As the scientific community races to establish treatment regimens for COVID-19, clinical trials have been thrust into the spotlight as clinicians and policymakers alike seek data to inform their decisions. The ability to interpret clinical trial data and expedite new clinical trials will be critical in obtaining and leveraging key insights on how to manage this pandemic.
Hydroxychloroquine has garnered much attention in this regard. It is currently approved in the United States for the treatment of malaria, lupus, and rheumatoid arthritis. While preclinical data suggest that hydroxychloroquine is an inhibitor of COVID-19 within in vitro cell lines1, the clinical data supporting its use as an antiviral treatment for COVID-19 remain limited.
In one highly cited clinical study, 26 confirmed COVID-19 patients in France received hydroxychloroquine 600 mg daily, with 6 of these patients also receiving azithromycin.2 This study has gained attention because the 6 patients who received combination treatment tested negative for COVID-19 after 6 days. However, due to a number of confounding factors in the study design and results, these data should be interpreted cautiously:
- This was not a randomized clinical trial (RCT), the gold standard for study design to detect treatment effects. Assigning treatment to patients “depending on their clinical presentation” introduces bias in patient selection and treatment selection.
- The sample size is small, and results are reported for only 20 of the 26 patients who received hydroxychloroquine. Of these 6 patients with no reported data, 3 were transferred to the ICU (presumably, for clinical decompensation), 1 died, 1 decided to leave the hospital, and 1 stopped treatment due to adverse effects.
Given the small sample size and confounding factors of this study and lack of any other confirmatory RCT data, the CDC and numerous other professional organizations have not formally recommended the widespread use of hydroxychloroquine outside of clinical trials3,4,5. Further study is especially warranted due to significant potential safety risks: in a randomized, double-blind, Phase IIb study of low dose vs. high dose chloroquine (a structurally similar compound to hydroxychloroquine) in Brazilian COVID-19 patients, the high dose arm had to be stopped due to higher rates of QTc prolongation and death compared to the low dose arm.6 While physicians around the world are understandably using hydroxychloroquine in the absence of other effective COVID-19 treatment options, it is still important to remember that the available study data have not definitively established hydroxychloroquine as a frontline treatment option.
Large-scale clinical trials are needed to validate the safety and efficacy of hydroxychloroquine for COVID-19 treatment. Per clinicaltrials.gov, more than 50 hydroxychloroquine clinical trials have already been initiated, presumably with many more to follow in the coming months. The speed with which these trials have been initiated is unprecedented and may conceivably set a new standard for the conduct of clinical trials moving forward.
Expediting the pace of COVID-19 research will require researchers and regulatory bodies alike to construct flexible, creative research paradigms. For example, researchers should consider adaptive (Bayesian) study designs for their RCTs, which will enable therapies to be introduced or removed within a study while still maintaining adequate statistical power. Novel clinical trial technologies such as telemedicine and geofencing can be utilized to facilitate adaptive study design and rapid data collection. The FDA has also created the Coronavirus Treatment Acceleration Program (CTAP) to expedite the review and approval of COVID-19 treatments; such regulatory frameworks dedicated to COVID-19 will be critical in establishing new treatments.
The promise of safe and effective COVID-19 treatment lies in clinical trials. Being able to appropriately interpret and apply these data will be critical in bringing this pandemic under control.
- Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis(2020 Mar 9). doi: https://doi.org/10.1093/cid/ciaa237. [Epub ahead of print]
- Gautret P, Lagier J-C, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Intl J Antimicrob Agents (2020 March 20). doi: https://doi.org/10.1016/j.ijantimicag.2020.105949. [Epub ahead of print]
- Centers for Disease Control and Prevention. Information for Clinicians on Therapeutic Options for Patients with COVID-19. Available from: https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html. Accessed 13 April 2020.
- Bhimraj A, Morgan RL, Shumaker AH, Lavergne V, Baden L, Cheng VC, et al. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19 Infection. Available from: https://www.idsociety.org/COVID19guidelines. Accessed 13 April 2020.
- American Medical Association, American Pharmacists Association, and American Society of Health-System Pharmacists. Joint statement on ordering, prescribing, or dispensing COVID-19 medications. Available from: https://www.ama-assn.org/delivering-care/public-health/joint-statement-ordering-prescribing-or-dispensing-covid-19. Accessed 13 April 2020.
- Silva Borba, M.G.; Almeida Val, F.F.; Sampaio, V.S. et al.Chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (SARS-CoV-2) infection: Preliminary safety results of a randomized, double-blinded, phase IIb clinical trial (CloroCovid-19 Study). MedRxiv website. Published April 12,2020. https://www.medrxiv.org/content/10.1101/2020.04.07.20056424v1.full.pdf. Accessed 14 April 2020.