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Assessing the efficacy and safety of hydroxychloroquine as outpatient treatment of COVID-19: a randomized controlled trial

Schwartz et al., CMAJ Open, doi:10.9778/cmajo.20210069

Jun 2021

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HCQ for COVID-19

1st treatment shown to reduce risk in March 2020

^*, now known with p < 0.00000000001 from 422 studies, recognized in 42 countries.

Lower risk for mortality, hospitalization, recovery, cases, and viral clearance.

No treatment is 100% effective. Protocols combine complementary and synergistic treatments. ^* >10% efficacy in meta analysis with ≥3 clinical studies.

4,100+ studies for 60+ treatments. c19hcq.org

Small early terminated late treatment RCT showing no significant differences. The HCQ group was a median of 7 days from symptom onset at baseline, which may not include the delay delivering the medication. From the 4 HCQ hospitalizations, only one is in the per-protocol analysis, and that patient was hospitalized one day after randomization (authors do not specify if the patient received and took any HCQ before the hospitalization). The trial was terminated early due to the fraudulent Lancet article (wording here is notably different between the submitted and published versions). Per-protocol analysis, the submitted version, and the peer-review comments (two reviewers, only one with substantial feedback) are in the supplementary material.

Long-term recovery results are reported in Ganesh. When a patient reported a symptom, they were asked whether they were still experiencing that symptom, and to choose between these three options when comparing the symptom to their pre-COVID-19 state: (1) “Yes, this problem remains the same”; (2) “Yes, but there’s been SOME improvement”; or (3) “No, this is back to normal”. The patient was classified as having “no improvement” at 1-year if they reported ≥1 symptom at both visits, for which they indicated that the problem remained the same at 1-year. Persistence refers to patients reporting ≥1 symptom that emerged post-COVID-19 and was still present at the time of assessment. For presence of symptoms, the patient reported ≥1 symptom that emerged with or after their COVID-19 infection at some point prior to the time of assessment.

1. Ganesh et al., Patient-reported outcomes of neurologic and neuropsychiatric symptoms in mild COVID-19: a prospective cohort study, CMAJ Open, doi:10.9778/cmajo.20220248.cmajopen.ca, doi.org.

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risk of ICU admission, 133.3% higher, RR 2.33, p = 1.00, treatment 1 of 111 (0.9%), control 0 of 37 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm).

risk of hospitalization, 533.3% higher, RR 6.33, p = 0.57, treatment 4 of 111 (3.6%), control 0 of 37 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm).

risk of ICU admission, 141.9% higher, RR 2.42, p = 1.00, treatment 1 of 74 (1.4%), control 0 of 31 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), per-protocol.

risk of hospitalization, 141.9% higher, RR 2.42, p = 1.00, treatment 1 of 74 (1.4%), control 0 of 31 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), per-protocol.

lack of improvement ≥1 year, 37.0% lower, OR 0.63, p = 0.15, treatment 90, control 89, day 365, RR approximated with OR.

persistence ≥1 year, 14.0% lower, OR 0.86, p = 0.16, treatment 90, control 89, day 365, RR approximated with OR.

presence of symptoms, 19.0% lower, OR 0.81, p = 0.37, treatment 90, control 89, RR approximated with OR.

ongoing symptoms, 27.8% higher, RR 1.28, p = 0.64, treatment 23 of 111 (20.7%), control 6 of 37 (16.2%), day 30.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

Schwartz et al., 18 Jun 2021, Double Blind Randomized Controlled Trial, Canada, peer-reviewed, 20 authors, study period April 2020 - September 2020, average treatment delay 7.0 days, dosage 800mg day 1, 400mg days 2-5.

This Paper HCQ All

Assessing the efficacy and safety of hydroxychloroquine as outpatient treatment of COVID-19: a randomized controlled trial

MD Ilan Schwartz, PhD Mari E Boesen, MSc Graziela Cerchiaro, PhD Craig Doram, MD Brett D Edwards, MD Aravind Ganesh, MPH Jamie Greenfield, Scott Jamieson, MD Vikram Karnik, Carol Kenney, MD Rachel Lim, MD Bijoy K Menon, MD Kwadwo Mponponsuo, MSc Sarah Rathwell, RN Karla J Ryckborst, RN Breanne Stewart, PhD Maryna Yaskina, MD Luanne Metz, MD Lawrence Richer, MD MSc Michael D Hill

CMAJ Open, doi:10.9778/cmajo.20210069

E ighteen years ago, the severe acute respiratory syndrome (SARS) experience 1-5 highlighted limited knowledge of early treatments for novel pandemic respiratory viruses. With the emergence of SARS-CoV-2, early experience in Wuhan, 6 the Lombardy region of Italy 7, 8 and New York City 9 demonstrated the need to suppress severe disease to prevent health system collapse. Hydroxychloroquine, derived from the centuries-old antimalarial medicine quinine, has broad antiviral effects and immunomodulatory properties, making it an attractive candidate to be repurposed for SARS-CoV-2 infection. The precise mechanisms of immunomodulation are uncertain, but the net result is inhibition of macrophage production of proinflammatory cytokines tumor necrosis factor (TNF)-α and

Ethics approval The trial was approved by health research ethics committees of the University of Calgary and the University of Alberta, and all participants provided informed consent. Research underpowered, leading to low precision and an inability to draw conclusions about the treatment. Conclusion There was no evidence that hydroxychloroquine reduced symptom duration or prevented severe outcomes among outpatients with proven COVID-19, but the early termination of our study meant that it was underpowered. Despite its premature termination, this trial successfully introduced several methodological innovations in the execution of trials in Alberta. While the SARS-CoV-2 vaccines give reason for hope, challenges in production and distribution, vaccine hesitancy, and the emergence of variants mean that the original premise of our study to investigate therapies to prevent severe disease remains real and urgent. Competing interests: Aravind Ganesh reports payments to his institution from the Canadian Institutes of Health Research (CIHR), the Canadian Cardiovascular Society, Alberta Innovates and Campus Alberta Neuroscience; consulting fees from MD Analytics, My Medical Panel, Atheneum, DeepBench and Research on Mind; meetings or travel support from American Academy of Neurology, Association of Indian Neurologists in America, American Heart Association and University of Calgary; and a provisional patent application for a system for patient monitoring and delivery of remote..

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Late treatment
is less effective

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