Results
Among 927 clinical trial registers recorded on the WHO-ICTRP database, 72 registers were identified as RCTs investigating the use of HQ or chloroquine for COVID-19 infection and considered potentially eligible to this study (Figure 1). Among these 72 registered trials, two were identified as duplicated entries of the same trial registered in more than one clinical trial register, seven trials have been cancelled, and 12 were trials testing prophylaxis treatments. Therefore, 51 clinical trial registers were included for analysis.
Table 1 summarizes the characteristics of the clinical trials planned to investigate the use of HQ or chloroquine to treat patients diagnosed with COVID-19. The proposal of RCTs to test the hypothesis of whether these drugs could be beneficial for people with COVID-19 started in February 2020 when 12 trials were registered. In the following month of March, the number of trials registered tripled. All trials planned to include adults of both sexes, and three trials (6%) also planned to include adolescents. A total of 27 registered RCTs (53%) were not yet actively recruiting patients.
The proposed dosing schedule and treatment duration varied among the trials. Seventeen trials reported at least one arm with a fixed dosing administration schedule of HQ or chloroquine ranging from a daily amount of 200 to 1,200 mg (Table 2). One trial planned to administer one single dose of HQ (200 mg) in combination with other drugs. Considering the dosing schedule of all treatment arms of either HQ or chloroquine, maximum treatment duration described ranged from seven days to 14 days. Twenty trials reported at least one arm with a variable dosing administration schedule of HQ or chloroquine (Table 3). Considering all treatment arms with a variable dosing schedule, treatment duration varied from 5 to 16 days. Fourteen registered trials did not report information on the treatment duration. One trial (2%) reported plans to monitor adherence and two trials (4%) reported funding support from sources with potential commercial interest (data not shown).
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Forty-five of the RCTs (90%) were planned to be conducted in one single country (Supplement, Table S1) with a mean sample size of 262 (IQR: 100, 520). Among the trials planned to be implemented in one single country, China was the main location (16; 32%) followed by the United States (5; 10%). Five (10%) of the registered RCTs were designed to be conducted in multiple countries; one trial register did not provide information on the location where the RCT was planned to be implemented. Overall, the proposed clinical trials anticipate recruiting a total of 37,303 participants, among outpatients and inpatients, to be randomized to receive a variety of experimental and comparison treatments with HQ, chloroquine or other agents in diverse combinations and dose schedules (Supplement, Table S2). Only fourteen (27%) of the trial registers reported the number of patients being recruited to the treatment and comparison arms; among these trials, a total of 1,138 patients would receive HQ or chloroquine alone or in combination with other drugs (data not shown).
Table 4 summarizes the type of outcomes described in the registry of the RCTs and the related assessment timeframe. One-third of the clinical trials included in their registered information a surrogate outcome to be measured as a primary endpoint; the remaining trials (34; 67%) described plans to assess one clinical outcome as a primary endpoint. The timeframe of outcome assessment varied substantially among the designs of the RCTs. Trials planning to measure only clinical efficacy/effectiveness outcomes described timeframes of assessment ranging from 5 to 120 days (median 15; IQR: 15, 28). Trials planning to measure only surrogate outcomes defined timeframes of assessment ranging from 3 to 56 days (median 15; IQR: 15, 28). The RCTs planning to evaluate a clinical outcome described longer timeframes for outcome assessment in comparison with trials planning to assess a surrogate outcome (MD 6.3; 95% CI: -10.51 to 23.12; P = 0.45). Among all 51 registered RCTs describing at least one clinical or surrogate efficacy/effectiveness outcome, 13 (26%) did not report a timeframe for outcome assessment.
Twenty-four (47%) of the registered RCTs did not describe plans to assess a single safety outcome. Among the trials including a description of at least one safety outcome (n=28), most (25; 89%) did not report the method to be implemented for the detection of adverse events. The timeframe for the assessment of safety outcomes was not defined in 13 (46%) of the trials reporting plans to measure at least one safety outcome. The timeframe for the assessment of the safety outcomes ranged from 7 to 120 days (median 28; IQR: 14, 30). The timeframe of safety outcome assessment was planned to be longer in comparison with the assessment of clinical outcomes (MD -9.8; 95% CI: -26.08 to 6.56; P = 0.23).
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Figure 2 describes the domains of the outcomes defined in the RCTs assessing the efficacy/effectiveness of HQ or chloroquine in the treatment of patients diagnosed with COVID-19. Twenty different clinical outcomes were described among trials with at least one clinical efficacy/effectiveness outcome defined in the trial registration. Clinical status/recovery and all-cause mortality/mortality accounted for 49% of the unique clinical outcome domains proposed to assess the efficacy/effectiveness of HQ or chloroquine treatment on patients diagnosed with COVID-19. Twenty-one different surrogate outcomes were identified in the registered RCTs planning to measure at least one surrogate outcome, with viral load and virologic clearance accounting for 36% of the surrogate outcomes identified.
Figure 3 summarizes the domains of the safety outcomes described to detect the potential harms of the treatment with hydroxychloroquine or chloroquine. The generic terminologies total, severe and serious adverse events accounted for 68% of the unique domains reported in at least two trial registers. Twenty-three different domains were reported by only one the registers of the clinical trials where the assessment of at least one safety outcome was identified.
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