COVID-19 Clinical Trials Report Card: Chloroquine and Hydroxychloroquine

May 11, 2020

Nicholas J. DeVito, Michael Liu, Jeffrey K Aronson

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

Chloroquine and hydroxychloroquine (CQ/HCQ) are antimalarial medications and are also used in the treatment of lupus erythematosus  and rheumatoid arthritis. Both have been prominently touted as prospective candidates for the treatment and/or prevention of infection by SARS-Cov-2. This has led to an explosion of research into these treatments. 

Here we assess the trial designs specified in national and international registry entries of CQ/HCQ trials.

What we did

We downloaded the ICTRP COVID-19 database on 29 April 2020 and applied our data cleaning and extraction code for Known cross-registrations are removed to avoid double-counting and fields are normalized to common terms (e.g. Phase II becomes Phase 2). For all current, planned, or completed studies in the final dataset (n=1760) we extracted all interventions explicitly mentioned in the relevant registry fields. For this report card, we included every trial that mentioned CQ/HCQ as an intervention, and extracted key trial characteristics (blinding, randomization, study type, control type) and the purpose of the trial (treatment, pre-exposure prophylaxis (PREP), or post-exposure prophylaxis (PEP)) from the registry entry. We further examined the registry entry for each study to determine if CQ/HCQ was the focus of the study, or if it was being used as a control, in combination with the active therapy of interest, or for other purposes.

Chloroquine and Hydroxychloroquine Trials

Chloroquine and/or hydroxychloroquine were mentioned in 218 studies. This represented 12% of all unique studies of COVID-19 in the ICTRP dataset. Of those, 158 (72%) were examining CQ/HCQ as active investigational treatments. The 60 trials in which either CQ or HCQ was being used as a control probably understates the true number, as many trials that plan to control with a “standard of care” are probably using CQ/HCQ. For example, in Iran it appears that use of hydroxychloroquine and lopinavir/ritonavir as a “standard of care” is widespread, even if not explicitly mentioned in the registration. Of the 159 trials focused on these therapies, 133 (84%) included hydroxychloroquine and 41 (26%) included chloroquine; 16 (10%) included both therapies either as separate arms or in a single arm in which either drug could be given.

Over 130,000 patients are planned for enrolment in studies assessing CQ/HCQ globally. While these drugs are primarily seen as a treatment option, there is also considerable interest in the prophylactic use of hydroxychloroquine. Randomization was nearly universal, the main exceptions being trials whose control arms include those who did not consent to receive treatment. However, under half (41%) of all CQ/HCQ trials reported any kind of blinding. The way studies are controlled varies considerably. While placebo designs were the most common, they only accounted for roughly a third (35%) of all trials. Active controls (11%), variably specified “standard of care” controls (25%), and single arm uncontrolled studies (13%) were also common. Just 52 trials (33%) meet the highest design standard (randomized, masked, and placebo controlled). Details of trials that contained only HCQ, only CQ, and both treatments are listed in Table 1. Figure 1 shows the trend in new and cumulative registration of trials that include CQ/HCQ in any capacity. The locations provided for CQ/HCQ-focused and all CQ/HCQ trials are listed in Table 2.

We plan on continuing to track the proliferation of trials involving chloroquine and hydroxychloroquine in research related to the COVID-19 pandemic and shall potentially explore other characteristics of these trials including outcomes (specifically adverse events), dosage regimens, and study population.

Table 1: Characteristics of Registered Chloroquine and Hydroxychloroquine Studies

Only HCQ Only CQ HCQ and/or CQ Total
Total 117 25 16 158
Planned Enrolment 122,721 4,740 11,760 137,221
Study Type
Interventional* 116 (99%) 25 (100%) 16 (100%) 157 (99%)
Observational 1 (0.8%) 0 0 1 (0.6%)
Treatment 70 (60%) 25 (100%) 12 (75%) 107 (68%)
PREP 38 (32%) 0 3 (19%) 41 (26%)
PEP 12 (10%) 0 1 (6.3%) 13 (8%)
Randomized 117 (100%) 19 (76%) 16 (100%) 153 (97%)
Blinded 53 (45%) 6 (24%) 5 (31%) 64 (41%)
Control type
Placebo 45 (38%) 5 (20%) 5 (31%) 55 (35%)
Active 13 (11%) 2 (8%) 3 (19%) 18 (11%)
“Standard of care” 24 (21%) 8 (32%) 8 (50%) 40 (25%)
Inactive therapy 7 (6%) 1 (4%) 0 8 (5.1%)
Non-consented 6 (5.1%) 0 0 6 (3.8%)
No treatment 6 (5.1%) 1 (4%) 0 7 (4.4%)
Not specified 0 2 (8%) 0 2 (1.3%)
Uncontrolled 15 (13%) 5 (20%) 0 20 (13%)
Other*** 0 1 (4%) 0 1 (0.6%)

















*Trials identified as “Interventional” on the ICTRP may include a broad array of study designs including dose-finding studies (e.g. ACTRN12620000447954)
**Trials may have more than one purpose; percentages may therefore may exceed 100%
***One trial, NCT04353037, combined an active comparator and a placebo

Figure 1: 

Note: The most recent week will likely underrepresent the true number of trials as additional registrations will appear in subsequent ICTRP data updates.

Table 2: Locations of Registered Chloroquine and Hydroxychloroquine Studies

Country CQ/HCQ Focused All CQ/HCQ
Total Trials 158 218
United States 32 33
China 20 23
No Country Given 20 24
France 15 18
Spain 13 18
Brazil 10 11
Iran 8 39
Canada 7 8
Australia, Denmark, UK 5 5
Germany, India, South Africa 4 4
Mexico, Netherlands 3 4
Norway, Thailand 3 3
Columbia, Egypt 2 3
Greece, Ireland, New Zealand, Nigeria 2 2
Each of 24 other countries* 1 1






























*See Appendix Box 1 for complete list

Appendix Box 1: Countries with a Single CQ/HCQ Trial

Argentina, Austria, Belgium, Czech Republic, Ghana, Honduras, Hungary, Indonesia, Israel, Italy, Japan, Jordan, Kenya, Lebanon, Malaysia, Monaco, Pakistan, Peru, Philippines, Qatar, Saudi Arabia, Switzerland, Vietnam, Zambia

Note: This work has not been peer-reviewed and the data are preliminary. We hope to continue to improve, expand, and update the data on trials of these and other drugs in the near future.

Nicholas J. DeVito is a doctoral student in the Nuffield Department of Primary Care Health Sciences, University of Oxford. He studies transparency in biomedical research and runs as part of the DataLab and Centre for Evidence-Based Medicine.
COI: NJD receives a doctoral studentship from the Naji Foundation, grant support from the Fetzer Franklin Fund, and has been employed on grants from the Laura and John Arnold Foundation and the Good Thinking Society.

Michael Liu is a graduate student in the Oxford Department of Social Intervention and Policy. He studies the use, cost, and regulation of pharmaceuticals in the US and UK at the DataLab and Centre for Evidence-Based Medicine.
COI: ML receives funding from the Rhodes Trust. 

Jeffrey Aronson is a physician and clinical pharmacologist working in the Centre for Evidence-Based Medicine in the Nuffield Department of Primary Care Health Sciences, University of Oxford. He is an Associate Editor of BMJ EBM and a President Emeritus of the British Pharmacological Society.
COI: JKA has written papers on the subject of clinical trials and has written papers and edited textbooks on clinical pharmacology, pharmacovigilance, and adverse drug reactions.