A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19

Therapeutic InfectiologyPulmonologyTransversalVirology
Boulware DR et al

Main result

  •   Inclusion of 821 randomized asymptomatic subjects in the hydroxychloroquine group (414 subjects) or placebo (407 subjects) with an average age of 40 years with 51.6% women and 27.4% co-morbidities. Two thirds of the subjects included were healthcare professionals (66.4%), a majority of whom were physicians. Exposure of healthcare professionals was mostly due to patients, while for those exposed at home, spouses were the main culprits. 87.6% of the subjects were not wearing personal protective equipment at the time of exposure and 60% never wore it.
  •     Of the total sample, 13% of the subjects developed the disease on day 14. There was no significant difference in the incidence of the disease between the groups: 11.8% for the hydroxychloroquine group versus 14.3% for the placebo group (p=0.35).
  •     Hospitalization in each group occurred and no arrhythmias or deaths were found. 11% of subjects were lost to follow-up but sensitivity analyses on these missing data did not alter the results.
  •     Significant difference in treatment compliance between groups: 75.4% for the hydroxychloroquine group and 82.6% for the placebo group (p=0.01). Treatment discontinuation was mainly due to adverse effects, mainly digestive, much more frequent in the hydroxychloroquine group: 40% vs 17% (p<0.001).
  •     Among the participants, there was no significant difference between the groups on the recognition of the treatment and thus on the risk of unblinding except for those who had no adverse effects at D5 who were mostly convinced that they had hydroxychloroquine: 68.2% vs 18.7% (p<0.001).



  •     Preventive treatment (prophylaxis) with hydroxychloroquine in subjects exposed to SARS-CoV-2 did not show a higher efficiency compared to placebo on the appearance of the disease on day 14: non-significant decrease of 2.4% in the incidence of the disease by hydroxychloroquine (11.8% vs 14.3% of COVID-19 infections).
  •     Adverse events were significantly more frequent in subjects treated with hydroxychloroquine (40% vs. 17%), although no serious adverse events, particularly cardiac, were reported.
  •     For example, treatment with hydroxychloroquine has not shown any prophylactic benefit at this time.

Strength of evidence Strong

This randomized, double-blind, controlled clinical trial is quite well conducted and remains one of the most robust trials currently available on this treatment. Its pragmatic recruitment approaches real-life effect. Nevertheless, some bias remains:
- Changing inclusion criteria during the trial introducing heterogeneity into the sample...
- Risk of recall bias and classification bias due to the chosen data collection methodology (remote self-questionnaire) and the possibility of death not being found
- The diagnosis of COVID-19 (primary endpoint) may be based solely on the patient's clinical symptomatology collected by questionnaire (no PCR test is required). The criteria defined are rather robust and in the absence of virological confirmation, patients are classified as "probable cases", but there is still a risk of classification bias.
- Follow-up of subjects may not be long enough (measured at D14), with some patients developing symptoms after 3 weeks and not considering asymptomatic cases representing a non-negligible proportion of COVID-19 infections.
- Robust statistical analysis design, including interim analyses, but use of a non-parametric test when a parametric test could certainly have been performed
- Rather female sample of young and healthy patients, not representative of the entire population infected with SARS-CoV-2: decrease in healthy worker possible (majority of healthcare professionals)
- Different patient adherence between groups with lower compliance in subjects taking hydroxychloroquine but caused by adverse treatment effects


Evaluate the efficacy of hydroxychloroquine compared to placebo in preventing the development of COVID-19 disease after exposure (prophylactic intake)


  •     Randomized, placebo-controlled, double-blind, multicentre, binational (North American) trial
  •     Eligibility criteria: exposure to SARS-CoV-2 within the previous 3 days (treatment objective during the incubation period) for subjects with occupational (caregiver) or domestic exposure, then inclusion of subjects exposed within 4 days to a patient with SARS-CoV-2 positive PCR. Exposure was defined as the presence of an infected person for 10 minutes within a radius of 1.80 m without personal protective equipment. Symptomatic or hospitalized subjects were excluded from this preventive trial.
  •     Data collection: Recruitment of participants via social networks and the media, then remote monitoring of subjects (by e-mail) at D1, D5, D10 and D14. Finally, a survey was conducted at the 4th and 6th week for data collection with several follow-up methods implemented. If failure, verification of the patient's vital status.
  •     Intervention: 1:1 randomization by permuted blocks stratified on the country and sequential assignment for each treatment participant, either placebo or hydroxychloroquine sulfate at a dose of 800 mg for the first dose, then 600 mg 6 to 8 hours later, then 600 mg/day for 4 days, i.e. a total treatment over 5 days (19 tablets). The dosage was chosen to allow a maximum plasma concentration at D14. This dosage was halved in case of prior gastrointestinal disorders. Collection of adverse reactions during these questionnaires.
  •     Primary endpoint = symptomatic COVID-19 disease confirmed by PCR at D14, otherwise "probable cases" on the basis of the clinic following the nationally defined criteria (presence of cough, dyspnea, fever, chills, myalgia, headache, pharyngitis, olfactory or taste disorders) or "possible case" if fewer symptoms are present.
  •     Secondary endpoints (at D14): incidence of hospitalization for confirmed COVID-19 infection, the incidence of COVID-19 symptoms, the incidence of discontinuation, and severity of symptoms at D5 and D14.
  •     Statistics :
  •         Staffing calculation based on the reasonable assumption of 10% post-exposure infection, 90% power and 20% lost to follow-up for a total of 750 subjects.
  •         Intermediate safety analyses planned for 25% and 50% of recruitment by the independent monitoring committee using the Lan-DeMets alpha risk expenditure method + power analysis for futility. Reduction of the sample size to 956 subjects at the second intermediate analysis because power greater than 90%.
  •         Statistical analysis: use of a Fisher test for judging criteria and analysis in intention to treat. Sensitivity analysis to take into account missing data as an event or not. Planned subgroup analyses according to health professional status or not, according to time after exposure, age and gender

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