Hydroxychloroquine as pre-exposure prophylaxis for COVID-19 in healthcare workers: a randomized trial
et al., Clinical Infectious Diseases, doi:10.1093/cid/ciaa1571, COVID PREP, NCT04328467, Sep 2020
PrEP RCT showing lower cases with HCQ prophylaxis. The trial was halted
after 47% enrollment, p < 0.05 would be reached for the pooled arms at ~75% enrollment if
similar results continued. Authors note that the trial was underpowered, investigation
into more frequent dosing may be warranted, and that the dosing may have been
insufficient.
HR 0.66/0.68 for full medication adherence, 0.72/0.74, p = 0.18/0.22
overall (1x/2x dosing). Efficacy for first responders was higher, OR 0.32, p = 0.04
(pooled arms). First responders had a much higher incidence, allowing greater power, and
reducing the effect of confounders such as misdiagnosis of other conditions or survey
issues.
Performance is similar to the control arm for the first 3 weeks. The effect
may be greater with a dosage regimen that achieves therapeutic levels faster1. ~40% of participants
suspected they might have been infected before the trial, the effect in people definitely
without prior COVID-19 could be higher.
Research shows the treatment used in the control arm (folic acid) may have
efficacy for COVID-192,3, so the true effectiveness of HCQ
could be higher than observed. Also
see4. 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 geographical severity variation.
Internet survey RCT subject to survey bias. There were no deaths or ICU
admissions. Low risk healthcare workers, median age ~40. 494 1x/week dosing, 495 2x/week
dosing, 494 control participants (1x and 2x participants received the same overall
dosage).
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.
6,700+ studies for
220+ treatments. c19early.org
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CRITICALBlinding broken; not discussed.
Blinding failed. Table S12 shows that patients were much more likely to guess their correct arm. Control (folic acid) tablets were 'similar but not identical', and side effects were more common with treatment. The Bang Blinding Index is +0.22, +0.29 and +0.20, at or above the 0.2 threshold typically used to indicate unblinding. Approximately 82% of primary endpoints were self-reported symptoms. Table S12 is not cited anywhere in the main text, and unblinding does not appear in the limitations.
CRITICALComposite endpoint biases towards null; not discussed.
With ~82% of events based on self-reported symptoms and a roughly constant background rate of other respiratory illnesses, non-differential misclassification attenuates the hazard ratio toward 1.0. Under plausible false-positive rates of 3-4.4% over 12 weeks, a true RR of 0.5 would be observed as ~0.69-0.78, close to the reported 0.72-0.74. Authors do not mention this, and their conclusion that weekly prophylaxis 'is ineffective' does not account for it.
CRITICALStatistical analysis plan missing.
The supplement reports 'Statistical analysis plan, May 28, 2020' as item 2, however no SAP is included.
CRITICALSerology sub-study missing.
Protocol Appendix A prespecified SARS-CoV-2 serology at baseline and at day 90 in up to 3,500 participants, in order to confirm endpoint cases ('Serologic testing will allow for confirmation of COVID-19 disease, which is the primary endpoint of the trial') and to detect prior infection. No serology results appear anywhere in the paper or appendix. This analysis would be very informative for ambiguities related to the composite endpoint and misclassification bias.
CRITICALEnrollment stopped at 47%; trial cannot exclude meaningful benefit.
1483 of 3150 planned participants enrolled (47%). With a 7.9% control event rate, the trial had 80% power only for a 59% per-arm relative reduction. The primary 95% CI of 0.44-1.16 does not exclude a 56% reduction. A clinically important effect remains compatible with the data.
SERIOUSDrug side effects overlap with COVID-19 ascertainment.
HCQ adverse effects overlap with symptoms used to identify possible or probable COVID-19, potentially affecting case referral and adjudication.
SERIOUS'Concentration too low' explanation contradicted by actual achieved concentrations.
The discussion attributes a null result to whole-blood troughs of 98-200 ng/mL being below an extrapolated whole-blood EC50 target of ~1690 ng/mL, however this comparison is plasma-referenced and ignores lung compartmentalization. Measured HCQ in lung epithelial lining fluid gives an ELF/plasma ratio of ~40 (median, IQR 7.3-162.7), which places even the once-weekly regimen ~2-5 fold above the in vitro EC50 rather than ~8-17 fold below.
SERIOUSRegimen may have delayed effective exposure.
The Kaplan-Meier curves show little separation during the early period where HCQ slowly accumulates. The study's own analysis considered about four weeks necessary to reach steady state. After excluding events prior to the fourth weekly survey, HRs improve to 0.66 and 0.69.
SERIOUSGreater effect with full adherence.
Efficacy estimates were stronger among participants classified as fully adherent than in the overall analysis.
SERIOUSFigure S6 lists 82 probable cases; Table S3 shows 80.
Figure S6 shows 82 rows labeled 'Probable'. Supplemental Table 3's five probable strata are 30+8+5+8+29 = 80, and 80 plus 17 PCR-positive equals the reported 97 primary events.
SERIOUSProportional hazards assumption should be tested.
The Kaplan-Meier curves show little early treatment separation followed by greater separation later, raising the possibility that the treatment effect varies over time (as the drug concentration accumulates) and a single Cox hazard ratio is inadequate.
SERIOUSStrong first-responder signal.
There was a larger effect among first responders, a prespecified subgroup with a much higher placebo event rate. Pooled treatment arms show OR 0.32, p = 0.036. The higher placebo incidence provides more information and may reduce dilution from unrelated symptom-defined illnesses.
SERIOUSDifferential outcome ascertainment from survey missingness.
Outcomes, symptoms, medication adherence, and side effects were collected mainly with weekly participant surveys, however arm-specific survey response and missingness data are not fully reported.
MAJORFigure 2 caption reversed.
The caption states the hazard ratio for twice-weekly was 0.72 (0.44-1.16; p=.18) and for once-weekly was 0.74 (0.46-1.19; p=0.22). The abstract, results text, and Table 2 all show these results reversed. Figure S3/S4 captions are aligned with Table 2.
MAJOR'No significant subgroup differences' contradicted by appendix.
The paper states that there were no significant differences in prespecified subgroup analyses. Figure S12 show a subgroup with p = 0.02 and Table S11 shows a significant interaction by age.
MAJORPolicy conclusion goes beyond what the data supports.
The discussion states that 'prophylaxis with 400 mg hydroxychloroquine weekly is ineffective, and recommendations for prophylactic use, such as those for healthcare workers in India, should be reconsidered.' The primary CI 0.44-1.16 is compatible with a 56% reduction, and the pooled CI 0.48-1.09 with a 52% reduction.
MAJORPrior infection may dilute efficacy.
~36-40% of participants did not answer 'no' when asked whether they suspected prior COVID-19 or exposure, raising the possibility that some already had natural immunity. The protocol itself recognized that undetected prior asymptomatic infection could bias the treatment effect toward the null and proposed baseline serology to address this.
MAJORModified ITT labeled as ITT.
Authors describe the analysis as intention-to-treat while excluding randomized participants who experienced the endpoint before starting study medication.
MAJORInterim analysis plan inconsistent.
The protocol describes interim analyses at approximately 25%, 50%, 75%, and 100% enrollment, however the boundary table lists only 50%, 75%, and final analyses.
MAJORPPE percentages incorrect.
Several reported placebo PPE percentages are inconsistent with their stated counts and denominators.
MAJORTable S8 itemizes more hospitalization reasons than it counts.
For the twice-weekly arm the table states 8 hospitalizations = 1 COVID-19 + 1 adverse event + 6 'other', then itemizes seven other reasons. For placebo it reports 7 participants hospitalized with 9 hospitalizations, but the itemized list implies at least 8 distinct persons unless the COVID-19 admission occurred in someone already counted.
MAJORProtocol commitment to release data unfulfilled.
Section 15 of the protocol states: 'Publication will be expeditiously made with a full, de-identified data made available.' There is no data availability statement or repository link in the paper.
MINOREffect by perceived treatment assignment not reported.
Because participant unblinding was substantial and the primary endpoint was predominantly symptom-defined, authors would ideally analyze treatment efficacy according to the assignment guesses of patients.
MINORNumerical and label inconsistencies.
Placebo weight IQR is 80 (68, 95) in Table 1 and 80 (68, 94) in Table S1. Twice-weekly emergency department is 207 (40.8%) in Table 1 but 207 (41.8%) in Table S2. The main text shows '21% (100 of 469)' for placebo side effects while Table S4 gives 21.4%, implying a denominator of 467. Table 2 lists 28 symptomatic cases for twice-weekly where Table S3 implies 29. Four of the six sensitivity-analysis tables have the row label 'PCR positive or probable Covid-19 or possible Covid-19' while reporting counts identical to the confirmed-plus-probable primary endpoint.
MINORFirst author served simultaneously as PI, IND sponsor, case adjudicator, and guarantor.
R. Rajasingham was principal investigator, FDA Investigational New Drug sponsor, one of three blinded case adjudicators, first author, and overall study guarantor. Fully independent adjudication would be stronger given that the adjudicated symptom endpoint constitutes 82% of primary events.
Standard of Care (SOC) for COVID-19 in the study country,
the USA, is very poor with very low average efficacy for approved treatments6.
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.
|
risk of hospitalization, 50.1% lower, RR 0.50, p = 1.00, treatment 1 of 989 (0.1%), control 1 of 494 (0.2%), NNT 987, COVID-19.
|
|
risk of hospitalization, 39.0% lower, RR 0.61, p = 0.34, treatment 11 of 989 (1.1%), control 9 of 494 (1.8%), NNT 141, all cause.
|
|
risk of case, 27.0% lower, HR 0.73, p = 0.07, treatment 58 of 989 (5.9%), control 39 of 494 (7.9%), NNT 49, adjusted per study, both arms combined, primary outcome.
|
|
risk of case, 28.0% lower, HR 0.72, p = 0.18, treatment 29 of 495 (5.9%), control 39 of 494 (7.9%), NNT 49, adjusted per study, twice weekly, primary outcome.
|
|
risk of case, 26.0% lower, HR 0.74, p = 0.22, treatment 29 of 494 (5.9%), control 39 of 494 (7.9%), NNT 49, adjusted per study, once weekly, primary outcome.
|
| Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates |
2.
Deschasaux-Tanguy et al., Nutritional risk factors for SARS-CoV-2 infection: a prospective study within the NutriNet-Santé cohort, BMC Medicine, doi:10.1186/s12916-021-02168-1.
3.
Farag et al., The Use of Folic acid as a Prophylaxis against COVID-19 among Healthcare Workers, Microbes and Infectious Diseases, doi:10.21608/mid.2022.170328.1405.
Rajasingham et al., 21 Sep 2020, Randomized Controlled Trial, USA, peer-reviewed, 22 authors, study period 6 April, 2020 - 13 July, 2020, this trial compares with another treatment - results may be better when compared to placebo, trial NCT04328467 (history) (COVID PREP).
Hydroxychloroquine as Pre-exposure Prophylaxis for Coronavirus Disease 2019 (COVID-19) in Healthcare Workers: A Randomized Trial
Clinical Infectious Diseases, doi:10.1093/cid/ciaa1571
Background. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging virus causing the ongoing coronavirus disease 2019 (COVID-19) pandemic with no known effective prophylaxis. We investigated whether hydroxychloroquine could prevent SARS-CoV-2 in healthcare workers at high risk of exposure. Methods. We conducted a randomized, double-blind, placebo-controlled clinical trial of healthcare workers with ongoing exposure to persons with SARS-CoV-2, including those working in emergency departments, intensive care units, COVID-19 hospital wards, and first responders. Participants across the United States and in the Canadian province of Manitoba were randomized to hydroxychloroquine loading dose then 400 mg once or twice weekly for 12 weeks. The primary endpoint was confirmed or probable COVID-19-compatible illness. We measured hydroxychloroquine whole-blood concentrations. Results. We enrolled 1483 healthcare workers, of whom 79% reported performing aerosol-generating procedures. The incidence of COVID-19 (laboratory-confirmed or symptomatic compatible illness) was 0.27 events/person-year with once-weekly and 0.28 events/person-year with twice-weekly hydroxychloroquine compared with 0.38 events/person-year with placebo. For once-weekly hydroxychloroquine prophylaxis, the hazard ratio was .72 (95% CI, .44-1.16; P = .18) and for twice-weekly was .74 (95% CI, .46-1.19; P = .22) compared with placebo. Median hydroxychloroquine concentrations in whole blood were 98 ng/mL (IQR, 82-120) with onceweekly and 200 ng/mL (IQR, 159-258) with twice-weekly dosing. Hydroxychloroquine concentrations did not differ between participants who developed COVID-19-compatible illness (154 ng/mL) versus participants without COVID-19 (133 ng/mL; P = .08). Conclusions. Pre-exposure prophylaxis with hydroxychloroquine once or twice weekly did not significantly reduce laboratoryconfirmed COVID-19 or COVID-19-compatible illness among healthcare workers. clinical Trials Registration. NCT04328467.
Supplementary Data Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Notes
References
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Al-Kofahi, Jacobson, Boulware, Finding the dose for hydroxychloroquine prophylaxis for COVID-19: the desperate search for effectiveness, Clin Pharmacol Ther, doi:10.1002/cpt.1874
Borba, Val, Sampaio, Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial, JAMA Netw Open
Boulware, Pullen, Bangdiwala, A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19, N Engl J Med
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Kucirka, Lauer, Laeyendecker, Boon, Lessler, Variation in falsenegative rate of reverse transcriptase polymerase chain reaction-based SARS-CoV-2 tests by time since exposure, Ann Intern Med
Lancet, Expression of concern: hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis, Lancet
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Liu, Cao, Xu, Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discov
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Prevention, Interim, for healthcare personnel with potential exposure to COVID-19
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DOI record:
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"abstract": "<jats:title>Abstract</jats:title>\n <jats:sec>\n <jats:title>Background</jats:title>\n <jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging virus causing the ongoing coronavirus disease 2019 (COVID-19) pandemic with no known effective prophylaxis. We investigated whether hydroxychloroquine could prevent SARS-CoV-2 in healthcare workers at high risk of exposure.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Methods</jats:title>\n <jats:p>We conducted a randomized, double-blind, placebo-controlled clinical trial of healthcare workers with ongoing exposure to persons with SARS-CoV-2, including those working in emergency departments, intensive care units, COVID-19 hospital wards, and first responders. Participants across the United States and in the Canadian province of Manitoba were randomized to hydroxychloroquine loading dose then 400 mg once or twice weekly for 12 weeks. The primary endpoint was confirmed or probable COVID-19–compatible illness. We measured hydroxychloroquine whole-blood concentrations.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Results</jats:title>\n <jats:p>We enrolled 1483 healthcare workers, of whom 79% reported performing aerosol-generating procedures. The incidence of COVID-19 (laboratory-confirmed or symptomatic compatible illness) was 0.27 events/person-year with once-weekly and 0.28 events/person-year with twice-weekly hydroxychloroquine compared with 0.38 events/person-year with placebo. For once-weekly hydroxychloroquine prophylaxis, the hazard ratio was .72 (95% CI, .44–1.16; P = .18) and for twice-weekly was .74 (95% CI, .46–1.19; P = .22) compared with placebo. Median hydroxychloroquine concentrations in whole blood were 98 ng/mL (IQR, 82–120) with once-weekly and 200 ng/mL (IQR, 159–258) with twice-weekly dosing. Hydroxychloroquine concentrations did not differ between participants who developed COVID-19–compatible illness (154 ng/mL) versus participants without COVID-19 (133 ng/mL; P = .08).</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Conclusions</jats:title>\n <jats:p>Pre-exposure prophylaxis with hydroxychloroquine once or twice weekly did not significantly reduce laboratory-confirmed COVID-19 or COVID-19–compatible illness among healthcare workers.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Clinical Trials Registration</jats:title>\n <jats:p>Clinicaltrials.gov NCT04328467.</jats:p>\n </jats:sec>",
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