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

Veronique M M M Schiffer; Emma B N J Janssen; Bas C T van Bussel; Laura L M Jorissen; Jeanette Tas; Jan-Willem E M Sels; Dennis C J J Bergmans; Trang H T Dinh; Sander M J van Kuijk; Anisa Hana; Jannet Mehagnoul-Schipper; Clarissa I E Scheeren; Dieter Mesotten; Bjorn Stessel; Gernot Marx; Arnoud W J van T Hof; Marc E A Spaanderman; Walther N K A van Mook; Iwan C C van der Horst; Chahinda Ghossein-Doha

doi:10.1016/j.eclinm.2020.100652

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

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

Authors

Veronique M M M Schiffer^{1

2}, Emma B N J Janssen^{1

3}, Bas C T van Bussel^{4

5}, Laura L M Jorissen¹, Jeanette Tas⁴, Jan-Willem E M Sels^{4

6}, Dennis C J J Bergmans⁴, Trang H T Dinh⁶, Sander M J van Kuijk⁷, Anisa Hana⁸, Jannet Mehagnoul-Schipper⁹, Clarissa I E Scheeren¹⁰, Dieter Mesotten¹¹, Bjorn Stessel¹², Gernot Marx¹³, Arnoud W J van T Hof⁶, 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

¹ Department of Obstetrics and Gynaecology, Maastricht University Medical Centre (MUMC+), Maastricht, the Netherlands.
² GROW, School for Oncology and Developmental Biology, Maastricht University, the Netherlands.
³ Cardiovascular Research Institute Maastricht (CARIM), Maastricht, the Netherlands.
⁴ Department of Intensive Care, MUMC+, Maastricht, the Netherlands.
⁵ Care and Public Health Research Institute (CAPHRI), Maastricht University, the Netherlands.
⁶ Department of Cardiology, MUMC+, Maastricht, MD 6200, the Netherlands.
⁷ Department of Clinical Epidemiology and Medical Technology Assessment, MUMC+, Maastricht, the Netherlands.
⁸ Department of Intensive Care, Laurentius Ziekenhuis, Roermond, the Netherlands.
⁹ Department of Intensive Care, VieCuri Medisch Centrum, Venlo, the Netherlands.
¹⁰ Department of Intensive Care, Zuyderland Medisch Centrum, the Netherlands.
¹¹ Department of Intensive Care, Ziekenhuis Oost-Limburg, Genk, Belgium.
¹² Department of Intensive Care, Jessa Hospital, Hasselt, Belgium.
¹³ Department of Intensive Care, Uniklinik RWTH Aachen, Aachen, Germany.
¹⁴ Department of Obstetrics and Gynaecology, Radboud University Medical Centre, Nijmegen, the Netherlands.
¹⁵ School of Health Professions Education, Academy for Postgraduate Medical Training, Maastricht University, Maastricht, the Netherlands.

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.