By Erik Sass, TES Editor-in-Chief
Following is a compilation of randomized controlled trials (and other types of studies) of hydroxychloroquine as a treatment for COVID-19, listing the flaws and errors which invalidate their conclusions. To add a trial entry or send corrections, please email TES Editor-in-Chief Erik Sass: eriksass@gmail.com .
- Boulware, et al. “A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19.” N Engl J Med August 6 2020; 383:517-525. Doi: 10.1056/NEJMoa2016638
- Virtually total lack of PCR testing for COVID-19, with just 2.6% receiving standard tests, forcing researchers to rely on subjective self-reporting of symptoms
- Treatment started an average of four days after COVID-19 exposure, rather than no later than two days as recommended
- Included mostly low-risk individuals who generally do well without treatment
- Not blinded: healthcare workers received identifiable pills
- Study stopped prematurely, before statistically significant figures
- Reanalysis shows the statistical significance of the large benefit of early treatment, contrary to the authors’ claims. After re-analysis, there was a reduced incidence of Covid-19 associated with HCQ compared with placebo (9.6% vs. 16.5%) when received up to 3 days (Early) after exposure.
- Skipper, et al. “Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19.” Annals of Internal Medicine, July 16, 2020. Doi: https://doi.org/10.7326/M20-4207
- Underpowered, with 491 subjects recruited over the Internet versus designed for 6,000
• Lack of testing, leading to inclusion of patients with “probable COVID-19”
• Changing metric, beginning with hospitalizations but transitioning to symptomatic endpoints - Study was not blinded to the participants
• Study used an active placebo medication (folate)
- Cavalcanti, Alexandre, et al. “Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19.” N Engl J Med July 23, 2020; DOI: 10.1056/NEJMoa2019014
- Changed endpoint from viral load at day three to viral load at day seven
- Changed endpoint to symptomatic rather than PCR test
- Patient pre-trial medications not controlled
- Median time from symptom onset to randomization 7 days, too late for HCQ to have early treatment benefit
- “RECOVERY” Trial. Horby, Peter, et al. “Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multi-centre, randomized, controlled trial.” medRxiv, July 15, 2020. Doi: https://doi.org/10.1101/2020.07.15.20151852
- Study was not a randomized trial; instead, the allocation of the drug was randomized, and the timing of drug administration varied widely
- Median number of days from symptom onset [to treatment] was 9 days – far too late for early treatment effect
- Study suffered from “confounding by indication”: patients who received HCQ were already sicker than those who didn’t
- Used dosage far exceeding recommended 600 mg per day
- “PATCH” Trial. Abella, Benjamin, et al. “Efficacy and Safety of Hydroxychloroquine vs Placebo for Pre-exposure SARS-CoV-2 Prophylaxis Among Health Care Workers. A Randomized Clinical Trial.” JAMA Intern Med. September 30, 2020. Doi: 10.1001/jamainternmed.2020.6319
- Small and terminated early, prompting authors to warn it “may have been underpowered to detect a clinically important difference”
- HCQ arm results include an early positive test likely representing infection before study started
- Low adherence (81%) relying on self-reporting rather than HCQ blood levels
- Rajasingham, Radha, et al. “Hydroxychloroquine as pre-exposure prophylaxis for COVID-19 in healthcare workers: a randomized trial.” medRxiv. September 18, 2020. Doi: 10.1101/2020.09.18.20197327
- Underpowered, with 1,483 healthcare workers enrolled versus total target 3,150
- Used low dose of HCQ, 400 mg once or twice weekly
- Study relied on symptom-based reporting and diagnosis due to limited availability of PCR testing, but failed to investigate other possible causes of symptoms
- Irregular reporting characterized by wide variation in timing of matching symptoms and PCR tests (where available). Study counted PCR+ tests within 14 days before/after symptoms, but PCR- tests within just four days of symptoms. Results suggest symptoms-based diagnosis is highly inaccurate
- Despite these shortcomings, study actually suggests positive effect with 28% relative risk reduction of infection by giving HCQ weekly for 6-8 weeks
- WHO Solidarity Trial (halted early) WHO Solidarity Trial Consortium. “Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results.” NEJM, Dec. 2, 2020. Doi: 10.1056/NEJMoa2023184.
- Most patients started on HCQ two days or more after admission, majority already receiving oxygen or ventilation, suggesting advanced disease with little likelihood of early treatment benefit
- No attempt to screen patients for markers of increased inflammation (D-dimer, LDH, high-sensitivity troponin) for indication of likely benefit from HCQ
- Intention to treat measurement only; no per protocol analysis, measurement of cumulative HCQ dose or days on therapy to determine dose response
- Hydroxychloroquine was often included in the standard of care comparator in many countries.
- Dosages far exceeding 600 mg per day
- Ulrich et al. “Treating Covid-19 With Hydroxychloroquine (TEACH): A Multicenter, Double-Blind, Randomized Controlled Trial in Hospitalized Patients.” Open Forum Infectious Diseases, Doi: 10.1093/ofid/ofaa446
- Very small study, with 67 HCQ patients versus 61 control
- Suffered confounding by indication: patients receiving HCQ were 82% more likely to have very severe symptoms at the beginning of the study. HCQ recipients included 32% more males, who are known to fare worse on average
- HCQ recipients were also more like to suffer cerebrovascular disease, cardiovascular disease (non-hypertension), renal disease (non-dialysis), and have a history of organ transplants
- Fiolet et al., “Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis.” Clinical Microbiology and Infection. August 26, 2020. DOI: 10.1016/j.cmi.2020.08.022
- Conflated hospital and outpatient studies
- Inclusion criteria required RT-PCR confirmed cases, but a number of studies included had negligible testing rates
- Authors do not consider different treatment delays, risk level of patients, differences in dosage, or usage of Zinc
- Magagnoli, Joseph, et al. “Outcomes of hydroxychloroquine usage in United States veterans hospitalized with COVID-19.” Med, June 5, 2020. Doi: 10.1016/j.medj.2020.06.001
- Not a randomized controlled trial at all. Suffered confounding by indication: choice of providing patients with HCQ was left to physicians, and cohort of 90 patients receiving HCQ prior to intubation were much sicker than the group of 177 patients not receiving HCQ prior to intubation
- Timing of treatment was apparently left up to the physicians as well, and the number of patients dying with and without ventilation indicates heavy “cross-over” to HCQ after patients were put on ventilators, and therefore much sicker; 75% of the patients not initially receiving HCQ prior to intubation were subsequently started on HCQ late in the clinical course, after they had deteriorated and required intubation
- Despite the supposedly negative conclusions of the VA study, just 7.8% of the initial HCQ patients later had to be intubated, compared to 14.2% of the other 177 patients not on HCQ who required intubation. In short, HCQ actually appeared to reduce the risk of intubation by 50% – even with bias favoring the non-intervention group
11. Barnabas, Ruanne V., et al. “Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Infection – A Randomized Trial.” Ann Int Med, December 8, 2020. Doi: 10.7326/M20-6519
- Used high cycle threshold (CT) measurements, 38+, detecting inactive virus fragments, suggesting many infections occurred weeks earlier
- Average time from exposure to PCR+ was seven days. Study results suggest ongoing or repeat exposures, with most infections occurring before enrollment or HCQ PEP reached therapeutic levels
- Failed to confirm medication adherence with HCQ blood levels
- Very low dose of HCQ, 400 mgs for three days followed by 200 mgs for 11 days
- Long lag to PEP initiation, average of two days after exposure, not reaching therapeutic levels for several weeks
- Study design changed during the study period to end point driven vs initial sample size determination driven
Download the full TES report on hydroxychloroquine at www.hcqwhitepaper.com