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).
<< Table 1 >>
<< Table 2 >>
<< Table 3 >>
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).
<<Table 4>>
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.
<< Figure 2 >>
<< Figure 3 >>