis plan. All applications will be assessed by the COVID-STEROID 2 Trial Management Committee. Applications from investigators with suitable academic capability to conduct the proposed work will be given consideration. Any proposal will require approval from the ethics committee which approved the conduct of this trial prior to sharing of any patient data. If a proposal is approved, a signed data transfer agreement will be required before data sharing.