Inclusion of racial and ethnic groups in clinical trials for COVID-19 and post-acute COVID-19 syndrome: An analysis of studies registered on ClinicalTrials.gov
Authors: Aasiya Chaka, Daniel Pan, Mohannad Irshad, Humayra Piranie, Molly Wells, Zainab Lal, Amani Al-Oraibi, Paul Bird, Joshua Nazareth, Shirley Sze, Pip Divall, Charlie S. Sullivan, Ben E. Appleby, Lucy Teece, Christopher A. Martin, Jatin Naidu, Laura B. Nellums, Laura J. Gray, Kamlesh Khunti, Manish Pareek
Journal: Journal of Infection (2024)

We read with interest the study by Juan and colleagues, who found in a network systematic review and meta-analysis of nine observational studies, that early use of oral antiviral drugs could protect against developing post-acute COVID-19 syndrome (PASC).1Jiang J. Li Y. Jiang Q. Jiang Y. Qin H. Li Y. Early use of oral antiviral drugs and the risk of post covid-19 syndrome: A systematic review and network meta-analysis.Journal of Infection. June 2024; (Published online)106190https://doi.org/10.1016/j.jinf.2024.106190Abstract Full Text Full Text PDF Scopus (0) Google Scholar The study of race and ethnicity reporting is critical for assessing equity, especially relating to COVID-19, where those from ethnic minority groups suffered disproportionately worse clinical outcomes than majority groups.2Sze S. Pan D. Nevill C.R. et al.Ethnicity and clinical outcomes in COVID-19: A systematic review and meta-analysis.EClinicalMedicine. 2020; 29-30100630https://doi.org/10.1016/j.eclinm.2020.100630Abstract Full Text Full Text PDF Scopus (438) Google Scholar, 3Irizar P. Pan D. Kapadia D. et al.Ethnic inequalities in covid-19 infection, hospitalisation, intensive care admission, and Death: A global systematic review and meta-analysis of over 200 million study participants.eClinicalMedicine. 2023; 57101877https://doi.org/10.1016/j.eclinm.2023.101877Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 4Irizar P. Pan D. Taylor H. et al.Disproportionate infection, hospitalisation and death from covid-19 in ethnic minority groups and indigenous peoples: An application of the Priority Public Health Conditions Analytical Framework.eClinicalMedicine. 2024; 68102360https://doi.org/10.1016/j.eclinm.2023.102360Abstract Full Text Full Text PDF Scopus (0) Google Scholar A previous review of UK COVID-19 randomised controlled trials conducted up to May 2022 found no trials screened for inclusion reporting effectiveness data by ethnicity.5Murali M. Gumber L. Jethwa H. et al.Ethnic minority representation in UK covid-19 trials: Systematic Review and meta-analysis.BMC Medicine. 2023; 21https://doi.org/10.1186/s12916-023-02809-7Crossref Scopus (12) Google Scholar A recent review of UK COVID-19 vaccine trials found that Black adults and other racial or ethnic minorities were underrepresented, highlighting the importance of considering the inclusion these groups from trial inception.6Herieka H. Babalis D. Tzala E. Budhathoki S. Johnson N.A. How inclusive were UK-based randomised controlled trials of COVID-19 vaccines? A systematic review investigating enrolment of Black adults and adult ethnic minorities.Trials. 2024; 25: 255https://doi.org/10.1186/s13063-024-08054-4Crossref Scopus (0) Google Scholar We searched ClinicalTrials.gov for clinical trials relating to either COVID-19 or post-acute COVID-19 syndrome (PASC). A total of 8,940 trials were registered between 1st December 2019 and 20th April 2023 when we searched for 'COVID-19'. Trials with fewer than 200 participants were excluded as preliminary data showed these trials were too small to determine whether racial or ethnic minorities were adequately represented. Ten investigators reviewed the studies, screened titles for inclusion and extracted data from the trial registries. We examined study documents attached to the 'Study Details' section of the trial registry to determine whether trials intended to (1) report demographic data on race or ethnicity, (2) consider the effect of race or ethnicity on clinical outcomes and (3) recruit participants from racial or ethnic minority groups in proportions representative of their population. If trial results were published on the 'Results Posted' section of the trial registry, we recorded (1) race or ethnicity demographic data and (2) clinical outcomes by race or ethnicity. Race and ethnicity are not equivalent nor concordant and there are complexities around how they are defined in research. As per ClinicalTrials.gov, we referred to race as 'Black, Asian and White' and ethnicity as 'Hispanic' or 'Non-Hispanic'. A total of 1,289 trials including 9,927,605 participants were reviewed; 1,230 (95%) trials studied COVID-19 and 59 (5%) studied PASC across 83 countries. 204 (16%) trials were multinational and 213 (17%) trials were conducted in the USA. Around a third (n=407, 32%) of registered trials had been published in peer reviewed journals. A total of 157 (12%) clinical trials had documents attached to the 'Study Details' section of the trial registry (Fig. 1a). Of these, 109 (69%) mentioned intention to collect data on race or ethnicity and 58 (37%) intended to consider the effect of race or ethnicity on clinical outcomes. Three studies mentioned recruiting those from racial or ethnic minority groups in proportions representative of their population, with detailed descriptions provided in Supplementary 1. Supplementary 2 shows the racial and ethnic breakdowns of all recruited participants and Supplementary 3 shows the breakdowns from trials conducted in the USA in relation to the proportion of that racial group in the US population based on 2022 census data population estimates, for trials that provided results.7United States Census Bureau . U.S Bureau QuickFacts: United States. U.S. Department of Commerce; n.d. [Accessed 04 Sept 2023]. Available from: https://www.census.gov/quickfacts/fact/table/US/PST045222Google Scholar Although the absolute number of participants recruited from different racial or ethnic minority groups were small (only around 1% of all participants had race or ethnicity recorded), the proportions were roughly representative of the different groups in the US. Fig. 1b shows 117 (9%) trials reported clinical outcomes on the 'Results Posted' section of the trial registry. Three study protocols mentioned recruiting ethnic minority groups in proportions representative of their population, but these trials did not report clinical outcomes by race or ethnic group (Supplementary 1). Of all registered trials, 112 (96%) reported demographic data on race or ethnicity and four studies reported outcomes by race or ethnicity. The four studies that reported outcomes by race or ethnicity were part of the Adaptive COVID-19 Treatment Trials (ACTT) group (Table 1). We noted that in ACTT-1, Hispanic or Latinx participants did not have a significantly shorter time to recovery on Remdesivir compared to placebo; these results were published in both Clinicaltrials.gov and within the final published manuscript.8ClinicalTrials .gov. Adaptive COVID-19 Treatment Trial (ACTT). ClinicalTrials.gov ID: NCT04280705. National Library of Medicine; 2022 . Accessed 12 Feb 2024 https://clinicaltrials.gov/study/NCT04280705?cond=NCT04280705&rank=1&tab=resultsGoogle Scholar, 9Beigel J.H. Tomashek K.M. Dodd L.E. et al.Remdesivir for the treatment of covid-19 — final report.New England Journal of Medicine. 2020; 383: 1813-1826https://doi.org/10.1056/nejmoa2007764Crossref PubMed Scopus (0) Google Scholar In ACTT-2, 3 and 4, all participants received Remdesivir plus another immunomodulatory intervention. We noted that those of Asian ethnicity consistently had worse clinical outcomes in these three trials, although differences by ethnic group were not formally assessed statistically.10Kalil A.C. Patterson T.F. Mehta A.K. et al.Baricitinib Plus remdesivir for hospitalized adults with covid-19.New England Journal of Medicine. 2021; 384: 795-807https://doi.org/10.1056/nejmoa2031994Crossref PubMed Scopus (0) Google Scholar, 11Kalil A.C. Mehta A.K. Patterson T.F. et al.Efficacy of interferon beta-1a plus remdesivir compared with Remdesivir alone in hospitalised adults with covid-19: A double-blind, randomised, placebo-controlled, phase 3 trial.The Lancet Respiratory Medicine. 2021; 9: 1365-1376https://doi.org/10.1016/s2213-2600(21)00384-2Abstract Full Text Full Text PDF PubMed Google Scholar, 12Wolfe C.R. Tomashek K.M. Patterson T.F. et al.Baricitinib versus dexamethasone for adults hospitalised with covid-19 (ACTT-4): A randomised, double-blind, double placebo-controlled trial.The Lancet Respiratory Medicine. 2022; 10: 888-899https://doi.org/10.1016/s2213-2600(22)00088-1Abstract Full Text Full Text PDF Google Scholar This could suggest that those from Asian ethnic groups have differing immune responses to COVID-19 compared to other groups.Table 1Clinical trials that presented outcomes by ethnicity on ClinicalTrials.gov (ACCT-1, 2, 3 and 4).ACCT-1Time to recovery by Race (days)PlaceboRemdesivirAsian12 (9-15)11 (9-15)Black/African-American15 (10-21)10 (7-16)White15 (12-19)9 (8-12)Other24 (15-N/A)9 (6-14)Time to recovery by Ethnicity (days)Not Hispanic/Latinx15 (13-18)*10 (8-12)*Hispanic/Latinx12.5 (9-22)10.0 (7-14)ACTT-2Time to recovery by RaceRemdesevir plus placeboRemdesevir plus BarcitinibAsian10 (9-13)10 (7-13)Black/African-American6 (5-8)7 (5-8)White7 (6-9)7 (5-8)Other8 (6-11)7 (6-8)Time to recovery by EthnicityNot Hispanic/Latinx9 (7-10)7 (6-8)Hispanic/Latinx7 (6-9)7 (6-8)ACCT-3Time to recovery by Race (days)Remdesivir plus placeboRemdesivir plus interferon beta-1aAsian8 (6-12)8 (6-9)Black/African-American4 (4-5)4 (4-5)White5 (4-5)4 (4-5)Other5 (4-6)6 (5-7)Time to recovery by Ethnicity (days)Not Hispanic/Latinx5 (4-5)5 (4-5)Hispanic/Latinx5 (N/A)6 (5-7)ACCT-4Proportion of participants not meeting criteria for death, hospitalisation, on invasive mechanical ventilation or ECMO within 30 days by Race (days)Remdesivir plus BaricitinibRemdesivir plus DexamethasoneAsian0.76 (0.58-0.87)0.88 (0.71-0.95)Black/African-American0.91 (0.83-0.96)0.86 (0.77-0.92)White0.87 (0.82-0.90)0.88 (0.83-0.91)Other0.87 (0.78-0.93)0.89 (0.80-0.94)Proportion of participants not meeting criteria for death, hospitalisation, on invasive mechanical ventilation or ECMO within 30 days by Ethnicity (days)Not Hispanic/Latinx0.87 (0.82-0.90)0.87 (0.83-0.91)Hispanic/Latinx0.88 (0.82-0.92)0.87 (0.81-0.92)Significant differences are highlighted by *. Open table in a new tab Significant differences are highlighted by *. Our study has some limitations. We conducted the searches only on the ClinicalTrials.gov database and many trials had not updated their registry with results. Nevertheless, updating the registry is best practice. In summary, we found that only a small proportion of clinical trials conducted globally for COVID-19 and PASC considered race or ethnicity either within their study design or the publication of results. By April 2023, after the height of the COVID-19 pandemic, only four trials (0.3% of all registered clinical trials on Clinicaltrials.gov and 3% of trials reporting outcomes) reported outcomes by race or ethnicity, which is unacceptable given the well documented disparities in clinical outcomes for COVID-19.2Sze S. Pan D. Nevill C.R. et al.Ethnicity and clinical outcomes in COVID-19: A systematic review and meta-analysis.EClinicalMedicine. 2020; 29-30100630https://doi.org/10.1016/j.eclinm.2020.100630Abstract Full Text Full Text PDF Scopus (438) Google Scholar, 3Irizar P. Pan D. Kapadia D. et al.Ethnic inequalities in covid-19 infection, hospitalisation, intensive care admission, and Death: A global systematic review and meta-analysis of over 200 million study participants.eClinicalMedicine. 2023; 57101877https://doi.org/10.1016/j.eclinm.2023.101877Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 4Irizar P. Pan D. Taylor H. et al.Disproportionate infection, hospitalisation and death from covid-19 in ethnic minority groups and indigenous peoples: An application of the Priority Public Health Conditions Analytical Framework.eClinicalMedicine. 2024; 68102360https://doi.org/10.1016/j.eclinm.2023.102360Abstract Full Text Full Text PDF Scopus (0) Google Scholar Furthermore, these trials were all on acute COVID-19 (not on SARS-CoV-2 prophylaxis, nor PASC), with significant differences found for Remdesivir treatment between Hispanic/Latinx groups and non-Hispanic/Latinx groups, and potential differences in overall outcomes between Asian and other minority groups relating to immune responses to treatment. We recommend prospective clinical trials on COVID-19 to include different racial and ethnic groups in a systematic manner from study inception to publication. Additionally, journals should strongly recommend clinical trials to report data by race and ethnicity where relevant. The authors declare no conflicts of interest. Download .docx (.02 MB) Help with docx files Supplementary material