Hydroxychloroquine or Chloroquine for treating COVID-19 – a PROTOCOL for a systematic review of IPD

April 14, 2020


Hydroxychloroquine or Chloroquine for treating Coronavirus Disease 2019 (COVID-19) – a PROTOCOL for a systematic review of IPD

Fontes LE, Riera R, Miranda E, Oke J, Heneghan CJ, Aronson JK, Pacheco RL, Martimbianco ALC, Nunan D

On behalf of the Oxford COVID-19 Evidence Service Team
Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences
University of Oxford

Correspondence to luis.fontes@ceo2.com.br

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Urgent research is needed to test potential therapeutic agents against COVID-19. Several studies are evaluating the benefit and harm profiles of different pharmacological interventions such as antimalarial drugs, antiviral drugs, biologics, and interferon. The number of trial registrations for hydroxychloroquine/cholorquine as a COVID-19 therapeutic rises each day and on April 5th 2020 we found three published trials and 100 ongoing studies.  A first published report from Gautret et al. (1) suggested a positive effect of hydroxychloroquine (plus azithromycin, an antibiotic, in some cases) on the disappearance of COVID-19, attracting intense media coverage worldwide. Another two publications have since shown equivocal findings (2,3). All the trials have serious methodological limitations and do not permit recommendations on the use of hydroxychloroquine/cholorquine in COVID-19. Known serious adverse effects associated with hydroxychloroquine/cholorquine administration also need to be considered.

OBJECTIVE: To assess the benefits and harms of chloroquine or hydroxychloroquine for the treatment of COVID-19 infection.

METHODS: A systematic review of Individual Participant Data (IPD). Inclusion criteria: randomized controlled trials assessing hydroxychloroquine/ chloroquine (alone or combined) for treating adults ( ≥16 years), either critically ill or not, with confirmed COVID-19. Comparison groups include placebo, standard care, antiviral drugs, other antimalarial drugs,  or biologics. The primary outcomes are COVID-19 mortality, pneumonia / acute respiratory distress syndrome, and adverse events. Secondary outcomes include all-cause mortality, hospitalization, admission to the intensive care unit, time to clinical improvement, and time to virus clearance. We shall include published and unpublished RCTs, irrespective of year, status, or the language of publication through a comprehensive search of electronic databases. IPD shall be retrieved by contacting primary investigators of included trials and searching data-sharing repositories or platforms. Certainty of evidence will be assessed using the GRADE approach, with the minimal important difference for the primary outcomes set as a 5% relative risk reduction (RRR). The estimates will be presented as risk ratios, mean differences (or standardized mean differences), or hazard ratios, with 95% confidence intervals, using intention-to-treat analysis.

Considering the likelihood of clinical or methodological heterogeneity, we shall use a random-effects model in a one-stage approach. We shall assess clinical/ methodological heterogeneity, using the chi² test to detect and the I² statistic to measure statistical heterogeneity. If we identify substantial (>50%) statistical heterogeneity, we shall explore it by prespecified subgroup analyses. If we can pool ten or more trials, we shall create funnel plots to explore possible publication biases.


  1. Gautret P, Lagier JC, Parola P, Hoang VT, Medded l, Mailhe M, et al. Hydroxychloroquine and Azithromycin as a treatment of COVID-19: preliminary results of an open-label non-randomized clinical trial. medRxiv [Internet]. 2020 Jan 1;2020.03.16.20037135. Available from: http://medrxiv.org/content/early/2020/03/20/2020.03.16.20037135.abstract
  2. Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv [Internet]. 2020 Jan 1;2020.03.22.20040758. Available from: http://medrxiv.org/content/early/2020/03/31/2020.03.22.20040758.abstract
  3. Chen JLL,Liu P, Xu Q, Xia L, Ling Y, Huang D, Song S, Zhang D, Qian Z, Li T,Shen Y, Lu H L. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19) [Internet]. Vol. 49, Journal of Zhejiang University (Medical Science). p. 0. Available from: http://www.zjujournals.com/med