Effective post-exposure prophylaxis of Covid-19 associated with hydroxychloroquine: Prospective dataset re-analysis incorporating novel, missing data
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Abstract
BACKGROUND
A key trial ( NCT04308668 ) of post-exposure prophylaxis found hydroxychloroquine-associated (HCQ) reductions of Covid-19 by 17% overall and 31% to 49% in subgroups. To understand these trends, we re-analyzed the dataset.
METHODS
Our protocol conformed to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT). We compared the incidence of Covid-19 after HCQ or placebo, stratifying by intervention lag, age, and gender.
RESULTS
Newly requested data missing from the dataset revealed that 52% and 19% of subjects received medication 1-2 days after intended and assumed overnight delivery or four-day intervention lag respectively. After re-analysis, we found reduced HCQ-associated incidence of Covid-19 with Early (up to 3 days post-exposure) (RR 0.58, 95%CI 0.35 - 0.97; p =0.044; NNT 14.5) but not Late (RR 1.22, 95%CI 0.72 - 2.04) prophylaxis.
We found a significant HCQ-associated Covid-19 reduction in subjects 18 to 45 years old with Early (RR 0.54, 95%CI 0.29-0.97; p =0.0448, NNT 11.5) but not Late (RR 1.02, 95%CI 0.55-1.89) prophylaxis, attenuated in older subjects (RR 0.75, 95%CI 0-27-2.05) and by co-morbidities. Although, we did not detect effects of gender, folate, zinc, or ascorbate, confounding effects cannot be excluded.
CONCLUSIONS
Using novel data and prospective re-analysis, hydroxychloroquine, in an age-dependent manner, was associated with reduced Covid-19 compatible illness when supplied for post-exposure prophylaxis between 1 and 3 days after high- or moderate-risk exposure, at higher loading and maintenance doses than in similar studies. The original study conclusions are controverted, and our finding warrants prospective confirmation.
Protocol registered at Open Science Framework: osf.io/fqtnw (last revised September 27, 2020,
Highlights
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Missing data integrated with dataset re-analysis reversed findings of original study
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Hydroxychloroquine associated reduction (42%) of Covid-19 compatible illness found
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Effect in Post-exposure Prophylaxis when received 1-3 days after exposure
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Risk Ratio 0.58 (95% CI 0.35-0.97, p=0.044, NNT14.5)
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Findings controvert the conclusions of original study
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SciScore for 10.1101/2020.11.29.20235218: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: Ethics Committee Approval: No ethics committee approval was required as we used a de-identified, publicly released dataset. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Limitations: Given the enormity of the pandemic, we adopted a drug-development approach to glean efficacy …
SciScore for 10.1101/2020.11.29.20235218: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: Ethics Committee Approval: No ethics committee approval was required as we used a de-identified, publicly released dataset. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Limitations: Given the enormity of the pandemic, we adopted a drug-development approach to glean efficacy signals possibly lost in the original study due to Type II errors related to underpowering, early termination and an environment of poorly understood pathogenesis. This could well justify shifting the threshold of toleration for Type I errors and other statistical challenges related to sub-group analysis.38 These are partially offset by our use of two-sided tests, when directionality in the original data may have justified otherwise. Our primary time stratification based on newly-acquired data essentially represents the a priori analysis intended by the original authors. Nonetheless, this does remain a post hoc study; results should be interpreted cautiously, and hypotheses should be tested in prospective studies sufficiently powered to accommodate multiple comparisons in sub-groups. Our study retains the limitations acknowledged by its original authors related to the availability and access to testing, the use of a clinical case definition of Covid-19, the reliance on self-reported data and the generally young population studied. There are other limitations. The study poorly represents African-American and Hispanic or Latino populations. The rapidly executed study overcame several logistical challenges to allow the collection of real-world data, having both advantages and disadvantages of a pragmatic design.11,39 Self-selection bias inherent in this type of study may hav...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04308668 Completed Post-exposure Prophylaxis / Preemptive Therapy for SARS-Coro… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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