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. 2020 Dec:29:100652.
doi: 10.1016/j.eclinm.2020.100652. Epub 2020 Nov 30.

The "sex gap" in COVID-19 trials: a scoping review

Veronique M M M Schiffer  1   2 , Emma B N J Janssen  1   3 , Bas C T van Bussel  4   5 , Laura L M Jorissen  1 , Jeanette Tas  4 , Jan-Willem E M Sels  4   6 , Dennis C J J Bergmans  4 , Trang H T Dinh  6 , Sander M J van Kuijk  7 , Anisa Hana  8 , Jannet Mehagnoul-Schipper  9 , Clarissa I E Scheeren  10 , Dieter Mesotten  11 , Bjorn Stessel  12 , Gernot Marx  13 , Arnoud W J van T Hof  6 , Marc E A Spaanderman  1   14 , Walther N K A van Mook  4   15 , Iwan C C van der Horst  4   3 , Chahinda Ghossein-Doha  1   4   6   3
Affiliations

The "sex gap" in COVID-19 trials: a scoping review

Veronique M M M Schiffer et al. EClinicalMedicine. 2020 Dec.

Abstract

Background: Many studies investigate the role of pharmacological treatments on disease course in Corona Virus Disease 2019 (COVID-19). Sex disparities in genetics, immunological responses, and hormonal mechanisms may underlie the substantially higher fatality rates reported in male COVID-19 patients. To optimise care for COVID-19 patients, prophylactic and therapeutic studies should include sex-specific design and analyses. Therefore, in this scoping review, we investigated whether studies on pharmacological treatment in COVID-19 were performed based on a priori sex-specific design or post-hoc sex-specific analyses.

Methods: We systematically searched PubMed, EMBASE, UpToDate, clinical trial.org, and MedRxiv for studies on pharmacological treatment for COVID-19 until June 6th, 2020. We included case series, randomized controlled trials, and observational studies in humans (≥18 years) investigating antiviral, antimalarial, and immune system modulating drugs. Data were collected on 1) the proportion of included females, 2) whether sex stratification was performed (a priori by design or post-hoc), and 3) whether effect modification by sex was investigated.

Findings: 30 studies were eligible for inclusion, investigating remdesivir (n = 2), lopinavir/ritonavir (n = 5), favipiravir (n = 1), umifenovir (n = 1), hydroxychloroquine/chloroquine (n = 8), convalescent plasma (n = 6), interleukin-6 (IL-6) pathway inhibitors (n = 5), interleukin-1 (IL-1) pathway inhibitors (n = 1) and corticosteroids (n = 3). Only one study stratified its data based on sex in a post-hoc analysis, whereas none did a priori by design. None of the studies investigated effect modification by sex. A quarter of the studies included twice as many males as females.

Interpretation: Analyses assessing potential interference of sex with (side-)effects of pharmacological therapy for COVID-19 are rarely reported. Considering sex differences in case-fatality rates and genetic, immunological, and hormonal mechanisms, studies should include sex-specific analyses in their design to optimise COVID-19 care.

Funding: None.

Keywords: COVID-19; Clinical trials; Diversity; Sex; Therapy.

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Conflict of interest statement

Dr. Marx reports grants and personal fees from Bbraun Melsungen AG, grants and personal fees from Sphingotec AG, grants and personal fees from 4TEEN4 Pharmaceuticals GmbH, outside the submitted work. In addition, Dr. Marx has a patent Modulation ofTLR4 signalling European Patent 2855519/US Patent: US9,745,369 B2 issued, and a patent Combination of C1-Inh and Lung surfactant for the treatment of respiratory disorders PatentÐo.: US 7053,176 B1 PCT/EP99/06845 issued. All other authors declare no interest. Furthermore, there are no known conflicts of interest associated with this publication, and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that all have approved the order of authors listed in the manuscript.

Figures

Fig. 1
Fig. 1
Flowchart of study selection and inclusion after systematic literature search.
Fig. 2
Fig. 2
Total male-to-female ratio of included patients stratified per pharmacological treatment under investigation, including the range of study-specific male-to-female ratios.
See this image and copyright information in PMC

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