A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19
et al., NEJM, June 3 2020, doi:10.1056/NEJMoa2016638, Jun 2020
Remote post-exposure prophylaxis RCT claiming "[HCQ] did not prevent illness compatible with Covid-19 or confirmed infection when used as postexposure prophylaxis within 4 days after exposure".
However, treatment was not within 4 days, there is a significant treatment delay-response relationship, and 6 independent analyses of the data show efficacy.
This trial has many serious issues:
HCQ for COVID-19
1st treatment shown to reduce risk in
March 2020, now with p < 0.0000000001 from 424 studies, used in 59 countries.
No treatment is 100% effective. Protocols
combine treatments.
6,600+ studies for
220+ treatments. c19early.org
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CRITICALAnalysis of enrollment time instead of treatment time; significant shipping delays; many treated outside the stated window.
The title, abstract and conclusion claim that treatment was given 'within 4 days after exposure', but the 4-day limit was for enrollment only. Medication was shipped to patients. Wiseman et al.1 analyzed trial data showing that 52% of patients received medication 1-2 days after intended overnight delivery, and 19% were outside the claimed four-day intervention delay. There may be an additional delay between receipt and first-dose.
CRITICALSignificant efficacy for early treatment.
Wiseman et al.1 perform re-analysis of the data including the shipping delay, showing significantly lower cases with early HCQ treatment (up to 3 days post-exposure) (RR 0.58, 95%CI 0.35-0.97; p=0.044; NNT 14.5), but not for late treatment (RR 1.22, 95%CI 0.72 - 2.04).
CRITICALSix independent analyses indicate efficacy.
6 independent analyses of the data report efficacy2-7.
CRITICALTreatment delay-response relationship is significant.
COVID-19 cases were reduced by [49%, 29%, 16%] respectively when taken within ~[70, 94, 118] hours of exposure (including shipping delay). The treatment delay-response relationship is significant at p=0.0028.
CRITICALPrimary endpoint was predominantly unconfirmed symptomatic illness.
Only 20 of the 107 primary endpoint events were laboratory-confirmed SARS-CoV-2 infections; approximately 81% were based on symptoms without laboratory confirmation. The headline result primarily measures COVID-compatible illness rather than confirmed infection.
CRITICALPartial blinding combined with a self-reported symptom endpoint.
Side effects occurred in 40% of HCQ vs 17% of placebo participants (p<0.001). Anyone reporting a day-5 side effect was 3.7 times more likely to believe they received HCQ (68% vs 19%, p<0.001). The primary endpoint was participant-reported symptoms, with only 20/107 events (19%) PCR-confirmed.
CRITICALTime of dosing was not recorded.
Time of dosing was not recorded9,10. Pullen et al.11 shows shipping delay of 19-68 hours. With enrollment up to 4 days from exposure, this implies delivery 19-164 hours after exposure.
CRITICAL100 randomized participants excluded from the prophylaxis analysis.
A total of 921 participants were randomized, but 100 who became symptomatic before receiving study medication were excluded from the prophylaxis analysis, leaving 821 participants. The publication nevertheless describes its analyses as following the intention-to-treat principle.
CRITICALSupplementary appendix silently revised six months post-publication with no change log.
The appendix includes the footer 'PDF last updated December 4, 2020', six months after the June 3, 2020 publication. There is no erratum, change log, version diff, or journal correction notice. The public dataset separately went through at least three documented revisions (September 9, October 6, October 30, 2020), with a fourth version described by third parties as inaccurate circulating in late October.
CRITICALTable S2 header contradicts main text and table body.
The Table S2 header states 'n=115 Symptomatic; 18 PCR+'. The main text reports 113 symptomatic participants and 16 PCR-confirmed, plus 4 asymptomatic PCR-positive = 20 PCR+. The Table S2 body totals 20 in the 'Definite' row, and Figure S2 plots 20 confirmed cases (11 in group 1, 9 in group 2). Table S2 columns sum to 116 symptomatic (88 + 17 + 11), matching neither 115 nor 113.
CRITICALAuthor reports fake data was submitted.
In an OFID podcast, Dr. Boulware notes there were fake submissions with 555 numbers. These were removed, however there could be many fake submissions that were not identified, and authors do not report any analysis aiming to identify them.
CRITICAL'All new symptoms' row reconciles only via unstated conventions - appendix quotes a different percentage.
Table 2 gives 57 (13.8%) vs 59 (14.5%). Cases + adjudicated non-cases gives 49+8 = 57 for HCQ but 58+2 = 60 for placebo. The row reconciles only by removing the 4 asymptomatic PCR-positive participants (1 HCQ, 3 placebo, visible in Table S7's 'None' row) and adding back the 3 who became symptomatic after day 14. The appendix reports '13.8% vs 14.6%'; 59/407 = 14.50% and 60/407 = 14.74%, so 14.6% is incorrect on either reading.
CRITICALPrimary outcome row 'confirmed or probable' includes single-symptom 'possible' cases.
Table S3 reports the 49 patients as 11 lab-confirmed + 32 probable + 6 possible, and the 58 as 9 + 42 + 7. 'Possible' means one compatible symptom plus epidemiologic linkage, including isolated sore throat, isolated anosmia, isolated myalgia or isolated fatigue (per Figure S4). The Table 2 label is therefore inaccurate for 13/107 (12%) of endpoint events.
CRITICALTrial compares with folic acid treatment.
Authors compare with folic acid treatment. Kaur et al. note that folic acid is predicted to bind to multiple SARS-CoV-2 proteins, folic acid levels are lower in COVID-19 patients with severe disease, folic acid supplementation may help with COVID-19 associated hypertension and hyperhomocystinemia, and differences in a folic acid-related enzyme could impact COVID-19 severity.
SERIOUSLow adherence to treatment.
Only 75% of patients took the treatment as prescribed.
SERIOUSEarly stopping for futility, conclusion stronger than the data supports.
The trial targeted 621 per arm powered for a 50% relative reduction, and halted at 821 with conditional power below 1% against that optimistic assumption. The observed 95% CI (-7.0 to +2.2 pp) is compatible with an absolute reduction of up to 7.0 pp, i.e. NNT 14, a clinically important effect the trial could not exclude. The abstract nonetheless concludes HCQ 'did not prevent illness'.
SERIOUSEndpoint definition finalized after enrollment began; symptom ascertainment incomplete.
Enrollment opened March 17, 2020 and the CSTE case definition used for the primary endpoint (Interim-20-ID-01) dates to April 5/6, 2020. Follow-up surveys consequently never directly queried chills, rigors or difficulty breathing, which entered only through free text, and adjudicators translated free text to the 'nearest symptom'.
SERIOUSMain text and Figure 1 conflict on how many did not complete day 14.
The text says '10.7% of the participants (46 hydroxychloroquine and 42 placebo) did not complete the day 14 survey'. The Figure 1 caption says 96 did not complete, with 8 formally withdrawing. Table S1 gives 725 completers, so 96 did not complete; 88 is the lost-to-follow-up count excluding the 8 withdrawals. 88/821 = 10.7%, 96/821 = 11.7%.
MAJORAll 31 other occupational exposure participants had zero events, subgroup omitted from forest plot.
Figure 1 records 245 household + 545 health care worker + 31 other occupational = 821. But the contact-type subgroups in Table S6/Figure S1 account for all 107 events (household 18+25=43; HCW 31+33=64) while covering only 790 participants. The remaining 31 (14 HCQ, 17 placebo) therefore contributed zero events. Under the trial-wide 13.0% risk, P(0 events in 31) = 0.87^31 ~ 1.3% which is possible, however the possibility of a classification or data-processing issue should be confirmed against participant-level data. Figure S1 silently omits the subgroup, preventing readers from noticing.
MAJORDiarrhea totals disagree between Table S4 and Tables S7/S2.
Table S4 states 28 participants reported diarrhea. Table S7 gives 16 HCQ + 9 placebo = 25 among cases, and Table S2 identifies 4 diarrhea-only non-cases, totalling 29. Table S4's itemization sums to 28 but implies only 24 cases.
MAJORStatistical analysis plan finalized at trial termination.
The formal statistical analysis plan is dated May 6, 2020, the same date the trial was stopped for futility, and modifications were made on May 24 after trial termination.
MAJORParticipants with missing outcomes remained in the primary denominator.
Participants lacking complete outcome data remained in the treatment-group denominators, effectively contributing no observed event to the headline event proportions unless an event had already been reported.
MAJORAdverse-event ascertainment changed during the trial.
The original protocol stated that adverse events would not be captured unless they resulted in hospitalization, whereas the paper reports questioning for common side effects plus open-ended adverse-event reporting.
MINORTable S8 placebo zinc denominators sum to 408, not 407.
Zinc Yes + No = 408, exceeding the 407-participant placebo arm by one.
MINORTable S3 placebo 'possible' percentage is wrong.
Reported as '7 (1.0%)'. 7/407 = 1.72%.
MINORNumber-needed-to-harm upper bound does not follow from the published confidence interval.
The Figure 2 caption and text states an upper 95% CI of 'number needed to treat to harm 1 person, 50 persons'. The published CI upper bound is +2.2 percentage points; 1/0.0219 = 45.6 and 1/0.022 = 45.5. Neither rounds to 50.
MINORFigure 1 caption misstates the randomized N.
The caption reports 'Of the 821 participants who underwent randomization...'. The figure itself shows 921 underwent randomization; 821 was the asymptomatic analysis population after excluding 100 who were symptomatic by day 1.
MINORItemized reasons for non-adherence account for only half the non-adherent.
102 HCQ participants were less than fully adherent, but Table 3's itemized reasons sum to 53. Placebo: 71 non-adherent, 25 reasons listed.
MINORAll outcome data participant-reported, with no source-data verification reported.
PCR results, adherence, symptoms, side effects and hospitalizations were all collected by participant self-report with internet surveys. No ICH-GCP monitoring plan, source-data verification, or query-resolution process is reported.
MINORPrimary endpoint terminology obscures inclusion of possible cases.
The supplementary table labels the primary outcome as confirmed or probable COVID-19, but the totals also include participants internally classified as possible cases.
Standard of Care (SOC) for COVID-19 in the study country,
the USA, is very poor with very low average efficacy for approved treatments13.
Only expensive, high-profit treatments were approved for early treatment. Low-cost treatments were excluded, reducing the probability of early treatment due to access and cost barriers, and eliminating complementary and synergistic benefits seen with many low-cost treatments.
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risk of case, 17.0% lower, RR 0.83, p = 0.35, treatment 49 of 414 (11.8%), control 58 of 407 (14.3%), NNT 41.
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risk of case, 25.1% lower, RR 0.75, p = 0.22, treatment 32 of 414 (7.7%), control 42 of 407 (10.3%), NNT 39, probable COVID-19 cases.
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| Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates |
5.
researchgate.net, www.researchgate.net/publication/344369617_Hydroxychloroquine_as_Post-Exposure_Prophylaxis_for_Covid-19_Why_simple_data_analysis_can_lead_to_the_wrong_conclusions_from_well-designed_studies.
6.
blog.philbirnbaum.com, blog.philbirnbaum.com/2020/08/the-nejm-hydroxychloroquine-study-fails.html.
7.
longdom.org, www.longdom.org/open-access/hydroxychloroquine-and-interferons-for-the-prophylaxis-and-early-treatment-of-covid19current-clinical-advances.pdf https://osf.io/vz8a7/.
Boulware et al., 3 Jun 2020, Randomized Controlled Trial, USA, peer-reviewed, 24 authors, study period 17 March, 2020 - 6 May, 2020, this trial compares with another treatment - results may be better when compared to placebo.
A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19
New England Journal of Medicine, doi:10.1056/nejmoa2016638
BACKGROUND Coronavirus disease 2019 (Covid-19) occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For persons who are exposed, the standard of care is observation and quarantine. Whether hydroxychloroquine can prevent symptomatic infection after SARS-CoV-2 exposure is unknown.
METHODS We conducted a randomized, double-blind, placebo-controlled trial across the United States and parts of Canada testing hydroxychloroquine as postexposure prophylaxis. We enrolled adults who had household or occupational exposure to someone with confirmed Covid-19 at a distance of less 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). Within 4 days after exposure, we randomly assigned participants to receive either placebo or hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 additional days). The primary outcome was the incidence of either laboratory-confirmed Covid-19 or illness compatible with Covid-19 within 14 days.
RESULTS We enrolled 821 asymptomatic participants. Overall, 87.6% of the participants (719 of 821) reported a high-risk exposure to a confirmed Covid-19 contact. The incidence of new illness compatible with Covid-19 did not differ significantly between participants receiving hydroxychloroquine (49 of 414 [11.8%]) and those receiving placebo (58 of 407 [14.3%]); the absolute difference was −2.4 percentage points (95% confidence interval, −7.0 to 2.2; P = 0.35). Side effects were more common with hydroxychloroquine than with placebo (40.1% vs. 16.8%), but no serious adverse reactions were reported.
CONCLUSIONS After high-risk or moderate-risk exposure to Covid-19, hydroxychloroquine did not prevent illness compatible with Covid-19 or confirmed infection when used as postexposure prophylaxis within 4 days after exposure. (Funded by David Baszucki and Jan Ellison Baszucki and others; ClinicalTrials.gov number, NCT04308668.
n engl j med nejm.org
8 T h e ne w e ngl a nd jou r na l o f m e dicine exposure prophylaxis would be effective in highrisk populations is a separate question, with trials ongoing. In order to end the pandemic, a reduction in community transmission is needed. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. A data sharing statement provided by the authors is available with the full text of this article at NEJM.org. We thank the participants who consented to participate in this randomized trial; the members of the data and safety monitoring board (Drs. George Thompson III, Andrej Spec, Tom Chiller, and Bozena Morawski) for their thoughtful, generous service; and Drs. Jakub Tolar, Alexis Turgeon, Brad Benson, Tim Schacker, and Peter Igarashi for institutional support. Dr. Boulware thanks Drs. Paul Bohjanen and Ed Janoff for their mentorship. * Values are through day 5, the date of the scheduled completion of the trial intervention. More than one side effect could occur. Ongoing side effects were reported by approximately 3% of the participants in the hydroxychloroquine group at days 10 and 14 and by less than 1% of those in the placebo group. There was no association between the occurrence of side effects and the incidence of Covid-19. Among participants in whom Covid-19 developed, 30.0% (30 of 100) reported a side effect, as compared with 28.2% (169 of 600) reporting a side effect in whom Covid-19 did not develop (P =..
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