Clinical Trials for COVID-19 Should Include Sex As a Variable

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Clinical Trials for COVID-19 Should Include Sex As a Variable VIEWPOINT The Journal of Clinical Investigation Clinical trials for COVID-19 should include sex as a variable Evelyne Bischof,1,2 Jeannette Wolfe,3 and Sabra L. Klein4,5 1Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy. 2College of Clinical Medicine, Shanghai University of Medicine and Health Sciences, Shanghai, China. 3Department of Emergency Medicine, UMass Medical School – Baystate Campus, Springfield, Massachusetts, USA. 4W. Harry Feinstone Department of Molecular Microbiology and Immunology and 5Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. The number of COVID-19 cases appears cases revealed that 13 of 26 states disaggre- Until recently, remdesivir was regard- to be comparable between men and wom- gated data using sex as a variable. Notably, ed as promising for COVID-19, but inter- en, but the severity of disease and death is all 13 states reported that men are twice as im published results are disappointing (8). two times greater for men than for women likely to die from COVID-19 (2), with pub- The still unpublished Adaptive COVID-19 (1, 2). History, including the 1918 influen- lished data from New York City revealing Treatment Trial reported a four-day dif- za pandemic, warned us that male biases male-biased death from COVID-19 in all ference in time to recovery (11 days vs. 15 in COVID-19 could occur. In this View- adults over the age of 20 (3). days) for patients on remdesivir, suggest- point, we focus on biological explanations, Disparities between men and women ing some benefit (9). Similar outcomes with a forward look at why clinicians and in outcomes of infectious diseases, includ- have been seen for favipiravir, lopina- biomedical researchers should consider ing those caused by pathogenic coronavi- vir, and ritonavir, with the latter causing sex as a biological variable that will affect ruses, are not new. During the 2002–2003 severe side effects (10). Some studies treatment outcomes for COVID-19. There SARS outbreak and the ongoing MERS showed that hydroxychloroquine and chlo- is a long history of not analyzing or report- outbreaks, a majority of patients were roquine caused a high number of harmful ing differences between women and men men, possibly because of predominantly and lethal casualties (11). All trials to date in the prophylactic or therapeutic treat- male contact with the animal reservoirs include both men and women, but take a ment of infectious diseases. We seek to for these coronaviruses (4, 5). However, sex-blind approach to the analyses of out- reverse this trend and call on investigators for many viral respiratory tract infections, come data, with no governmental guide- developing and testing therapeutic and including but not limited to coronaviruses, lines mentioning sex-specific prophylactic prophylactic approaches for COVID-19 to the prevalence and severity of infection or therapeutic recommendations (except design studies that are inclusive of male is greater for men (6). Preclinical studies for pregnant and postpartum women). The versus female differences in drug respons- show that in mice, males are significantly lack of consideration of sex biases in drug es, immunotherapies, vaccines, and non- more susceptible to coronavirus infec- efficacy and reactivity inevitably may lead pharmacological interventions. tions, as they are less capable of controlling to increased adverse (potentially lethal) virus replication, exhibit more post-infec- reactions. A study of chloroquine treat- Disaggregating data by sex tion pulmonary damage, and have lower ment in Brazil, in which 24.7% of the sub- Initial reports from Wuhan involving immune responses than females (7). jects were female, was prematurely ceased more than 40,000 cases showed that men because of complications (especially accounted for nearly two-thirds of deaths, Drug efficacy arrhythmias and QTc prolongation, 25%) with more severe symptoms and reduced As of this writing, no antiviral agent has and lethality (17%). No sex disaggrega- recovery rates (1). This report provided the been FDA approved as a specific COVID-19 tion was provided for either outcome (12), first alarm and set a precedent for other treatment. For those drugs being tested in despite the fact that women are known countries to disaggregate their data by sex randomized clinical trials, there has been to suffer more from cardiac intricacies. (Figure 1). As reports emerged from Italy, no explicit consideration of sex biases in After the initial therapeutic and suggested Spain, France, and the United Kingdom, efficacy or adverse reactions. This occurs prophylactic use of hydroxychloroquine men have consistently been twice as likely despite studies showing clear and some- in patients with COVID-19 in March, the to die from COVID-19 as women, with the times profound differences in drug treat- FDA released a report on April 24, noting Global Health 50/50 initiative providing ment responses, including antivirals. Drug severe and lethal outcomes. It remains real-time sex-disaggregated data from most trials are typically designed and analyzed underreported whether most of these countries worldwide. Although the United without attention toward sex-specific dos- occurred in women. States has been less consistent with sex-dis- ages or differential side effects, while they Ongoing trials on hydroxychloro- aggregated reporting, a recent analysis of the should be considered in both novel and quine do not include sex-disaggregated 26 states with more than 2000 COVID-19 repositioned drugs. comparisons in their objectives. Available preliminary results of studies on remde- sivir and favipiravir also lack sex-specific Conflict of interest: The authors have declared that no conflict of interest exists. Copyright: © 2020, American Society for Clinical Investigation. data on adverse reactions or appropriate Reference information: J Clin Invest. 2020;130(7):3350–3352. https://doi.org/10.1172/JCI139306. dose adjustments. As long as drug trials 3350 jci.org Volume 130 Number 7 July 2020 The Journal of Clinical Investigation VIEWPOINT hypoxic patients by using a combination of noninvasive ventilatory support devices and patient positioning (20). As there are sex-based differences in lung physiology including airway caliber, lung volumes, diaphragmatic excursion, accessory mus- cle mechanics, and abdominal fat distribu- tion (21), sex-disaggregated outcome data on different invasive and noninvasive ven- Figure 1. Sex-disaggregated COVID-19 data. The Global Health 50/50 research initiative provides tilatory modalities are crucial, but have not real-time sex-disaggregated data from countries worldwide (accessed May 3, 2020). Based on their been included in preliminary studies. analyses of data from 69 countries, 50% of the countries are sex-disaggregating COVID-19 cases, Another rapidly evolving area of deaths, or both. For the 44 countries that have sex-disaggregated COVID-19 cases, 34% report a male bias, 45% report a female bias, and 21% report no sex bias (i.e., 50% ± 1% for each sex). For the 45 interest is the increase in thrombotic/ countries reporting sex-disaggregated COVID-19 deaths, 87% report a male bias, 2% report a female thromboembolic events in patients with bias, and 11% report no sex bias (i.e., 50% ± 1% for each sex). COVID-19 (22). Although the main driv- er of these events is currently unknown, direct viral effects, secondary hypoxia, continue to enroll both men and women Empirical evidence illustrates that liver impairment, or the amplification of but fail to sex-disaggregate outcome data, females and males differ in outcomes fol- more classical risk factors, such as severe costly mistakes will continue. Current- lowing the use of therapeutic immuno- inflammatory response and immobility, ly, there are over 1000 registered trials therapies in autoimmune diseases, infec- have been suggested (23). A recent review on COVID-19, more than half of which tious diseases, and solid tumors. Females on this topic reinforced the importance of include pharmacologic intervention or tend to experience more immunotherapy- liberal prophylaxis, suggesting therapeutic observation, and seven completed trials. related adverse reactions (17). For immu- anticoagulation of all admitted high-risk Although the latter were open to both notherapies aimed at stimulating an COVID-19 patients who lack contraindica- sexes, none reported an objective to bal- immune response, e.g., vaccines, females tions and prophylactic anticoagulation in ance participants or compared outcomes develop stronger responses and may expe- outpatients with mild disease and a history between men and women. rience greater efficacy than males. In of venous thrombosis or immobility (23). contrast, immunotherapies that repress Importantly, sex-disaggregated results Immunotherapies an immune response, e.g., cytokine or have not been reported except for a single Immunotherapies for COVID-19 are checkpoint inhibitors, are reportedly more sentence in the Helms et al. paper, noting critical for mitigation of disease and efficacious in males (18, 19). One-size-fits- that 24 of the 25 patients with pulmonary eventual long-term protection against all approaches to immunotherapies will emboli were male (22). As both under- and SARS-CoV-2. Because a vaccine is not not work, and sex/gender may contribute overanticoagulation can carry patient risk, yet available, other immunotherapies are to variable treatment success, including
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