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

The only strategies that worked so far in COVID-19 to mitigate transmission are rapid identification of cases, isolation, contact tracing, and self-quarantine of those exposed. To date, no medication has been shown to prevent SARS-CoV-2 transmission.

This trial hypothesized that hydroxychloroquine could potentially be used as postexposure prophylaxis, to prevent symptomatic infection after exposure to Covid-19.

Setting

The study was conducted in Canada and the US.

Methods

Multicentre Randomised controlled trial.

Inclusion Criteria – 

1. subjects who were within 3 days of known high-risk exposure (as self-reported) pending formal testing. ( Later, it was changed to within 4 days of exposure, and only in those with laboratory-confirmed Covid-19.
2. subjects who were exposed to a person with confirmed Covid-19 at a distance of fewer than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure). The exposure could be household or occupational.

Exclusion Criteria :

1. younger than 18 years of age, were hospitalized
2.  Subjects with symptoms of Covid-19 or with PCR-proven SARS-CoV-2 infection were also excluded.
3. On hydroxychloroquine or chloroquine at the time of exposure
4. On cardiac medication: flecainide, amiodarone, digoxin, procainamide, sotalol
5. On medication with potential for QT prolongation
6. Known allergy to hydroxychloroquine
7. Retinal disease
8. G-6PD deficiency
9. ESRD on dialysis
10. Porphyria
11. Less than 40kg bodyweight
12. On chemotherapy
13. Pregnant or breastfeeding
14. Severe diarrhea or vomiting
15. Cirrhosis with ascites or encephalopathy
16. Baseline QT prolongation
17. Ventricular arrhythmia or history of sudden cardiac death
18. QT-prolonging medicines

Setting

Participants were self-enrolled through a secure Internet-based survey using the REDCAP system. Follow-up by email survey on days 1, 5, 10, and 14. A later survey was carried out 4–6 weeks to assess illness, hospitalization, and follow-up testing. The study subject was contacted first; if this was not possible, the emergency contact was contacted for follow-up information.

Intervention: The initial dose of hydroxychloroquine:

800 mg (4 tablets) once

600 mg (3 tablets) 6 to 8 hours later

600 mg (3 tablets) daily for 4 more days for a total course of 5 days. This dose was calculated based on the in vitro half-maximal effective concentration of HCQ against SARS-CoV-2 (the plasma concentration was targeted to be above this level).

Control: Placebo folate tablets, which were similar in appearance to the hydroxychloroquine tablets, prescribed as an identical regimen.

Sample size:

A 10% possibility of acquiring infection was assumed. The sample size was calculated based on a 50% relative effect size to reduce new symptomatic infections. For a two-sided alpha of 0.05, and 90% power, 621 persons were required in each group. Allowing for 20% attrition, 750 were planned to be included in each group.

The study was stopped for futility at the 3^rd interim analysis after enrollment of 821 patients (HCQ: 414 participants vs. placebo: 407 participants).

Overall, Overall, new Covid-19 infection (either PCR-confirmed or symptomatically compatible) occurred in 107 of 821 participants (13.0%) during the 14 days of follow-up. Of all study subjects, 66.4% were HCWs (545 of 821). This included physicians or physician assistants (62.8%) and nurses or nursing assistants (23.5%).

Primary outcome

symptomatic illness confirmed by a positive molecular assay or, if testing was unavailable,

Covid-19– related symptoms –  included probable cases (presence of cough, shortness of breath, or difficulty breathing, or the presence of two or more symptoms of fever, chills, rigors, myalgia, headache, sore throat, and new olfactory and taste disorders), and possible cases (the presence of one or more compatible symptoms, which could include diarrhea)

Access to testing was limited. Four ID physicians arbitrated on whether the subjects met the criteria for COVID-19 diagnosis.

46 subjects in the hydroxychloroquine group and 42 in the placebo group did not complete the day 14 survey.

The vital status was unknown for 36 in the hydroxychloroquine group and 33 in the control group.

No difference in sensitivity analysis either including or excluding them from the final analysis.

The primary outcome occurred in 49 of 414(11.8%) patients in the HCQ groups vs. 58 of 407 (14.3%) in the placebo group (P=0.35).

Secondary outcomes

1. The incidence of hospitalization for Covid-19: There were only 2 hospitalizations, one in each group

2. Death: No death occurred in either group

113 subjects developed symptomatic illness; 4 remained asymptomatic during the 14-day follow-up period.

Of the 113 subjects who developed symptomatic illness:

16 subjects had PCR-confirmed disease. (4 were asymptomatic positive; out of this, 3 developed symptoms after the 14-d follow-up period)

74 subjects developed probable illness (Covid-19 according to the U.S. case definition)

13 subjects experienced possible illness (compatible symptoms and epidemiologic linkage)

10: adjudicated as not having Covid-19

Adherence: 75.4% of participants with hydroxychloroquine group (312 of 414) and 82.6% with the placebo group (336 of 407) (P=0.01) adhered to the protocol

Adverse events

Adverse events were observed in 17 participants in the hydroxychloroquine group vs. 8 in the placebo group. Nausea, loose stools, and abdominal discomfort were the most common side effects.

There were no serious intervention-related adverse reactions or cardiac arrhythmias.

Limitations – 

• Not sure how authors came up with the dose
• Formal testing was very low; laboratory-confirmed diagnosis only in 20/821 patients (2.4%). Others were diagnosed based on clinically compatible symptoms
• Adherence significantly lower with HCQ
• 57% of participants did not take the intervention until 3-4 days after exposure
• No report on QTc prolongation
• Majority of participants were young and without any co-morbidities.
• Did not evaluate the role of HCQ in pre-exposure prophylaxis.

Summary – 

Welcome trial as it tried to address the right question.

Limitations of the trial make it difficult to draw any conclusions just based on this trial. This trial is considered more provocative than definitive.

However, most of the countries have already stopped using HCQ for Post-exposure prophylaxis.