text:
INDIVIDUAL LOGIN | REGISTER or
INSTITUTIONAL ADMIN LOGIN
Can't sign in? Forgot your password?
Enter your email address below and we will send you the reset instructions
If the address matches an existing account you will receive an email with instructions to reset your password.
Can't sign in? Forgot your username?
Enter your email address below and we will send you your username
If the address matches an existing account you will receive an email with instructions to retrieve your username
Too Short Weak Medium Strong Very Strong Too Long
Password Changed Successfully
Enter the verification code
Your Phone has been verified
ACP Journals
Annals of Internal Medicine
Annals of Internal Medicine: Clinical Cases
ACP Journal Club Archives
Enter words / phrases / DOI / ISBN / keywords / authors / etc
Advanced searchCitation search
Close Drawer MenuOpen Drawer MenuMenu
IN THE CLINIC
CME / MOC
Authors / Submit
Original Research20 October 2020
Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19
A Randomized Trial
Caleb P. Skipper, MD,
Katelyn A. Pastick, BSc,
Nicole W. Engen, MS,
Ananta S. Bangdiwala, MS,
Mahsa Abassi, DO, MPH,
Sarah M. Lofgren, MD,
Darlisha A. Williams, MPH,
Elizabeth C. Okafor, BSc,
Matthew F. Pullen, MD,
Melanie R. Nicol, PharmD, PhD,
Alanna A. Nascene, BA,
Kathy H. Hullsiek, PhD,
Matthew P. Cheng, MD,
Darlette Luke, PharmD,
Sylvain A. Lother, MD,
Lauren J. MacKenzie, MD, MPH,
Glen Drobot, MD,
Lauren E. Kelly, PhD,
Ilan S. Schwartz, MD, PhD,
Ryan Zarychanski, MD, MSc,
Emily G. McDonald, MD, MSc,
Todd C. Lee, MD, MPH,
Radha Rajasingham, MD,
David R. Boulware, MD, MPH
Caleb P. Skipper, MD
University of Minnesota, Minneapolis, Minnesota (C.P.S., K.A.P., N.W.E., A.S.B., M.A., S.M.L., D.A.W., E.C.O., M.F.P., M.R.N., A.A.N., K.H.H., R.R., D.R.B.)
Search for more papers by this author
Katelyn A. Pastick, BSc
Nicole W. Engen, MS
Ananta S. Bangdiwala, MS
Mahsa Abassi, DO, MPH
Sarah M. Lofgren, MD
Darlisha A. Williams, MPH
Elizabeth C. Okafor, BSc
Matthew F. Pullen, MD
Melanie R. Nicol, PharmD, PhD
Alanna A. Nascene, BA
Kathy H. Hullsiek, PhD
Matthew P. Cheng, MD
Research Institute of the McGill University Health Centre and McGill University, Montréal, Quebec, Canada (M.P.C., E.G.M., T.C.L.)
Darlette Luke, PharmD
M Health Fairview Investigational Drug Service Pharmacy, Minneapolis, Minnesota (D.L.)
Sylvain A. Lother, MD
University of Manitoba, Winnipeg, Manitoba, Canada (S.A.L., L.J.M., G.D., R.Z.)
Lauren J. MacKenzie, MD, MPH
Glen Drobot, MD
Lauren E. Kelly, PhD
George & Fay Yee Centre for Healthcare Innovation, Winnipeg, Manitoba, Canada (L.E.K.)
Ilan S. Schwartz, MD, PhD
University of Alberta, Edmonton, Alberta, Canada (I.S.S.)
Ryan Zarychanski, MD, MSc
Emily G. McDonald, MD, MSc
Todd C. Lee, MD, MPH
Radha Rajasingham, MD
Author, Article and Disclosure Information
https://doi.org/10.7326/M20-4207
Eligible for CME Point-of-Care
Visual Abstract
Track Citations
Visual Abstract. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19
There is no known effective oral therapy for early COVID-19. This randomized, double-blind, placebo-controlled trial evaluated effects of oral hydroxychloroquine on symptoms and disease severity in adult outpatients with early COVID-19.
No effective oral therapy exists for early coronavirus disease 2019 (COVID-19).
To investigate whether hydroxychloroquine could reduce COVID-19 severity in adult outpatients.
Randomized, double-blind, placebo-controlled trial conducted from 22 March through 20 May 2020. (ClinicalTrials.gov: NCT04308668)
Internet-based trial across the United States and Canada (40 states and 3 provinces).
Symptomatic, nonhospitalized adults with laboratory-confirmed COVID-19 or probable COVID-19 and high-risk exposure within 4 days of symptom onset.
Intervention:
Oral hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 more days) or masked placebo.
Symptoms and severity at baseline and then at days 3, 5, 10, and 14 using a 10-point visual analogue scale. The primary end point was change in overall symptom severity over 14 days.
Of 491 patients randomly assigned to a group, 423 contributed primary end point data. Of these, 341 (81%) had laboratory-confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or epidemiologically linked exposure to a person with laboratory-confirmed infection; 56% (236 of 423) were enrolled within 1 day of symptoms starting. Change in symptom severity over 14 days did not differ between the hydroxychloroquine and placebo groups (difference in symptom severity: relative, 12%; absolute, −0.27 point [95% CI, −0.61 to 0.07 point]; P = 0.117). At 14 days, 24% (49 of 201) of participants receiving hydroxychloroquine had ongoing symptoms compared with 30% (59 of 194) receiving placebo (P = 0.21). Medication adverse effects occurred in 43% (92 of 212) of participants receiving hydroxychloroquine versus 22% (46 of 211) receiving placebo (P < 0.001). With placebo, 10 hospitalizations occurred (2 non–COVID-19–related), including 1 hospitalized death. With hydroxychloroquine, 4 hospitalizations occurred plus 1 nonhospitalized death (P = 0.29).
Limitation:
Only 58% of participants received SARS-CoV-2 testing because of severe U.S. testing shortages.
Hydroxychloroquine did not substantially reduce symptom severity in outpatients with early, mild COVID-19.
Private donors.
No effective oral therapy exists for the outpatient treatment of coronavirus disease 2019 (COVID-19). Reducing symptom severity and decreasing hospitalizations for outpatients is an important public health mitigation strategy for overcoming this pandemic. Hydroxychloroquine has in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has been proposed as a potentially effective treatment (1).
Most clinical studies investigating therapies for COVID-19 have examined hospitalized patients with moderate to severe disease. The initial hydroxychloroquine studies were small and had methodological limitations, such as the absence of a control group (2, 3). Among large, nonrandomized, observational studies and clinical trials, emerging evidence suggests that antiviral therapy late in the course of COVID-19 may have, at best, minimal benefit (4–6). However, this therapy may have clinical benefits in the treatment of mild or moderate disease when given early in the disease course. To our knowledge, no randomized clinical trials to date have investigated agents for early COVID-19 in nonhospitalized patients.
We hypothesized that starting hydroxychloroquine therapy within the first few days of symptoms could alter the course of COVID-19 by reducing symptom severity and duration and preventing hospitalizations.
We conducted a multisite, international, randomized, double-blind, placebo-controlled trial with a parallel design (ClinicalTrials.gov: NCT04308668) (7). Because therapy is most likely to be effective if given early in the disease course, we sought to enroll persons as soon as possible after symptom onset; however, several challenges existed. First, in the United States during March and April 2020, SARS-CoV-2 diagnostic testing was extremely limited, nonhospitalized persons were often ineligible for testing, and turnaround time for results was multiple days. Second, SARS-CoV-2 can be undetectable when symptoms begin: The median false-negative rate of polymerase chain reaction (PCR) testing has been reported to be 38% on day 1 of symptoms (range, 18% to 65%), decreasing over subsequent days (8, 9). To overcome these challenges and initiate therapy as early as possible, we enrolled persons with either laboratory-confirmed COVID-19 or COVID-19–compatible symptoms and an epidemiologic link to a contact with laboratory-confirmed COVID-19. Participants were randomly assigned 1:1 to receive hydroxychloroquine or placebo. Recruitment began on 22 March 2020, enrollment stopped on 6 May, follow-up concluded on 20 May, and final hospital outcomes were known by 15 June 2020.
This study was approved by the University of Minnesota Institutional Review Board and conducted under an investigational new drug application (number 148257) from the U.S. Food and Drug Administration. In Canada, the study was conducted without objection from Health Canada (control number 237355), and ethics approval was obtained for each province separately from the Research Institute of the McGill University Health Centre, University of Manitoba, and University of Alberta.
Setting and Participants
We enrolled participants through internet-based surveys throughout the United States and the Canadian provinces of Quebec, Manitoba, and Alberta. Outreach for the trial was via traditional and social media. Participants completed a self-screening survey to determine eligibility. If eligible, after reading the consent form, participants answered a series of multiple-choice questions to assess study comprehension. Participants provided a digitally captured signature to document informed consent.
We enrolled nonhospitalized adults who were required to have 4 or fewer days of symptoms and either PCR-confirmed SARS-CoV-2 infection or compatible symptoms after a high-risk exposure to a person with PCR-confirmed COVID-19 within the past 14 days. High-risk exposure was defined as an immediate household contact or a close occupational exposure to someone with COVID-19 (for example, health care worker or first responder). Health care workers who had COVID-19–compatible symptoms and high-risk exposure but whose contact had PCR results pending were enrolled after symptom review by an infectious diseases physician. All of these participants met the COVID-19 case definition of the U.S. Council of State and Territorial Epidemiologists (Supplement) (10). Participants were excluded if they were younger than 18 years, were hospitalized, received certain medications, or met other safety exclusion criteria (Supplement).
Participants in a third group had a high-risk exposure and were asymptomatic at the time of consent for a companion postexposure prophylaxis trial, which had the same inclusion and exclusion criteria (11); however, these participants became symptomatic before starting their study medicine on day 1 and were analyzed as part of this trial.
Randomization and Interventions
Research pharmacists dispensed masked, 200-mg tablets of hydroxychloroquine sulfate or masked placebo. Allocation assignment was concealed from investigators and participants because the study medicine and placebo were similar in appearance: Both were white oblong tablets dispensed in opaque bottles. Study medication was shipped overnight to participants by commercial courier. Hydroxychloroquine was prescribed at 800 mg (4 tablets) once, then 600 mg (3 tablets) 6 to 8 hours later, then 600 mg (3 tablets) once daily for 4 more days (5 days in total). This dose was chosen on the basis of simulations that used previously published pharmacokinetic parameters and were designed to rapidly achieve and maintain a hydroxychloroquine concentration above the estimated half-maximal effective concentration (EC50) for SARS-CoV-2 (12). Simulations estimated that 94% of participants would achieve concentrations above this EC50 value on day 1 and that concentrations would be maintained for 10 to 14 days. Placebo tablets of folic acid, 400 mcg, were prescribed as an identical regimen for the control group. In Canada, the placebo tablets were lactose. If gastrointestinal upset occurred, we advised dividing the total daily dose into 2 or 3 doses.
Sequential randomization occurred at research pharmacies in Minneapolis, Minnesota, and Montreal, Canada. The trial statistician generated a permuted block randomization sequence using differently sized blocks in a 1:1 allocation, stratified by country. A separate randomization stratum also existed for persons who were initially asymptomatic at the time of informed consent but became symptomatic before receiving the study medication on day 1. The research pharmacies held this list, and statisticians verified that the randomization sequence was followed.
Outcomes and Follow-up
We collected self-reported survey data using the Research Electronic Data Capture (REDCap) system (13). We e-mailed participants follow-up surveys on days 1 (medication start date), 3, 5 (medication stop date), 10, and 14 to assess study medication adherence, adverse effects, presence and severity of COVID-19 symptoms, COVID-19 test results, and hospitalization status. If participants were hospitalized within 14 days, we continued follow-up past study completion to assess outcomes. We assessed symptom severity on a 10-point visual analogue scale, where 0 indicated no symptoms and 10 indicated severe symptoms (Supplement). Medication-related adverse events were collected with directed questioning on the most common adverse effects and an open-ended free-text field. For participants who did not respond to follow-up surveys, investigators used text messages, e-mails, or telephone calls to ascertain outcomes from them or their designated third-party contacts. If this was unsuccessful, investigators searched the internet for obituaries or other evidence of vital status.
Study End Points
The initial primary outcome was an ordinal outcome by day 14 of not hospitalized, hospitalized, or intensive care unit stay or death. Secondary end points were symptom severity at day 5 and day 14 by 10-point visual analogue scale, nominal incidence of all hospitalizations and deaths, and incidence of study medicine withdrawal.
Changes in End Point and Sample Sizes
Before the first interim analysis on 24 April 2020, it became apparent that the pooled event rate of hospitalization or death was substantially lower than our initial 10% expectation (original sample size calculations as described in Statistical Analysis section). Without unblinding of treatment allocation or analysis of the data, the principal investigator proposed to the data and safety monitoring board (DSMB) that we modify the primary end point to the change in overall symptom severity over 14 days as longitudinally measured on a 10-point visual analogue scale. The DSMB approved the change on 24 April 2020. The change was necessary because the low event rate of hospitalizations or deaths in the trial would have required increasing the sample size to 6000 participants, which was not attainable. With enrollment of at least 200 participants per group, we determined that the revised trial would have 90% power (with a 2-sided α level of 0.05) to detect a statistically significant difference between the groups for a change in symptom severity score as small as 0.25 point on the 10-point visual analogue scale. The trial halted at the second DSMB meeting on 6 May 2020, when the DSMB determined that sufficient statistical power had been achieved to evaluate the primary outcome.
We had originally designed the trial assuming an 8% incidence of hospitalization and 2% incidence of intensive care unit stay or death (10% in total for these adverse outcomes) (14, 15). Using a proportional odds model with an estimated 50% effect size to reduce these ordinal outcomes with a 2-sided α level of 0.05 and 90% power, we had estimated 621 participants per group. With a novel internet-based trial, we had assumed that loss to follow-up might be higher than in a traditional trial; therefore, we had adjusted the sample size by 20% to 750 participants per group.
The primary analysis cohort included participants who completed at least 1 follow-up survey, so that change in symptom severity score could be assessed. The symptom severity score was self-assessed using a 10-point visual analogue scale (0 to 10, with 0.1-point increments). We assigned a severity score of 0 to those with no symptoms. Those who died of complications related to COVID-19 were assigned a severity score of 10 for any surveys missed up until the date of death. Both actual severity scores and changes in score from baseline were assessed for normality (Supplement Figure 4). We used a longitudinal mixed model, adjusted for baseline severity score, to analyze the primary end point of change in symptom severity through day 14. The absolute difference and 95% CI for change in severity score from baseline between groups are presented, along with the relative difference, calculated as [(hydroxychloroquine mean − placebo mean) / placebo mean]. A priori–specified subgroups for the primary outcome included days of symptoms before enrollment, age, sex, and laboratory-confirmed infection versus probable COVID-19. The primary end point was additionally assessed by medication adherence, zinc use, or vitamin C use as post hoc analyses. The Supplement gives additional detail on statistical methods and sensitivity analyses.
Analysis of the ordinal secondary end point of no hospitalization, hospitalization, or admission to the intensive care unit or death was not done because of the low event rate. The overall incidence of hospitalization or death was compared between the groups with Fisher exact tests. The analysis cohort for the outcome of hospitalization or death included all randomly assigned participants with vital status known at any point during follow-up. The presence of symptoms at each time point was assessed with the Fisher exact test, and we analyzed change from baseline symptom severity score at each visit using linear regression, adjusted for baseline severity score. We did analyses with SAS software, version 9.4 (SAS Institute), according to the intention-to-treat principle (that is, all participants with data are included in the analyses regardless of their medication status) with a 2-sided type I error using an α of 0.05. No adjustments for type I error were made to account for the number of secondary and subgroup analyses; therefore, subgroup analyses should be interpreted with caution.
The funders did not contribute to design, collection, management, analysis, interpretation of data, writing of the report, or the decision to submit the report for publication.
We enrolled 491 participants from the United States and Canada (Figure 1), of whom 423 completed at least 1 follow-up survey with symptom data (to contribute data to the primary end point) and 465 contributed vital status data after enrollment (to contribute to the secondary end point of hospitalization or death). Twenty-six participants (5.3%) contributed no data after enrollment and are not included in any analyses. Of the 423 participants contributing data for the primary end point, there were 241 (57%) health care workers, 106 (25%) household contacts, and 76 (18%) with other exposures (Table). The median age was 40 years (interquartile range [IQR], 32 to 50 years), and 56% (n = 238) were women. Persons identifying as Black or African American were underrepresented (3%). Frequent comorbid conditions included asthma (11%), hypertension (11%), and diabetes (4%); 68% of participants reported no chronic medical conditions.
Figure 1. Study flow diagram.
Eligible participants were allocated in a 1:1 ratio to receive masked placebo or hydroxychloroquine, 800 mg (4 tablets) once, then 600 mg (3 tablets) in 6–8 h, then 600 mg (3 tablets) daily for 4 more days. Persons who were exposed to a contact with a positive result on a polymerase chain reaction (PCR) test and who remained asymptomatic (n = 821) were enrolled in our companion trial on postexposure prophylaxis (11); however, 100 persons became symptomatic before receiving study medicine on day 1 and were included in this early treatment trial, as per the protocol-specified plan. Of these, 81 met the U.S. coronavirus disease 2019 (COVID-19) case definition on day 1 on the basis of their symptom complex, whereas 19 were possible COVID-19 on day 1 (10). Most of the 2237 symptomatic persons who were ineligible had >4 d of symptoms (55%) or did not have access to PCR testing (41%). PrEP = preexposure prophylaxis.
Table. Baseline Characteristics of Primary End Point Cohort, by Treatment Group*
Overall, 341 participants (81%) ultimately had either a positive PCR result or a high-risk exposure to a PCR-positive contact (Figure 2). Of these 341 persons, 145 were PCR-positive for SARS-CoV-2 and 280 had known high-risk exposure to a PCR-positive contact; 84 had both. The remaining 82 participants (19%) were enrolled with suspected COVID-19: They had COVID-19–compatible symptoms and reported high-risk exposure, but the contact's PCR was pending or unavailable. Of these, 37 had 2 of 3 symptoms of cough, fever, and shortness of breath. Those with a PCR-confirmed diagnosis took a mean of 2.2 days of symptoms to enroll, compared with 1.3 days for those enrolled via symptoms and an epidemiologic link to a PCR-positive contact (Supplement Table 7).
Figure 2. Venn diagram of qualification for study enrollment.
Venn diagram showing the distribution of how 378 participants qualified for enrollment. Two of 3 major symptoms were from among cough, shortness of breath, and fever. An additional 26 participants qualified by having pending (or unavailable) PCR tests at entry, having symptoms compatible with coronavirus disease 2019 (COVID-19), and meeting the case definition after adjudication by an infectious disease physician (10). Five persons later reported PCR-positive contact, with test results returning after enrollment. In addition, 19 initially asymptomatic persons who had been randomly assigned in the postexposure prophylaxis trial (11) developed new symptoms on day 1 but not 2 of 3 major symptoms. Figure 5 shows hierarchical outcomes by confirmed PCR positive, contact PCR positive, or probable case only. PCR = polymerase chain reaction.
At enrollment, 413 participants (98%) reported at least 1 COVID-19–compatible symptom; cough (65%), fatigue (52%), and headache (51%) were the most prevalent. Baseline symptoms were similar between study groups, and the median number of COVID-19–compatible symptoms reported was 4 (IQR, 2 to 6 symptoms). Overall, 56% (236 of 423) of participants enrolled within 1 day of symptom onset (Table).
We assessed the prevalence and severity of symptoms at each survey time point. By the fifth day, 54% (109 of 203) of participants receiving hydroxychloroquine reported symptoms, compared with 56% (108 of 194) receiving placebo. At day 14 of the trial, 24% (49 of 201) receiving hydroxychloroquine reported symptoms versus 30% (59 of 194) receiving placebo (P = 0.21) (Figure 3). These findings remained true when the comparisons were limited to symptoms of fever, cough, or shortness of breath at day 14 (16% receiving hydroxychloroquine vs. 22% receiving placebo).
Figure 3. Percentage of participants with ongoing COVID-19 symptoms.
The percentage of participants reporting symptoms over time did not statistically differ by use of hydroxychloroquine or placebo. By day 14, the proportion of hydroxychloroquine participants with symptoms was 6 percentage points less than that of placebo participants (24% vs. 30%; P = 0.21). The stacked bar graph distinguishes the relative proportions of those with presentation of cough, fever, or shortness of breath vs. other COVID-19–related symptoms. Exact percentages can be found in Supplement Figure 2. COVID-19 = coronavirus disease 2019.
For the primary outcome, we assessed the change in symptom severity score over 14 days in those given hydroxychloroquine versus placebo for 423 participants with available longitudinal data on symptom severity. The hydroxychloroquine group had a mean reduction from baseline of 2.60 points on the 10-point visual analogue scale for symptom severity, compared with a 2.33-point reduction in the placebo group (absolute difference, −0.27 point [95% CI, −0.61 to 0.07 point]; P = 0.117) (Figure 4). This equates to a non–statistically significant difference in average improvement in symptom severity of 12% between the hydroxychloroquine and placebo groups. Overall, hydroxychloroquine failed to cause a statistically significant decrease in symptom prevalence or severity over the 14-day study period.
Figure 4. Overall symptom severity score over 14 d.
At each visit, participants reported their overall severity of coronavirus disease 2019 (COVID-19) symptoms on a continuous visual analogue scale of 0–10 points. The primary end point (overall change in symptom severity score) was calculated with linear mixed-effects models, adjusted for baseline severity score. Hydroxychloroquine was associated with a 12% relative difference over placebo, based on an absolute difference of −0.27 (95% CI, −0.61 to 0.07; P = 0.117) on the visual analogue scale. Supplement Table 4 shows mean values and 95% CIs. At day 5, symptom severity had worsened from baseline in 16% of participants receiving hydroxychloroquine and 20% of those receiving placebo.
We analyzed a priori–defined, baseline subgroups by change in symptom severity score through 14 days (Figure 5). Subgroup results were generally consistent with the overall result. Of note, inclusion of persons without a laboratory-confirmed diagnosis did not dilute the hydroxychloroquine effect because there was no significant interaction between those who had PCR-confirmed disease (nonsignificant 5.2% relative improvement) and those who did not have PCR-confirmed disease (nonsignificant 14.7% relative improvement) (P for interaction = 0.51). We explored the change in symptom severity score by medication adherence as a post hoc analysis and found improvement in those receiving hydroxychloroquine compared with placebo when they took at least 75% of the prescribed study medication (19.5% relative benefit). However, within the hydroxychloroquine group, improvement in symptom scoring by day 14 did not differ between participants who were more than 75% adherent (change, −2.57 points) and those who were less than 75% adherent (change, −2.70 points). Additional post hoc analyses showed that self-reported use of zinc or vitamin C in addition to hydroxychloroquine did not improve symptoms over use of hydroxychloroquine alone (Supplement Table 2).
Figure 5. Change in symptom severity score over 14 d, by a priori subgroups.
Mean change from baseline and estimated difference from a longitudinal mixed model adjusted for baseline severity score. P values for trend of continuous variables are in parentheses. Subgroups were defined a priori in the protocol. The final diagnosis includes all diagnostic testing results during the study period. Probable diagnosis is based on the U.S. clinical case definition (10). The final diagnosis categories are hierarchical as listed (and thus mutually exclusive). Participants with symptom duration of 1–2 d before enrollment in the hydroxychloroquine group had a larger reduction in symptom score than those receiving placebo, but this was not observed in those who enrolled with symptom durations <1 d, where one might expect an even greater effect if hydroxychloroquine therapy helped mitigate disease severity if started very early in the disease course. Additional post hoc subgroups of medication adherence, zinc, and vitamin C are presented in Supplement Table 2.
The incidence of hospitalization or death was 3.2% (15 of 465) among participants with known vital status. With hydroxychloroquine, 4 hospitalizations and 1 nonhospitalized death occurred (n = 5 events). With placebo, 10 hospitalizations and 1 hospitalized death occurred (n = 10 events); of these hospitalizations, 2 were not COVID-19–related (nonstudy medicine overdose and syncope). The incidence of hospitalization or death did not differ between groups (P = 0.29).
On completion of the study medication regimen, 77% (157 of 203) of participants receiving hydroxychloroquine reported complete adherence to the regimen, compared with 86% (166 of 194) receiving placebo. Adverse effects were more common in those receiving hydroxychloroquine than placebo through the 5-day regimen (43% [92 of 212] vs. 22% [46 of 211]; P < 0.001). With hydroxychloroquine, gastrointestinal symptoms were the most commonly reported adverse effect: 31% (66 of 212) of participants reported upset stomach or nausea, and 24% (50 of 212) reported abdominal pain, diarrhea, or vomiting (Supplement Table 3). We observed no association between the presence of adverse effects and that of symptoms (Supplement Table 8). Adverse effect prevalence decreased markedly after day 5. No serious adverse events attributable to the study drug occurred.
We assessed the efficacy of study medicine masking on day 14. Of the 194 participants who completed day-14 surveys in the intervention group, 49% (n = 94) correctly identified that they had received hydroxychloroquine, 7% (n = 14) believed that they had received placebo, and 44% (n = 86) were unsure. Of the 182 who completed day-14 surveys in the placebo group, 30% (n = 54) correctly guessed placebo, 25% (n = 46) incorrectly guessed hydroxychloroquine, 42% (n = 76) were unsure of their randomization assignment, and 3% (n = 6) did not respond. Thus, masking was generally effective, with adverse effects markedly differing between groups.
In this randomized, double-blind, placebo-controlled trial of symptomatic outpatient adults with probable or confirmed early COVID-19, a 5-day course of hydroxychloroquine failed to show a substantial clinical benefit in improving the rate of resolution of COVID-19 symptoms in the enrolled clinical trial participants. Of those receiving placebo, 70% reported no COVID-19 symptoms by day 14 of the study, 96% had not been hospitalized, and 99.6% survived. The change in symptom severity was not statistically significant: only a 12% relative improvement over placebo. For comparison, oseltamivir in influenza showed a 25% to 35% relative reduction in symptom severity score in clinical trials (16, 17). Therefore, the modest clinical effect that practitioners ascribe to oseltamivir is still 2-fold greater than that observed with hydroxychloroquine.
To our knowledge, this is the first randomized clinical trial investigating treatment of COVID-19 among outpatients (a search of PubMed and MEDLINE on 24 June 2020 for publications in all languages using the keyword COVID-19 revealed no published outpatient randomized clinical trials). This builds on other randomized trial data on hydroxychloroquine, which have not shown any benefit for postexposure prophylaxis or for treatment of hospitalized patients (11, 18, 19). In addition, after this trial was completed, in vivo animal models have reported no hydroxychloroquine activity against SARS-CoV-2 in hamsters, ferrets, or nonhuman primates (20–22).
Change in symptom severity score using a 10-point continuous visual analogue scale is a clinically relevant end point describing participant improvement over time. Validated scoring instruments for symptom severity were not yet available for outpatients with COVID-19 when we designed this trial. Although the visual analogue scale is a subjective measure, the within-person measurement of symptom severity is internally consistent over time. For our outpatient trial, time to resolution of an individual symptom was not considered appropriate because individuals presented with differing symptoms. For example, 65% had cough, and 38% had fever. In addition, some isolated symptoms, such as fatigue, may persist after the overall syndrome subsides. Thus, we believe that the intraperson change in overall symptom severity over time represents a clinically meaningful end point, particularly in a disease that exhibits such heterogeneous symptomatology. Using a continuous end point results in smaller sample sizes than required for categorical or ordinal end points—thereby expediting phase 2 trials and allowing early assessment of potential clinical benefit.
Our original end point was an ordinal outcome of reduced hospitalization, intensive care unit stay, or death. Among the enrolled participants, the incidence of hospitalization was only 3% and incidence of death only 0.4%, making the planned analysis of the ordinal end point futile. We do note that 8 COVID-19–related hospitalizations (including 1 death) occurred with placebo versus 4 COVID-19 hospitalizations (and 1 additional death; 5 events in total) with hydroxychloroquine. Our population was relatively young with 77% of participants being aged 50 years or less, with few comorbid conditions; thus, our trial findings are most generalizable to such populations. It is possible that hydroxychloroquine is more effective in populations at higher risk for complications, such as older persons in long-term care facilities (23). Performing randomized trials in long-term care facilities could test whether hydroxychloroquine can reduce hospitalizations; however, the risk for medication adverse effects and drug–drug interactions will also be higher (24).
The primary limitation of our trial is the lack of confirmed SARS-CoV-2 infection in all participants, although participants met international and U.S. COVID-19 case definitions (10, 25). The trial began on 22 March 2020, when PCR testing supplies were severely limited in the United States with outpatients ineligible for testing or with frequent delays in receiving test results. We countered this by enrolling participants with known epidemiologic links to index cases with PCR positivity and proven high-risk exposures. The use of epidemiologic linkage to enroll symptomatic persons is both a limitation and a strength. Although these persons did not have PCR-confirmed diagnoses, using epidemiologically linked cases enabled rapid enrollment after symptoms began: 56% of participants enrolled within 1 day of symptom onset. Only 16% of participants contributing data to the primary end point had a confirmed negative result on a PCR test; this falls within the known false-negative rate of current molecular techniques (8). In subgroup analyses, participants with epidemiologic linkage or probable COVID-19 by case definition only had similar responses to those with PCR-confirmed COVID-19. PCR-confirmed cases had the least effect observed.
In conclusion, finding effective therapies against COVID-19 remains critical. Effective treatment of early, outpatient COVID-19 could decrease hospitalizations and, ultimately, morbidity and mortality. Hydroxychloroquine did not substantially reduce symptom severity or prevalence over time in nonhospitalized persons with early COVID-19. This trial may not inform whether an effect would be observed in populations at higher risk for severe COVID-19. Further randomized controlled clinical trials are needed in early COVID-19.
1. Yao X , Ye F , Zhang M , et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020. [PMID: 32150618] doi:10.1093/cid/ciaa237 CrossrefMedlineGoogle Scholar
2. Pastick KA , Okafor EC , Wang F , et al. Review: hydroxychloroquine and chloroquine for treatment of SARS-CoV-2 (COVID-19). Open Forum Infect Dis. 2020;7:ofaa130. [PMID: 32363212] doi:10.1093/ofid/ofaa130 CrossrefMedlineGoogle Scholar
3. Million M , Lagier JC , Gautret P , et al. Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: a retrospective analysis of 1061 cases in Marseille, France. Travel Med Infect Dis. 2020;35:101738. [PMID: 32387409] doi:10.1016/j.tmaid.2020.101738 CrossrefMedlineGoogle Scholar
4. Geleris J , Sun Y , Platt J , et al. Observational study of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med. 2020;382:2411-2418. [PMID: 32379955] doi:10.1056/NEJMoa2012410 CrossrefMedlineGoogle Scholar
5. Beigel JH , Tomashek KM , Dodd LE , et al; ACTT-1 Study Group Members.. Remdesivir for the treatment of Covid-19 — preliminary report. N Engl J Med. 2020. [PMID: 32445440] doi:10.1056/NEJMoa2007764 CrossrefMedlineGoogle Scholar
6. Wang Y , Zhang D , Du G , et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395:1569-1578. [PMID: 32423584] doi:10.1016/S0140-6736(20)31022-9 CrossrefMedlineGoogle Scholar
7. Lother SA , Abassi M , Agostinis A , et al. Post-exposure prophylaxis or pre-emptive therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): study protocol for a pragmatic randomized-controlled trial. Can J Anaesth. 2020. [PMID: 32383125] doi:10.1007/s12630-020-01684-7 CrossrefMedlineGoogle Scholar
8. Kucirka LM , Lauer SA , Laeyendecker O , et al. Variation in false-negative rate of reverse transcriptase polymerase chain reaction-based SARS-CoV-2 tests by time since exposure. Ann Intern Med. 2020;173:262-7. [PMID: 32422057]. doi:10.7326/M20-1495 LinkGoogle Scholar
9. Cheng MP , Papenburg J , Desjardins M , et al. Diagnostic testing for severe acute respiratory syndrome-related coronavirus 2: a narrative review. Ann Intern Med. 2020;172:726-734. [PMID: 32282894]. doi:10.7326/M20-1301 LinkGoogle Scholar
10. Council of State and Territorial Epidemiologists. Interim-20-ID-01: standardized surveillance case definition and national notification for 2019 novel coronavirus disease (COVID-19). Accessed at www.cste.org/resource/resmgr/2020ps/Interim-20-ID-01_COVID-19.pdf on 20 April 2020. Google Scholar
11. Boulware DR , Pullen MF , Bangdiwala AS , et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. N Engl J Med. 2020. [PMID: 32492293] doi:10.1056/NEJMoa2016638 CrossrefMedlineGoogle Scholar
12. Al-Kofahi M , Jacobson P , Boulware DR , et al. Finding the dose for hydroxychloroquine prophylaxis for COVID-19: the desperate search for effectiveness. Clin Pharmacol Ther. 2020. [PMID: 32344449] doi:10.1002/cpt.1874 CrossrefMedlineGoogle Scholar
13. Harris PA , Taylor R , Minor BL , et al; REDCap Consortium. The REDCap consortium: building an international community of software platform partners. J Biomed Inform. 2019;95:103208. [PMID: 31078660] doi:10.1016/j.jbi.2019.103208 CrossrefMedlineGoogle Scholar
14. Burke RM , Midgley CM , Dratch A , et al. Active monitoring of persons exposed to patients with confirmed COVID-19 — United States, January–February 2020. MMWR Morb Mortal Wkly Rep. 2020;69:245-246. [PMID: 32134909] doi:10.15585/mmwr.mm6909e1 CrossrefMedlineGoogle Scholar
15. World Health Organization. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19). February 2020. Accessed at www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdf on 9 March 2020. Google Scholar
16. Nicholson KG , Aoki FY , Osterhaus AD , et al. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group. Lancet. 2000;355:1845-50. [PMID: 10866439] CrossrefMedlineGoogle Scholar
17. Treanor JJ , Hayden FG , Vrooman PS , et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group. JAMA. 2000;283:1016-24. [PMID: 10697061] CrossrefMedlineGoogle Scholar
18. Horby P , Mafham M , Linsell L , et al. Effect of hydroxychloroquine in hospitalized patients with COVID-19: preliminary results from a multi-centre, randomized, controlled trial. medRxiv. Preprint posted online 15 July 2020. doi:10.1101/2020.07.15.20151852 CrossrefGoogle Scholar
19. World Health Organization. Q&A : hydroxychloroquine and COVID-19. 19 June 2020. Accessed at www.who.int/news-room/q-a-detail/q-a-hydroxychloroquine-and-covid-19 on 19 June 2020. Google Scholar
20. Kaptein SJF , Jacobs S , Langendries L , et al. Antiviral treatment of SARS-CoV-2-infected hamsters reveals a weak effect of favipiravir and a complete lack of effect for hydroxychloroquine. bioRxiv. Preprint posted online 19 June 2020. doi:10.1101/2020.06.19.159053 CrossrefGoogle Scholar
21. Park SJ , Yu KM , Kim YI , et al. Antiviral efficacies of FDA-approved drugs against SARS-CoV-2 infection in ferrets. mBio. 2020;11. [PMID: 32444382] doi:10.1128/mBio.01114-20 CrossrefMedlineGoogle Scholar
22. Maisonnasse P , Guedj J , Contreras V , et al. Hydroxychloroquine in the treatment and prophylaxis of SARS-CoV-2 infection in non-human primates. Research Square. Preprint posted online 6 May 2020. doi:10.21203/rs.3.rs-27223/v1 CrossrefGoogle Scholar
23. McMichael TM , Currie DW , Clark S , et al; Public Health–Seattle and King County, EvergreenHealth, and CDC COVID-19 Investigation Team. Epidemiology of Covid-19 in a long-term care facility in King County, Washington. N Engl J Med. 2020;382:2005-2011. [PMID: 32220208] doi:10.1056/NEJMoa2005412 CrossrefMedlineGoogle Scholar
24. Ross SB , Wilson MG , Papillon-Ferland L , et al. COVID-SAFER: deprescribing guidance for hydroxychloroquine drug interactions in older adults. J Am Geriatr Soc. 2020. [PMID: 32441771] doi:10.1111/jgs.16623 CrossrefMedlineGoogle Scholar
25. World Health Organization. Global surveillance for human infection with coronavirus disease (COVID-19). 20 March 2020. Accessed at www.who.int/publications-detail/global-surveillance-for-human-infection-with-novel-coronavirus-(2019-ncov) on 20 March 2020. Google Scholar
Sign In to Submit A Comment
The EditorsAnnals of Internal Medicine30 April 2021
Response from the Editors
The Editors thank Dr. Boulware and colleagues for their detailed response to Dr. Wiseman's concerns about the conduct of their clinical trial of hydroxychloroquine in non-hospitalized patients with COVID-19 (1) and his accusations that they failed to respond appropriately to his request for study information. The trial report underwent Annals' usual rigorous peer review process and the editors found the trial to be carefully conducted as specified in the protocol and, importantly, to reflect the real world challenges of quickly delivering medication for an acute condition to non-hospitalized patients. We also note that Boulware and colleagues provided study information and data as specified in their data-sharing plan and aligned with protection of potentially identifiable protected health information. Dr. Wiseman's comparison of the trial published in Annals to the Surgisphere observational study that was retracted because of suspected data fabrication is unjustified. Readers should not interpret this comparison as reflecting similar issues with the conduct of Boulware and colleagues' trial. It is disturbing to learn that Boulware and colleagues have observed that their well-intentioned data sharing was followed by manipulation of the data by those who used it to conduct post-hoc analyses. We agree that, even without altering the data, post-hoc analyses of small subgroups can achieve a desired p-value, based on artifacts within the placebo group and such analyses should be interpreted with substantial caution. While effective interventions to prevent and treat COVID-19 are sorely needed, there is substantial evidence that hydroxychloroquine is unfortunately not such an intervention.
Caleb P Skipper MD, Katelyn A Pastick BSc, Nicole W Engen MS, Ananta S Bangdiwala MS, Mahsa Abassi DO MPH, Sarah M Lofgren MD, Darlisha A Williams MPH, Elizabeth C Okafor BSc, Matthew F Pullen MD, Melanie R Nicol PharmD PhD, Alanna A Nascene BA, Kathy H Hullsiek PhD, Matthew P Cheng MD, Darlette Luke PharmD, Sylvain A Lother MD, Lauren J MacKenzie MD MPH, Glen Drobot MD, Lauren E Kelly PhD, Ilan S Schwartz MD PhD, Ryan Zarychanski MD MSc, Emily G McDonald MD MSc, Todd C Lee MD MPH, Radha Rajasingham MD, David R. Boulware MD MPHUniversity of Minnesota, McGill University, M Health Fairview Investigational Drug Service Pharmacy, University of Manitoba, University of Alberta29 April 2021
Authors' Response to Wiseman
The protocol and statistical analysis plan were provided to the Annals of Internal Medicine at time of manuscript submission. These have also been available online since June 24, 2020 at https://clinicaltrials.gov/ct2/show/NCT04308668.
We have provided a de-identified public use dataset of the published clinical trial data which is available open-access upon completing a request at www.covidpep.umn.edu/data. Requests for potentially identifiable protected health information, such as exact dates and times, which is protected by Health Insurance Portability and Accountability Act of 1996 (HIPAA) and/or Canadian Personal Information Protection and Electronic Documents Act (PIPEDA), must be denied. Polite, professional requests for further unpublished information from multiple investigators have been generally accommodated, and the dataset and data dictionary have been updated several times since initial release to enhance clarity. With collegial interactions, we have also assisted other researchers to understand the dataset, and colleagues' feedback has been incorporated to improve the data dictionary. All persons requesting datasets are provided the uniform resource locator (URL) to access the most updated datasets and data dictionaries. The International Committee of Medical Journal Editors (ICJME) policy does not require unpublished data to be released, nor does ICJME require the provision of free PhD biostatistician time to fulfill requests for unpublished data or analyses. All analyses published in the manuscript can be replicated from the public de-identified dataset (1).
We have sought to be entirely transparent with how our trials were conducted, including answering politely asked questions and sharing our experience with others. Additionally, we have published supplemental data in peer-reviewed journals on the logistics of how our trials operated (2). We have published the time from trial enrollment to drug delivery with a graphical representation of the data for maximal transparency (2). As these were internet-based trials (1, 3), two-thirds of participants (875/1312) enrolled outside of typical weekday, business hours. The convenience of enrolling from home during non-business hours likely enabled rapid enrollment. Thus, the overall median time from enrollment (i.e. time of informed consent) to drug delivery was 36 hours (IQR, 23.7 to 42.4). Operationally, this equates to a median participant enrollment time of 10:30pm CDT whereby the next morning, the investigational pharmacy randomized participants and dispensed study medicines up until ~4pm Monday through Friday (and until ~3pm on Saturday). Thereafter, medicines were sent by courier overnight arriving before 10:30am Monday-Saturday. Federal Express does not deliver on Sunday. In Canada, the study pharmacies dispensed on Sunday, and Purolator delivered on Sunday. We have provided shipping times in our open-access datasets for >6 months.
Regarding nomenclature of symptom duration prior to enrollment. Persons who enrolled while asymptomatic but who became symptomatic by time of receipt of study medicine were classified as having <1 day of symptoms at time of enrollment. Those enrolling on the same day that their symptoms began were categorized as having symptoms for 1 day. While some might categorize that as 0 calendar days, we categorized this as 1 day of symptoms. The overall mean (+SD) days of symptoms prior to study drug receipt was 2.7 days +2.0 days with median 3 days (IQR 1 to 4 days) in our early treatment trial (1).
In our prior postexposure prophylaxis trial (3), we have also published the effect of time from high risk exposure and time from last exposure to study drug initiation (4). With visual representation of the data, there is no conclusive effect on incidence of Covid-19 infection by timing of when hydroxychloroquine was initiated nor any statistical difference (4). The total time from reported high-risk exposure to study medicine receipt was a median of 3 days (IQR, 2 to 4) in the postexposure prophylaxis trial (2).
Unfortunately, we have learned that some persons have altered the data from our provided public dataset in their unpublished, non-peer reviewed post-hoc analyses. This is unfortunate and unnecessary. Even without altering data, we are precisely cognizant of how manipulation of small subgroups can achieve a desired p-value, based on artifacts within the placebo groups. There is significant danger in the over-interpretation of such post-hoc analyses (5), in that many of these may be incorrect. Ultimately, two other postexposure prophylaxis trials have also failed to demonstrate any benefit of hydroxychloroquine for postexposure prophylaxis (6, 7) and there was no evidence of significant effect on decreasing hospitalization in the four outpatient treatment trials evaluated in a April 2021 updated network meta-analysis (8) .
Unfortunately, it appears that hydroxychloroquine is not effective for either the prevention or treatment of Covid-19. We had hoped hydroxychloroquine would have worked, but it is time to move on to other strategies with more promise.
Skipper CP, Pastick KA, Engen NW, Bangdiwala AS, Abassi M, Lofgren SM, et al. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 : A Randomized Trial. Ann Intern Med. 2020; 173(8): 623-31.
Pullen MF, Pastick KA, Williams DA, Nascene AA, Bangdiwala AS, Okafor EC, et al. Lessons Learned From Conducting Internet-Based Randomized Clinical Trials During a Global Pandemic. Open Forum Infect Dis. 2021; 8(2): ofaa602.
Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2020; 383(6): 517-25.
Nicol MR, Boulware DR, Rajasingham R. Reply to author. Clin Infect Dis. 2020; In Press. doi:10.1093/cid/ciaa1809.
Lagakos SW. The challenge of subgroup analyses--reporting without distorting. N Engl J Med. 2006; 354(16): 1667-9.
Mitjà O, Corbacho-Monné M, Ubals M, Alemany A, Suñer C, Tebé C, et al. A Cluster-Randomized Trial of Hydroxychloroquine for Prevention of Covid-19. New England Journal of Medicine. 2020; In Press. doi:10.1056/NEJMoa2021801.
Barnabas RV, Brown ER, Bershteyn A, Stankiewicz Karita HC, Johnston C, Thorpe LE, et al. Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Infection : A Randomized Trial. Ann Intern Med. 2021; 174(3): 344-52.
Lamontagne F, Agoritsas T, Siemieniuk R, Rochwerg B, Bartoszko J, Askie L, et al. A living WHO guideline on drugs to prevent covid-19. BMJ. 2021; 372: n526.
David Boulware, MD, MPH, CTropMed, FIDSAUniversity of Minnesota27 April 2021
Authors' Response
The protocol and statistical analysis plan were provided to the Annals of Internal Medicine with manuscript submission. These have been available since June 24, 2020 at https://clinicaltrials.gov/ct2/show/NCT04308668
David Wiseman PhD, MRPharmSSynechion, Inc.22 April 2021
Scientific concerns
Without implying fabrication, several "serious scientific questions"1 on the Surgisphere study also apply to this study, rendering it uninterpretable.
Methodology, analysis, data integrity concerns
This "Post-exposure Early Treatment" (PET) study reports subjects who were symptomatic before drug receipt. Under the same protocol (NCT04308668), an asymptomatic "Post-Exposure Prophylaxis" (PEP) cohort was separately published.2
Although in both cohorts, drug was reportedly shipped to subjects overnight, our PEP dataset re-analysis3 revealed that 52% of subjects received drug 1 or 2 days later. Obtaining from the authors data that included actual shipping times, we found a 42% Covid-19 reduction associated with early (< 3 days) receipt of hydroxychloroquine (RR 0.58, 95%CI 0.35 - 0.97; p=0.044).
Sharing protocol and logistics with the PEP cohort, a similar problem in this PET cohort is reasonably suspected. With overnight shipping to subjects with < 4 days of symptoms, critically timed treatment was expected < 5 days after onset. Some subjects may have received drug 1 or 2 days later, violating the protocol, oppugning the overall analysis, and controverting a primary a priori subgroup "days of symptoms before enrollment" (Fig 5, Table S6).
Obtaining this dataset (covidpep.umn.edu/data), we have repeatedly requested actual shipping times. In extensive correspondence (osf.io/udx28/), the authors have not disputed our suspicions.
Substandard dataset prevents replication of analysis
The 423 ITT subjects are not identified within the 491 subjects listed.
The 100 subjects transferred from the PEP arm are unidentified, nor is time from exposure provided.
Key data for the 38 Canadian subjects are absent.
The nomenclature describing the timing of study events needs clarification as in the PEP paper.
For the only variable apparently describing the intervention lag there are 196 subjects with a blank or zero value, and 10 with a value of 1-5 days (the maximum possible according to the paper). It is unclear how there can be 63 and 222 subjects with times of 6-10 or 11-49 days respectively.
Other issues (io/udx28/) impede replication of the analysis.
Journal policy requires protocol sharing.
Lack of transparency, refusal to clarify
Similar to the issue cited by the Surgisphere retraction,4 we have been unable to fully review the PET dataset or replicate its analyses. Our requests for clarification have been unanswered, although a dataset revision corrected some minor issues. Despite numerous requests, this dataset was provided some three months after the Data Sharing commitment. The journal editors advised submitting this comment.
The Lancet E. Expression of concern: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. The Lancet 2020. http://doi.org/10.1016/S0140-6736(20)31290-3
Boulware DR, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med 2020; 383:517-25. http://doi.org/10.1056/NEJMoa2016638
Wiseman DM, et al., Effective post-exposure prophylaxis of Covid-19 is associated with use of hydroxychloroquine: Prospective re-analysis of a public dataset incorporating novel data. medRxiv 2020 http://doi.org/10.1101/2020.11.29.20235218
Mehra MR, et al. Retraction - Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. The Lancet 2020. http://doi.org/10.1016/S0140-6736(20)31324-6
Caleb P Skipper MD, David R. Boulware MD MPHUniversity of Minnesota9 December 2020
Authors' Response to Pavia and de Castro Araujo
In response to Pavia, the protocol and statistical analysis plan called for intent-to-treat analysis, whereby everyone randomized was analyzed. A modified intent to treat analysis has similar results when excluding those who did not start study medicine, who used open-label hydroxychloroquine (n=1), and with carryforward of symptom status for those hospitalized, dead, or with resolved symptoms at day 10. Ongoing symptoms were present at day +5 in 54.9% (100/182) receiving hydroxychloroquine and 57.5% (104/181) receiving placebo. At day +14, ongoing symptoms were present in 24.9% (46/185) who received hydroxychloroquine and 31.1% (56/180) who received placebo. The number needed to treat (NNT) to have 1 additional person be without symptoms at 14 days is 16 persons (95%CI, -34(harm) to 6.5). The original intention-to-treat analysis reported 24.4% vs. 30.4% having symptoms at day 14 (1).
A "per protocol analysis" is generally recognized as a biased analysis as this ignores those who stop medications due to side effects. In this randomized double-blind trial, <100% adherence (range 5-89%) occurred more frequently with hydroxychloroquine (11.8%, 24/203) than with placebo (7.8%, 15/194), often due to medication side effects or spontaneous improvement. As Supplemental Table 2 presents, those with <75% adherence, which includes those never starting the medicine, had greater resolution of symptom severity. Yet when restricting to those with 100% adherence as a per protocol analysis, ongoing symptoms existed at day 5 in 54.1% (85/157) receiving hydroxychloroquine versus 56.6% (94/166) receiving placebo. At day 14, 25.2% (39/155) of hydroxychloroquine participants had ongoing symptoms. Thus neither a modified intent-to-treat or per protocol analysis substantially differs from the original intent-to-treat analysis.
In response to Bruno Luís de Castro Araujo, we did not find a statistical difference in COVID-related hospitalizations or death (2.2% [5/231] with hydroxychloroquine vs. 3.4% [8/234] with placebo). Two non-COVID events occurred in the placebo arm requiring hospital observations of <24 hours. In a similar early outpatient treatment randomized trial (n=293), Mitja and colleagues found zero virologic effect of hydroxychloroquine (+0.07 log10 copies/mL higher at 7 days) compared with no therapy (2). Their incidence of all-cause hospitalization was 5.9% (8/136) with hydroxychloroquine versus 7.0% (11/157) with standard of care in Catalonia (2). Whether this 1.3% reduction in hospitalizations (95%CI, -1.5% to 4.2%) in the two trials is a real difference requires further data (1, 2). A third large randomized trial in Brazil was halted for futility with no effect on hospitalization or death (risk ratio: 1.00; 95%CI, 0.45–2.21) (3). An ongoing effort is pursuing this by pooling data across eight outpatient randomized trials.
In response to Bhattacharyya, the data are underwhelming regarding whether folic acid has activity against SARS-CoV-2 in humans to prevent or mitigate COVID-19. In-silica studies, while interesting, are low quality evidence. In pregnant women, Acosta-Elias reported a 0.95-fold risk of COVID-19-related hospitalization, which is decreased relative to influenza (4), yet CDC reported pregnant women were 2-3 fold more likely to require intensive care unit stay, invasive ventilation support, or extracorporeal membrane oxygenation (5), despite being a population commonly taking prenatal folate supplementation. The referenced 50 person case-control study is of a different population of hospitalized COVID-19 which utilized a substantially higher 150mg total dose of folic acid versus 7.6mg given in our trial (6). In our trial when comparing symptom severity by placebo composition, the mean (+SD) visual analog score did not differ at day 5 (folic acid 2.1 +2.5 vs. 2.5 +2.7 lactose; P=0.51) nor at days 10 (P=0.27) or 14 (P=0.76). Further, Mitja and colleagues, who used no placebo, reported similar overall results (2). As the available data currently stands, we feel our placebo remains valid. Effective early outpatient therapy to prevent disease progression is important, and of repurposed oral medicines, fluvoxamine appears more promising than hydroxychloroquine or folic acid (7).
Mitja O, Corbacho-Monne M, Ubals M, Tebe C, Penafiel J, Tobias A, et al. Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial. Clin Infect Dis. 2020; In Press. doi:10.1093/cid/ciaa1009.
Lee Z, Rayner CR, Forrest JI, Nachega JB, Senchaudhuri E, Mills EJ. The rise and fall of hydroxychloroquine for the treatment and prevention of COVID-19. Am J Trop Med Hyg. 2020; In Press. doi:10.4269/ajtmh.20-1320.
Acosta-Elias J, Espinosa-Tanguma R. The Folate Concentration and/or Folic Acid Metabolites in Plasma as Factor for COVID-19 Infection. Front Pharmacol. 2020; 11: 1062.
Zambrano LD, Ellington S, Strid P, Galang RR, Oduyebo T, Tong VT, et al. Update: Characteristics of Symptomatic Women of Reproductive Age with Laboratory-Confirmed SARS-CoV-2 Infection by Pregnancy Status - United States, January 22-October 3, 2020. MMWR Morb Mortal Wkly Rep. 2020; 69(44): 1641-7.
Boyko A.N., Shamalov N.A., Boyko O.V., Arinina E.E., Lyang O.V., Dubchenko E.A., et al. The first experience with Angiovit in the combination treatment of acute COVID-19 infection. Neurology, Neuropsychiatry, Psychosomatics. 2020; 12(3): 82-6.
Lenze EJ, Mattar C, Zorumski CF, Stevens A, Schweiger J, Nicol GE, et al. Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: A randomized clinical trial. JAMA. 2020; In Press. doi:10.1001/jama.2020.22760.
Anusuya Bhattacharyya1, Phulen Sarma2, Hardeep Kaur2, Bikash Medhi21Department of Ophthalmology, GMCH-32, Chandigarh, India ; 2Department of Pharmacology, PGIMER, Chandigarh, India16 October 2020
Hydroxychloroquine (HCQ) vs. folic acid: evaluation of absolute efficacy or relative efficacy against COVID agents?
We read with great interest, the published randomized control trial by Skipper et al [1] in your esteemed journal. It is a well conducted multicentered trial, conducted in two locations (United states and Canadian provinence) with the intention to evaluate the absolute "therapeutic efficacy" of hydroxychloroquine in "symptomatic non-hospitalized" adults. Patients were randomly allocated into either hydroxychloroquine or and placebo arm. While looking into the composition of placebo we could find that folic acid tablet 400 mcg was used as placebo in the US population and lactose tablet in Canada population.
Respected Sir, in in-silico studies folic acid came as a good binder against SARS-CoV-2 furin (required for viral entry to host cell) [2]. In clinical studies, Itelman et al [3] reported lower blood folic acid levels among patients with severe disease compared to those with mild disease. Pregnant women appears to be less likely to require a hospitalization from COVID-19 [4] and Acosta-Elias J et al, 2020 postulated that "folic acid" uptake may be the protective factor. A product Angiovit (containing folic acid & vitamin B12) is associated with a lower duration of "hospital stay" and "fever" compared to control [5]. Many trials evaluating folic acid as therapeutic agent against COVID-19 are currently under way (NCT04354428, PACTR202005599385499).
Skipper et al, 2020 [1], concluded that there was no statistically significant difference in terms of "COVID-19 related symptoms", "incidence of hospitalization" and "death" between both the arms. This comparable efficacy does not indicate the absolute efficacy of HCQ; rather we can say its comparative efficacy between HCQ and folic acid and both performed equally. Again, rather than calling this trial a placebo controlled trial, it will be better to address as a "head-on" comparison between HCQ and folic acid.
Skipper CP, Pastick KA, Engen NW et al. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 : A Randomized Trial. Ann Intern Med. 2020 Jul 16:M20-4207. doi: 10.7326/M20-4207.
Sheybani Z, Dokoohaki MH, Negahdaripour M et al. (2020): The Role of Folic Acid in the Management of Respiratory Disease Caused by COVID-19. ChemRxiv. Preprint. https://doi.org/10.26434/chemrxiv.12034980.v1
Itelman E, Wasserstrum Y, Segev A, et al. Clinical Characterization of 162 COVID-19 patients in Israel: Preliminary Report from a Large Tertiary Center. Isr Med Assoc J 2020;22:271–4.
Acosta-Elias J, Espinosa-Tanguma R. The Folate Concentration and/or Folic Acid Metabolites in Plasma as Factor for COVID-19 Infection. Front Pharmacol 2020;11:1062. doi:10.3389/fphar.2020.01062
Boyko A.N, Shamalov N.A, Boyko O.V et al. The first experience with Angiovit in the combination treatment of acute COVID-19 infection. Neurology, Neuropsychiatry, Psychosomatics. 2020; 12(3):82-86.
None of the authors declared any conflict of interest
Caleb P Skipper MD, David R. Boulware MD MPHUniversity of Minnesota24 September 2020
Authors' response to Pavia and Tausk, Bruno Luís de Castro Araujo
In response to Pavia and Tausk, the a priori written protocol and statistical analysis plan called for an intent-to-treat analysis, whereby everyone randomized was analyzed. A modified intent to treat analysis has similar results when excluding those who did not start study medicine, including open-label hydroxychloroquine use (n=1), and carryforward of symptom status for those hospitalized, dead, or with resolved symptoms at day 10. Ongoing symptoms were present at day +5 in 54.9% (100/182) receiving hydroxychloroquine and 57.5% (104/181) receiving placebo. At day +14, ongoing symptoms were present in 24.9% (46/185) who received hydroxychloroquine and 31.1% (56/180) who received placebo. The number needed to treat (NNT) to have 1 additional person be without symptoms at day 14 is 16 persons (95%CI, -34(harm) to 6.5). In restricting to those with 100% adherence to hydroxychloroquine, 25.2% (39/155) of participants had ongoing symptoms at day 14. The original intention-to-treat analysis in the manuscript reported 24.4% vs. 30.4% having symptoms at day 14. Thus, whether modified intention-to-treat or per protocol analysis, the original conclusions remain the same.
Supplemental Table 2 does have a typo in the label of "<75% adherence" which should include zero tablets in the label of <75% adherence. Supplemental Table 3 presents the breakdown on study medicine adherence. A "per protocol analysis" is generally recognized as a biased analysis as this ignores those who stop medications due to side effects. Those who cannot complete a treatment cannot be expected to benefit from the therapy. In this randomized double-blind trial, <100% adherence (range 5-89%) occurred more frequently with hydroxychloroquine at 11.8% (24/203) than with placebo at 7.8% (15/194), most often due to medication side effects or spontaneously improving. At study day 5 when adherence was assessed, among those with 100% adherence, 54.1% (85/157) had ongoing symptoms with hydroxychloroquine versus 56.6% (94/166) with placebo. This minimally differs from the modified intent-to-treat analysis.
In response to Bruno Luís de Castro Araujo, we did not find a statistical difference in covid-related hospitalizations or death (2.2% [5/231] with hydroxychloroquine vs. 3.4% [8/234] with placebo). Whether the magnitude of benefit would be greater in a higher risk population at a greater risk of severe disease, is unknown, as mentioned in the discussion. In a similar early outpatient hydroxychloroquine trial in Barcelona (n=293), Mitja and colleagues found zero virologic effect of hydroxychloroquine (+0.07 log10 copies/mL higher at 7 days, 95%CI, -0.29 lower to 0.44 higher).(1) Their incidence of hospitalization was 5.9% (8/136) with hydroxychloroquine versus 7.0% (11/157) with standard of care in Catalonia.(1) Whether this trend of ~1.3% reduction in hospitalization (95%CI, -1.5% to 4.2%) in the two trials is indeed a real statistically significant difference is the subject of ongoing efforts to pool data across 8 early treatment trials to generate a larger sample size. At present, there is no statistical difference with a NNT of 76 (95%CI, -65(harm) to 24) to prevent a hospitalization in the population studied to date in these two trials, which has encompassed approximately 70% healthcare workers with a median age of ~40 years. Other early treatment trials are ongoing, and outpatient PCR testing in the United States has greatly expanded since our trial's conduct in March and April 2020.
Mitja O, Corbacho-Monne M, Ubals M, et al. Hydroxychloroquine for early treatment of adults with mild covid-19: A randomized-controlled trial. Clin Infect Dis. 2020; doi: 10.1093/cid/ciaa1009. PMCID: 7454406.
Claudia N. Paiva, Daniel V. TauskUFRJ, USP7 September 2020
Patients who never started treatment kept in analysis
We read the article intitled "Hydroxychloroquine in nonhospitalized adults with COVID-19", by Skipper et al, with much interest. We disagree with some of the authors' conclusions, which we believe could not be taken from the data shown.
(1) In suppl table 3, concerning medication adherence, the sum of all categories in HCQ group is: 100% of the tablets, 157; 75-99% of the tablets, 8; <75% of the tablets, 16; never started medication, 22, so = 157+8+16+22= 203. In placebo group, the sum of these categories is 166+3+12+13=194. In suppl table 2, concerning the analysis of symptoms severity according to medication adherence, table states that in HCQ group, 165 patients took >75% of the tablets (15-19) and 38 <75% (1-14), 165+38= 203. In placebo group, 169+25= 194. Comparing these two tables, it becomes clear that in suppl table 2 if category <75% was in fact 1-14 tablets, we should be missing 22 patients in group HCQ and 13 patients in placebo group, who never started medication (0 tablets). Since we are not missing them, in both tables group HCQ has 203 patients and group placebo has 194 patients, I assume the author kept patients who never started medication in HCQ and placebo groups. It is not a question of writing 0-14 instead of 1-14 tablets; it is about excluding patients who did not start treatment from ITT analysis. The "1-14 tablets" induces the reader to assume that authors performed the usual analysis, excluding patients who did not start treatment. We recall that even in intention-to-treat analysis, if no treatment was applied at all, the usual procedure is to exclude these patients from the full analysis set. https://www.clinfo.eu/itt-vs-pp/
(2) We acknowledge that ignoring those patients who stopped the medicine because of side effects introduces biases. However, it does not apply to this situation, since these 22 patients who never started HCQ treatment never experienced any side effects and there were also 13 patients who never started placebo; they did not start treatment for reasons not related to group allocation. While no biases might arise from excluding patients who never started treatment allocated to both HCQ and placebo groups, keeping them in the full analysis set might mask any positive HCQ effects. Masking the positive effects of a drug during a pandemic is a harmful choice.
(3) If a medication is found to work under optimal conditions in the trial setting, the adherence to this medication in the field will be far better. We recall that the uncertainty about the efficacy of a drug being tested in the trial setting may mean that trial participants are less likely to persevere with unpleasant side effects of treatment than those who have been assured of the efficacy of their treatment (1). Yet the authors seem to disregard their own HCQ positive results found when patients taking >75% of the tablets are considered, a significant 19.5% relative benefit in symptom severity (two-tailed p-value=0.022).
(4) Authors "caution against over-interpretation of this result", a 19.5% relative benefit in symptom severity, arguing that "this [adherent HCQ] group did not improve any more than the non-adherent hydroxychloroquine group nor the non-adherent placebo group". However, unlike comparison between treated and untreated group, the comparison between adherent and non-adherent group is invalid as the latter groups are not selected by randomization and are subject to "non-adherence bias", i.e., non-adherent patients might have not taken the drug for instance because they were healthier than adherent patients. This is corroborated by the data in the table which shows that the small non-adherent group did overall much better than the larger adherent group.
(5) We understand that the proper way to analyze the data is by doing both an analysis of the intention-to-treat population (excluding, as usual, patients who took zero tablets) and a per protocol analysis of the patients with 75% adherence to the treatment.
The consequence of these considerations is that conclusions such as the one in the abstract and discussion, "hydroxychloroquine did not substantially reduce symptom severity in outpatients with early, mild COVID-19", cannot be assumed when a possible positive effect might arise from the rightful exclusion of patients who never started treatment and there is a clear 19.5% effect of hydroxychloroquine over placebo when patients who took the tablets are compared, i.e., per-protocol analysis.
Dodd S, White IR, Williamson P. Nonadherence to treatment protocol in published randomised controlled trials: a review. Trials. 2012;13:84.
Claudia Neto Paiva – Associate Professor, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Brazil
Daniel Victor Tausk – Associate Professor, Instituto de Matemática e Estatística, Universidade de São Paulo
David Wiseman PhD, MRPharmSSynechion, Inc.23 July 2020
Hydroxychloroquine: an age- and stage- nuanced, clinically and economically meaningful COVID-19 strategy?
Hydroxychloroquine's (HCQ) apparent inefficacy, with generally safe use in mild COVID-19, reported by Skipper et al.1 and similar RCTs (Tang, cited in2; Mitja3), might be unsurprising given data in more severe disease cited by the accompanying editorial2 were not a consideration of methodology, age, comorbidity and disease stage to suggest otherwise.
Skipper's initial endpoint of at least hospitalization proved inappropriate; a problem shared by Mitja.3 Mitja's use of nasopharyngeal viral load reduction suffers from acknowledged limitations, test unreliability, and temporo-spatial differences in viral shedding in the respiratory tract.4 Further challenging are Skipper's unvalidated and left-censored symptom VAS and possible activity5 of the folate placebo, an issue shared by its companion post-exposure prophylaxis study.6
Categorical measures of disease persistence are (other than their comparisons being underpowered in these already small studies) undiluted by a large majority of participants with good prognoses and, more reliably and meaningfully, inform economically devastating lockdown decisions, driven partly by resource consumption. A 20% relative reduction of symptom persistence from 30% to 24% with HCQ could non-trivially preserve healthcare and essential worker resources and limit (still poorly understood) infectivity of symptomatic cases. Mitja's3 reduction of hospitalization from 7.1% to 5.9% (reported as RR 0.75) could be similarly meaningful as would Tang's finding of a 22% reduction in persistence of PCR positivity associated with HCQ from 18.7% to 14.6%.
Obscured by considering VAS changes is an apparent population bimodality ("improvers" vs. "non-improvers") that could be exploited to stratify risk. With only 24% and 30% of participants accounting for the 28-day VAS of 1.5 (HCQ) and 1.87 (placebo) respectively, average scores in still-symptomatic patients increased to 6.15 and 6.14 respectively.
With no treatment options on the immediate horizon, the secondary surging of COVID-19, the prospect of more lockdowns and their economic consequences, further analysis of this study and related studies is demanded before decisions to abandon HCQ are made. The possibility must also be entertained that zinc or ascorbate, used prevalently and without definition here, may accomplish as much as HCQ in this population.
Along with suggestions of an effect of HCQ in younger subjects for early post-exposure prophylaxis6 as well as synergy between HCQ and zinc7 or methylprednisolone8 in more severe cases, the Skipper and related studies support prospective evaluation of a stage- and age- nuanced approach to COVID-19.
Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19: A Randomized Trial. Ann Int Med 2020. Epub Jul 16 http://doi.org/10.7326/M20-4207
Schluger NW. The Saga of Hydroxychloroquine and COVID-19: A Cautionary Tale. Ann Int Med 2020. Epub Jul 16 http://doi.org/10.7326/M20-5041
Mitjà O, Corbacho-Monné M, Ubals M, et al. Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial. Clin Infect Dis 2020. Epub Jul 17 http://doi.org/10.1093/cid/ciaa1009
Wang K, Zhang X, Sun J, et al. Differences of SARS-CoV-2 Shedding Duration in Sputum and Nasopharyngeal Swab Specimens Among Adult Inpatients With COVID-19. Chest 2020. Epub Jun 23 http://doi.org/10.1016/j.chest.2020.06.015
Serseg T, Benarous K, Yousfi M. Hispidin and Lepidine E: two Natural Compounds and Folic acid as Potential Inhibitors of 2019-novel coronavirus Main Protease (2019-nCoVMpro), molecular docking and SAR study. Current computer-aided drug design 2020. Epub Apr 24 http://doi.org/10.2174/1573409916666200422075440
Boulware DR, Pullen MF, Bangdiwala AS, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med 2020. Epub 2020 June 4 http://doi.org/10.1056/NEJMoa2016638
Carlucci P, Ahuja T, Petrilli CM, et al. Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-19 patients. medRxiv 2020:2020.05.02.20080036. Epub http://doi.org/10.1101/2020.05.02.20080036
Arshad S, Kilgore P, Chaudhry ZS, et al. Treatment with Hydroxychloroquine, Azithromycin, and Combination in Patients Hospitalized with COVID-19. Int J Infect Dis 2020. Epub 2020 Jul 1 http://doi.org/10.1016/j.ijid.2020.06.099
Author does not have an conflict of interest
Ricardo Francalacci SavarisUniversidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil20 July 2020
Where is the power?
I read with great interest the paper published by Skipper et al on Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19: A Randomized Trial (Ann Intern Med. 2020 Jul 16. doi: 10.7326/M20-4207).
I tried to calculate the power of their results from Figure 3, considering that symptoms were 24.4% and 30.4% in the hydroxychloroquine (n=201) and placebo (194) group respectively. Post-hoc test for power was 26.7%; if these are the results, the implications are quite serious.
Furthermore, I would expect a more rigorous study. The heavily criticized [1] article published by Gautret et al., the French group used RT-PCR results as the main outcome in patients [2].
In the study presented by Skipper et al. , they used self-reported survey data using the REDCap system, i.e., individuals would have to access the internet and send their impressions.
Sadly enough, the major headlines present that hydroxychloroquine does not work. At least, they found that the incidence of side effects is lower than it has been announced.
1 eliesbik. Thoughts on the Gautret et al. paper about Hydroxychloroquine and Azithromycin treatment of COVID-19 infections. Science Integrity Digest. 2020.https://scienceintegritydigest.com/2020/03/24/thoughts-on-the-gautret-et... (accessed 17 May 2020).
2 Gautret P, Lagier J-C, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020;:105949.
Bruno Luís de Castro Araujo, MD, MScHospital do Câncer II, National Cancer Institute of Brazil20 July 2020
Is it time to exclude efficacy for hydroxychloroquine in early COVID-19?
We read with interest the article from Skipper et al about the use of hydroxychloroquine for treatment of early outpatient patients with COVID-19 compatible symptoms or confirmed diagnosis (1). Despite the absence of statistically significant difference in any of the selected outcomes, the negative results of that pertinent study must be interpreted with caution. At first, the study authors established initially as primary outcome an ordinal scale of disease severity (outpatient, inpatient, ICU, death). The evaluation was influenced by the lower than expected incidence of hospitalizations, requiring after interim analysis the change of the primary outcome. Another relevant issue is that the study was originally sized to find a 50% reduction in those outcomes, which seems utopic.
Surprisingly, hydroxychloroquine group had 50% lower incidence of a composite outcome for hospitalization and death for any cause (reported P = 0.29). Hydroxychloroquine treated patients had 24% of patients with persistence of COVID-19 compatible symptoms at 14 days, versus 30% of placebo, denoting a non-significant absolute reduction of 20% between groups (P = 0.21). If confirmed in adequately dimensioned trials, this difference is clinically meaningful. The new primary outcome, mean reduction from baseline in a 10-point visual analogue scale (VAS) for disease severity, at day 14 was close to one in the placebo group, indicating lack of relevance of that endpoint in practice at that time of follow-up. Nevertheless, at 10 days of randomization (11 to 14 days after the start of the symptoms) there was a 0.42 points absolute reduction in VAS scale (P = 0.050).
Hydroxychloroquine use in patients with COVID-19 has a low a priori belief of clinical benefit due to unavailable translational evidence, lack of benefit in previous research with other viruses, and no benefit in previous adequately performed observational research and randomized controlled trials (2,3). The absolute results reported must be considered with caution and interpreted within the limits of the confidence interval for all outcomes. Naturally, the results of this study do not support the use of hydroxychloroquine in early COVID-19. However, the present study findings offer an insight for future research in such specific population and not a proof of lack of any clinically relevant benefit.
Conflicts of interest: none.
1. Skipper CP, Pastick KA, Engen NW, Bangdiwala AS, Abassi M, Lofgren SM, et al. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19. Annals of Internal Medicine [Internet]. 16 de julho de 2020 [citado 18 de julho de 2020]; Disponível em: https://www.acpjournals.org/doi/10.7326/M20-4207
2. Schluger NW. The Saga of Hydroxychloroquine and COVID-19: A Cautionary Tale. Annals of Internal Medicine [Internet]. 16 de julho de 2020 [citado 18 de julho de 2020]; Disponível em: https://www.acpjournals.org/doi/10.7326/M20-5041
3. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19 | NEJM [Internet]. [citado 18 de julho de 2020]. Disponível em: https://www.nejm.org/doi/full/10.1056/NEJMoa2016638
Leeann Naughton-20 July 2020
It is unfortunate that zinc was not administered concomitantly. I would like to see a similar trial with zinc, and also with an option for long term periodic follow up, since we are beginning to see complications emerge weeks later. Zinc makes sense from a pharmacological standpoint, and it is not surprising that without zinc the hydroxychloroquine is not effective.
Dr Manigreeva KrishnatreyaB Borooah Cancer Institute, Guwahati,India20 July 2020
Symptom severity: A surrogate for disease severity?
Comment: Authors of the present study should be commended for their work to determine the role of hydroxychroloquine for reducing severity of symptoms due to coronavirus disease 2019 (COVID-19). Notwithstanding the fact that more than 50% of study participant's test reports were unknown for novel coroanvirus (SARS-CoV-2), I have few comments to make.
Investigators of the study should have stated the reason for considering symptoms severity as a surrogate for disease severity for clarity of novice readers like me. Severity of symptoms is not directly correlated to severity of the disease or in this case COVID-19. As treating doctors, we emphasize on clinical signs to determine disease severity, which everyone follows. For example, if I report cough or shortness of breath today, my symptom severity over the next few days will be different from another person, because of my resilience, prior experience of cough or breathing difficulty, and my present status of health, etc. Authors of the study note that eight COVID19 -related hospitalizations (including 1 death) occurred with placebo versus 4 COVID-19 hospitalizations (and 1 additional death; 5 events in total) in the other arm, but fails to mention the cause of death in nonhospitalized patient in the hydroxychroloquine arm. The authors should investigate the cause of death of the patient in hydroxychroloquine arm. In case death of that patient is not due to COVID-19, then there is around 40% reduction (P = 0.29) in hospitalization and death in the hydroxychroloquine arm, though events (n=15) were too less for such a conclusion. Authors mention in the discussion "our trial findings are most generalizable to populations below 50 years of age" and further suggest "performing randomized trials in long-term care facilities could test whether hydroxychloroquine can reduce hospitalizations".
However, the accompanying editorial concludes "it is time to move on from hydroxychloroquine". It appears there is a bias for writing the epitaph for hydroxychroloquine sooner than later! The editorial states "many good ideas in medicine do not work" . Yes, I agree, but who determines which idea is working or not. In this case, insufficient evidences are being presented to "kill an idea"
James W. Hanway, M.D., F.A.C.P*20 July 2020
Wrong group studied.
This study, with 77% of the participants age 50 or below, does not answer the most critical question; can early use of hydroxychloroquine, or chloroquine, reduce the incidence of severe disease and death. About half of Covid-19 deaths in the U.S. occur in the age 65+ group, about 80% in Canada; this is the group that should be studied, and all the participants should have a positive test before inclusion. The lay press will give undeserved credence to this paper.
Author does not have any conflict of interests
Rochita Venkataramanan, Refai Shoukath Ali, Abdul Ghafur, Akash VenkataramananRochita Venkataramanan - Department of Radiology, Apollo Hospital, Chennai. Refai Shoukath Ali - Department of Cardiology, Apollo Hospital, Chennai. Abdul Ghafur - Department of Infectious Diseases, Apollo Hospital, Chennai. Akash Venkataramanan - Rotating Residential Intern, Madras Medical College.20 July 2020
Is Hydroxychloroquine effective in non-hospitalized adults with early COVID-19?
We read with interest the article titled "Hydroxychloroquine in non-hospitalized adults with early COVID-19: A randomized trial" by Caleb Skipper et al published on 16 July 2020.1
The authors demonstrate only a 12% relative improvement in symptom severity over placebo in patients taking Hydroxychloroquine (HCQ). However, there are some confounders in the study. Study participants (423) were those who completed at least 1 follow-up survey with symptom data. The outcome would be impacted if some participants did not complete all the follow up surveys with this small sample size.
The number of hospitalization and/or death were half (n=5) in the HCQ group as compared to the placebo group (n=10), giving a 'p' value of 0.2. As discussed in the statistics section, the primary endpoint was changed from the ordinal outcome of not-hospitalized, hospitalized, intensive care unit stay or death to overall symptom severity during the first interim analysis, due to the substantially lower event rate than expected. This was because the authors decided that a sample size of 6000 participant is needed to show difference in the event rates, which was considered impossible at that time. Therefore, the doubling of event rate in this relatively small sample size cannot be ignored and needs further evaluation.
There were fewer (77%) participants receiving HCQ who reported complete adherence to the regimen compared with those receiving placebo (86%) likely reducing the performance of HCQ in this study.
Among hospitalized patients, use of HCQ alone and in combination with azithromycin has been demonstrated to be associated with a significant reduction in-hospital mortality compared to not receiving HCQ.2 Further, consumption of four or more maintenance doses of HCQ has been shown to be associated with a significant decline in the odds of getting infected.3 In view of above points, a larger sample size study would be worthwhile to see if HCQ performs better than placebo in non-hospitalized adults with COVID-19.
Skipper C B, Pastick K A, Engen N W, Bangdiwala A S, Abassi M, Lofgren S M, et al. Hydroxycholoroquine in non-hospitalized adults with early COVID-19.Ann Int Med. https://doi.org/10.7326/M20-4207 (available online 16 July 2020)
Arshad S, Kilgore P, Chaudhry ZS, Jacobsen G, Wang DD, Huitsing K, Brar I, Alangaden GJ, Ramesh MS, McKinnon JE, O'Neill W. Treatment with Hydroxychloroquine, Azithromycin, and Combination in Patients Hospitalized with COVID-19. International Journal of Infectious Diseases. 2020 Jul 2.
Chatterjee P, Anand T, Singh KJ, Rasaily R, Singh R, Das S, Singh H, Praharaj I, Gangakhedkar RR, Bhargava B, Panda S. Healthcare workers & SARS-CoV-2 infection in India: A case-control investigation in the time of COVID-19. Indian J Med Res. 2020 Jun 5.
The authors disclose no conflict of interest.
Acknowledgment: The authors thank the research volunteers for consenting to participate in this trial and the late Dr. Charlie Van der Horst for inspiration in infectious diseases research and a commitment to social justice. They also thank the trial's research collaborators, Alyssa Agostinis, Sarah Elsayed, Derek LaBar, Alek Lefevbre, Nicole Marten, Kristen Moran, and Lulu Smith.
Financial Support: By Steve Kirsch, Jan and David Baszucki, the Minnesota Chinese Chamber of Commerce, the Alliance of Minnesota Chinese Organizations, and the University of Minnesota Foundation. Drs. Nicol, Rajasingham, and Pullen are supported by the National Institute of Allergy and Infectious Diseases (K08AI134262, K23AI138851, and T32AI055433). Dr. Lofgren is supported by the National Institute of Mental Health (K23MH121220). Dr. Skipper is supported by a combined Fogarty International Center/National Institute of Neurological Disorders and Stroke grant (D43TW009345). Ms. Pastick and Ms. Okafor are Doris Duke International Clinical Research Fellows supported through the Doris Duke Charitable Foundation. Drs. Boulware, Hullsiek, Engen, and Bangdiwala are supported by grants R01AI118511 and U01AI125003 from the National Institutes of Health, with an emergency supplement request made. Drs. Lee and McDonald receive salary support from the Fonds de recherche du Québec – Santé. Canadian funding was received from various sources. In Quebec, funds were received from the Clinical Practice Assessment Unit of the McGill University Health Centre and the McGill Interdisciplinary Initiative in Infection and Immunity's Emergency COVID-19 Research Funding. In Manitoba, research support was received from the Manitoba Medical Service Foundation and Research Manitoba. Purolator Canada provided in-kind courier support for the participating Canadian sites. Apotex Canada and Rising Pharmaceuticals in the United States provided a donation of some of the hydroxychloroquine tablets used.
Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M20-4207.
Data Sharing Statement: The following data will be made available beginning 22 July 2020: deidentified participant data, data dictionary (covidpep.umn.edu). The following supporting documents will be made available with publication: informed consent form (ClinicalTrials.gov). These data will be made available for open access (restrictions: none).
Corresponding Author: David R. Boulware, MD, MPH, 689 23rd Avenue, Minneapolis, MN 55455; e-mail, faq.[email protected]com.
Current Author Addresses: Drs. Skipper, Abassi, Lofgren, Pullen, Rajasingham, and Boulware; Ms. Pastick; Ms. Williams; and Ms. Okafor: 689 23rd Avenue SE, Minneapolis, MN 55455.
Ms. Engen, Ms. Bangdiwala, and Dr. Hullsiek: School of Public Health, University of Minnesota, 2221 University Avenue SE, Suite 200, Minneapolis, MN 55414.
Dr. Nicol: 2001 6th Street SE, MTRF 4-210, Minneapolis, MN 55455.
Ms. Nascene: Department of Psychiatry, 717 Delaware Street SE, Suite 516, Minneapolis, MN 55414.
Dr. Cheng: Divisions of Infectious Diseases and Medical Microbiology, McGill University Health Centre, 1001 Décarie Boulevard, Room E05.1709, Montréal, QC H4A 3J1, Canada.
Ms. Luke: 420 Delaware Street SE, MMC 611 Mayo, Minneapolis, MN 55455.
Dr. Lother: JJ399-820 Sherbrook Street, Winnipeg, MB R3A 1R9, Canada.
Dr. MacKenzie: 543 Basic Medical Sciences Building, 745 Bannatyne Avenue, Winnipeg, MB R3E 0J9, Canada.
Dr. Drobot: C5010 - 409 Taché Avenue, Winnipeg, MB R2H 2A6, Canada.
Dr. Kelly: 417-753 McDermot Avenue, Winnipeg, MB R3E 0T6, Canada.
Dr. Schwartz: 1-124 Clinical Sciences Building, 11304-83 Avenue NW, Edmonton, AB T6G 2G3, Canada.
Dr. Zarychanski: ON4005 – 675 McDermot Avenue, Winnipeg, MB R3M 3M6, Canada.
Dr. McDonald: 5252 De Maisonneuve, Room 3E.03, Montréal, QC H4A 3S9, Canada.
Dr. Lee: 1001 Décarie Boulevard, Room E5.1820, Montréal, QC H4A 3S1, Canada.
Author Contributions: Conception and design: C.P. Skipper, K.A. Pastick, M. Abassi, S.M. Lofgren, M.F. Pullen, M.R. Nicol, K.H. Hullsiek, L.J. MacKenzie, R. Zarychanski, R. Rajasingham, D.R. Boulware.
Analysis and interpretation of the data: C.P. Skipper, K.A. Pastick, N.W. Engen, A.S. Bangdiwala, S.M. Lofgren, E.C. Okafor, M.F. Pullen, M.R. Nicol, K.H. Hullsiek, I.S. Schwartz, R. Zarychanski, T.C. Lee, R. Rajasingham, D.R. Boulware.
Drafting of the article: C.P. Skipper, K.A. Pastick, N.W. Engen, A.S. Bangdiwala, M. Abassi, S.M. Lofgren, E.C. Okafor, M.F. Pullen, A.A. Nascene, L.J. MacKenzie, G. Drobot, L.E. Kelly, T.C. Lee, D.R. Boulware.
Critical revision of the article for important intellectual content: C.P. Skipper, S.M. Lofgren, M.F. Pullen, M.R. Nicol, K.H. Hullsiek, M.P. Cheng, S.A. Lother, L.J. MacKenzie, L.E. Kelly, I.S. Schwartz, E.G. McDonald, T.C. Lee, R. Rajasingham, D.R. Boulware.
Final approval of the article: C.P. Skipper, K.A. Pastick, N.W. Engen, A.S. Bangdiwala, M. Abassi, S.M. Lofgren, D.A. Williams, E.C. Okafor, M.F. Pullen, M.R. Nicol, A.A. Nascene, K.H. Hullsiek, M.P. Cheng, D. Luke, S.A. Lother, L.J. MacKenzie, G. Drobot, L.E. Kelly, I.S. Schwartz, R. Zarychanski, E.G. McDonald, T.C. Lee, R. Rajasingham, D.R. Boulware.
Provision of study materials or patients: M.F. Pullen, M.P. Cheng, D. Luke, G. Drobot, L.E. Kelly, I.S. Schwartz, E.G. McDonald, T.C. Lee.
Statistical expertise: N.W. Engen, A.S. Bangdiwala, K.H. Hullsiek.
Obtaining of funding: M.P. Cheng, R. Zarychanski, E.G. McDonald, T.C. Lee, D.R. Boulware.
Administrative, technical, or logistic support: C.P. Skipper, K.A. Pastick, A.S. Bangdiwala, S.M. Lofgren, D.A. Williams, E.C. Okafor, M.F. Pullen, A.A. Nascene, S.A. Lother, L.E. Kelly, I.S. Schwartz, T.C. Lee, D.R. Boulware.
Collection and assembly of data: C.P. Skipper, K.A. Pastick, A.S. Bangdiwala, M. Abassi, D.A. Williams, E.C. Okafor, M.F. Pullen, A.A. Nascene, L.J. MacKenzie, L.E. Kelly, I.S. Schwartz, E.G. McDonald, T.C. Lee, D.R. Boulware.
This article was published at Annals.org on 16 July 2020.
Previousarticle
Nextarticle
The Saga of Hydroxychloroquine and COVID-19: A Cautionary Tale
Neil W. Schluger
Anusuya Bhattacharyya ,
Phulen Sarma ,
Hardeep Kaur , and
Bikash Medhi
Claudia N. Paiva and
Daniel V. Tausk
Caleb P. Skipper and
David R. Boulware
Bruno Luís de Castro Araujo
Many trials of hydroxychloroquine for SARS-CoV-2 were redundant and potentially unethical: an analysis of the NIH clinical trials registry
Risk factors for delirium among SARS-CoV-2 positive veterans
Perspectives on Virtual (Remote) Clinical Trials as the "New Normal" to Accelerate Drug Development
Triangle of cytokine storm, central nervous system involvement, and viral infection in COVID-19: the role of sFasL and neuropilin-1
Treatment and therapeutic agents
QTc prolongation and mortality in SARS-2-CoV-infected patients treated with azithromycin and hydroxychloroquine
Antimalarial drugs—are they beneficial in rheumatic and viral diseases?—considerations in COVID-19 pandemic
Representativeness of Racial and Ethnic Groups in COVID-19 Outpatient Trials in the United States
Comparative effectiveness of pharmacological interventions on mortality and the average length of hospital stay of patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials
SARS-CoV-2 Antiviral Therapy
ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic: part 2—care pathways, treatment, and follow-up
Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials
Hydroxychloroquine in the treatment of outpatients with mildly symptomatic COVID-19: a multi-center observational study
Cost utility analysis of Remdesivir and Dexamethasone treatment for hospitalised COVID-19 patients - a hypothetical study
Severe COVID-19 in pediatric age: an update on the role of the anti-rheumatic agents
Effect of azithromycin and hydroxychloroquine in patients hospitalized with COVID‐19: Network meta‐analysis of randomized controlled trials
Clinical Management of Adult Patients with COVID-19 Outside Intensive Care Units: Guidelines from the Italian Society of Anti-Infective Therapy (SITA) and the Italian Society of Pulmonology (SIP)
COVID-19 in Children: Update on Diagnosis and Management
Implementation of a fully remote randomized clinical trial with cardiac monitoring
Update on Retinal Drug Toxicities
Therapeutic Options for Coronavirus Disease 2019 (COVID-19): Where Are We Now?
Impact of hydroxychloroquine used as DMARD on SARS-CoV-2 tests and infection evolution in a population of 871 patients with inflammatory rheumatic and musculoskeletal diseases
Hydroxychloroquine and mortality in COVID-19 patients: a systematic review and a meta-analysis of observational studies and randomized controlled trials
A Narrative Review of Existing Options for COVID-19-Specific Treatments
Potent Anti-SARS-CoV-2 Activity by the Natural Product Gallinamide A and Analogues via Inhibition of Cathepsin L
Inhaled and intranasal ciclesonide for the treatment of covid-19 in adult outpatients: CONTAIN phase II randomised controlled trial
Utilization of drugs with reports on potential efficacy or harm on COVID ‐19 before, during, and after the first pandemic wave
Effects of chloroquine or hydroxychloroquine treatment on non‐SARS‐CoV2 viral infections: A systematic review of clinical studies
A hitchhiker's guide through the COVID-19 galaxy
A Retrospective Analysis of the Impact of the Coronavirus Disease 2019 Pandemic on Health Care Workers in a Tertiary Hospital in Turkey
Mesenchymal stem cells in SARS-CoV-2 infection: A hype or hope
Decision-making in the midst of uncertainty: appraising expensive medicines in England
Photo-mediated and advanced oxidative processes applied for the treatment of effluents with drugs used for the treatment of early COVID-19: Review
ESCMID COVID-19 living guidelines: drug treatment and clinical management
Abstracts for reports of randomized trials of COVID-19 interventions had low quality and high spin
Clinical trials in COVID-19 management & prevention: A meta-epidemiological study examining methodological quality
Inflammatory but not respiratory symptoms are associated with ongoing upper airway viral shedding in outpatients with uncomplicated COVID-19
Current Updates on Covid-19 Vaccine Research and an Overview of Therapeutic Drug Research
HeberNasvac, a Therapeutic Vaccine for Chronic Hepatitis B, Stimulates Local and Systemic Markers of Innate Immunity: Potential Use in SARS-CoV-2 Postexposure Prophylaxis
Risk of coronavirus disease 2019 hospitalization and mortality in rheumatic patients treated with hydroxychloroquine or other conventional disease-modifying anti-rheumatic drugs in Italy
Reply to Neves
Pharmacological interventions for COVID-19: a systematic review of observational studies and clinical trials
Medication safety in a pandemic: A multicentre point prevalence study of QTc monitoring of hydroxychloroquine for COVID‐19
Efficacy and safety of hydroxychloroquine as pre-and post-exposure prophylaxis and treatment of COVID-19: A systematic review and meta-analysis of blinded, placebo-controlled, randomized clinical trials.
Efficacy and safety of current medications for treating severe and non-severe COVID-19 patients: an updated network meta-analysis of randomized placebo-controlled trials
COVID-19: Pulmonary and Extra Pulmonary Manifestations
Efficacy of COVID-19 Treatments: A Bayesian Network Meta-Analysis of Randomized Controlled Trials
Randomized study of rivaroxaban vs. placebo on disease progression and symptoms resolution in high-risk adults with mild COVID-19
Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial
Doxycycline for community treatment of suspected COVID-19 in people at high risk of adverse outcomes in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial
Nigella sativa for the treatment of COVID-19: An open-label randomized controlled clinical trial
Characteristics of patients with immune-mediated inflammatory diseases hospitalized for SARS-CoV-2 infection
Cardiovascular Safety of Hydroxychloroquine in US Veterans With Rheumatoid Arthritis
Effet d'un traitement par hydroxychloroquine prescrit comme traitement de fond de rhumatismes inflammatoires chroniques ou maladies auto-immunes systémiques sur les tests diagnostiques et l'évolution de l'infection à SARS CoV-2 : étude de 871 patients
Efficacy of chloroquine and hydroxychloroquine in treating COVID-19 infection: A meta-review of systematic reviews and an updated meta-analysis
India and management of COVID-19: A case study on published guidelines
Remdesivir and Mortality in Patients With Coronavirus Disease 2019
Antirheumatic drugs and COVID-19: frustrations and hopes
Examining reporting and representation of patients with cancer in COVID ‐19 clinical trials
HIV and COVID-19: Lessons From HIV and STI Harm Reduction Strategies
Negacionismo religioso: Bolsonaro e lideranças evangélicas na pandemia Covid-19
Analysis of COVID-19 Guideline Quality and Change of Recommendations: A Systematic Review
Hydroxychloroquine in the treatment of coronavirus disease 2019: Rapid updated systematic review and meta‐analysis
Evidence-based approach to early outpatient treatment of SARS-CoV-2 (COVID-19) infection
Does hydroxychloroquine still have any role in the COVID-19 pandemic?
Concerning Pathophysiology and Justifying Clinical Trials
Clinical presentation, outcomes and factors associated with mortality: A prospective study from three COVID-19 referral care centres in West Africa
Clinical outcomes of patients with mild COVID-19 following treatment with hydroxychloroquine in an outpatient setting
Evaluating the methodology of studies conducted during the global COVID-19 pandemic: A systematic review of randomized controlled trials
Pharmacokinetics and pharmacodynamics of hydroxychloroquine in hospitalized patients with COVID-19
Advances in the computational landscape for repurposed drugs against COVID-19
Molecular Perspectives of SARS-CoV-2: Pathology, Immune Evasion, and Therapeutic Interventions
Safety and efficacy of a COVID‑19 treatment with nebulized and/or intravenous neutral electrolyzed saline combined with usual medical care vs. usual medical care alone: A randomized, open‑label, controlled trial
Disentangling the Association of Hydroxychloroquine Treatment with Mortality in Covid-19 Hospitalized Patients through Hierarchical Clustering
Discovery of Cyclic Peptide Ligands to the SARS-CoV-2 Spike Protein Using mRNA Display
COVID-19—Lessons Learned and Questions Remaining
Pharmacological considerations for the treatment of COVID-19 in people living with HIV (PLWH)
Exploring the room for repurposed hydroxychloroquine to impede COVID-19: toxicities and multipronged combination approaches with pharmaceutical insights
QTc prolongation in COVID ‐19 patients treated with hydroxychloroquine, chloroquine, azithromycin, or lopinavir/ritonavir: A systematic review and meta‐analysis
The Rise and Fall of Hydroxychloroquine with the COVID-19 Pandemic: Narrative Review of Selected Data
A scheme for inferring viral-host associations based on codon usage patterns identifies the most affected signaling pathways during COVID-19
Efficacy and safety of hydroxychloroquine/chloroquine against SARS-CoV-2 infection: A systematic review and meta-analysis
Infection à SARS-CoV-2 : connaissances au 15 avril 2021
COVID-19 in patients with systemic lupus erythematosus: lessons learned from the inflammatory disease
Hydroxychloroquine as Pre-exposure Prophylaxis for Coronavirus Disease 2019 (COVID-19) in Healthcare Workers: A Randomized Trial
Hydroxychloroquine for Prevention of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: Challenges to Trial Conduct During the Global Pandemic
COVID ‐19 and the generation of novel scientific knowledge: Research questions and study designs
EULAR points to consider on pathophysiology and use of immunomodulatory therapies in COVID-19
Immunomodulatory therapies for SARS-CoV-2 infection: a systematic literature review to inform EULAR points to consider
Platform Randomised trial of INterventions against COVID-19 In older peoPLE (PRINCIPLE): protocol for a randomised, controlled, open-label, adaptive platform, trial of community treatment of COVID-19 syndromic illness in people at higher risk
Considerations of the effects of commonly investigated drugs for COVID-19 in the cholesterol synthesis pathway
Therapeutic strategies to fight COVID‐19: Which is the status artis ?
The Course of COVID-19 in Four Patients with HIV During the Pandemic
A two-arm, randomized, controlled, multi-centric, open-label phase-2 study to evaluate the efficacy and safety of Itolizumab in moderate to severe ARDS patients due to COVID-19
Epidemiology, pathogenesis, clinical presentations, diagnosis and treatment of COVID-19: a review of current evidence
Reply to Million et al
COVID‐19 pathogenesis, prognostic factors, and treatment strategy: Urgent recommendations
COVID-19 and Disease-Modifying Anti-rheumatic Drugs
Unproven Therapy Algorithms for Early SARS-CoV-2 Infection Are Dangerous
Asthma in patients with coronavirus disease 2019
National Psoriasis Foundation COVID-19 Task Force guidance for management of psoriatic disease during the pandemic: Version 2—Advances in psoriatic disease management, COVID-19 vaccines, and COVID-19 treatments
Complementary and alternative medicines use in COVID-19: A global perspective on practice, policy and research
Correlation of the rise and fall in COVID-19 cases with the social isolation index and early outpatient treatment with hydroxychloroquine and chloroquine in the state of Santa Catarina, southern Brazil: A retrospective analysis
Coronavirus Disease 2019 in Kidney Transplant Recipients: Single-Center Experience and Case-Control Study
Recent Antiviral Treatment and Vaccination Strategies Against SARS-CoV-2
Mortality, viral clearance, and other clinical outcomes of hydroxychloroquine in COVID‐19 patients: A systematic review and meta‐analysis of randomized controlled trials
Ivermectin in combination with doxycycline for treating COVID-19 symptoms: a randomized trial
Exploring insights of hydroxychloroquine, a controversial drug in Covid-19: An update
Ethical dimensions in randomized trials and off-label use of investigational drugs for COVID-19 treatment
Concerns About the Special Article on Hydroxychloroquine and Azithromycin in High-Risk Outpatients With COVID-19
COVID-19: Antiviral Tedavi
Use of hydroxychloroquine and chloroquine in patients with COVID-19: a meta-analysis of randomized clinical trials
Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19
Zoonotic coronavirus epidemics
The first 12 months of COVID-19: a timeline of immunological insights
How Are Emerging Data Translated Into Clinical Practice? A Mixed Methods Investigation of Coronavirus Disease 2019 Institutional Treatment Protocols
Management of hospitalised adults with coronavirus disease 2019 (COVID-19): a European Respiratory Society living guideline
Deep Transfer Learning Approach for Automatic Recognition of Drug Toxicity and Inhibition of SARS-CoV-2
Neutralizing Antibody Therapeutics for COVID-19
Assessing the efficacy and safety of hydroxychloroquine as outpatient treatment of COVID-19: a randomized controlled trial
Current evidence for COVID-19 therapies: a systematic literature review
Correction: Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19
Claudia N. Paiva, PhD,
Daniel V. Tausk, PhD
Bruno Luís de Castro Araujo, MD, MSc
Anusuya Bhattacharyya, MBBS, DO, DNB (Ophthalmology),
Phulen Sarma, MBBS, MD, DM (Clinical Pharmacology), PDCR,
Hardeep Kaur, MSc,
Bikash Medhi, MBBS, MD, MAMS
Evaluation of the Current Therapeutic Approaches for COVID-19: A Systematic Review and a Meta-analysis
Assessment of the Temporal Trajectory of Clinical Trials for COVID-19 Interventions After Highly Publicized Lay and Medical Attention
Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial
Hydroxychloroquine for the treatment of COVID-19 and its potential cardiovascular toxicity: Hero or villain?
Clinically applicable approach for predicting mechanical ventilation in patients with COVID-19
Therapeutic strategies for severe COVID-19: a position paper from the Italian Society of Infectious and Tropical Diseases (SIMIT)
Pharmacological strategies to prevent SARS-CoV-2 infection and treat the early phases of COVID-19
Características de pacientes con enfermedades inflamatorias inmunomediadas hospitalizados por infección por SARS-CoV-2
Systems and Clinical Pharmacology of COVID-19 Therapeutic Candidates: A Clinical and Translational Medicine Perspective
Outcomes of COVID-19 Patients Hospitalized at Acute Care Services
Management of COVID-19 in cancer patients receiving cardiotoxic anti-cancer therapy. Future recommendations for cardio-oncology
From hydroxychloroquine to ivermectin: what are the anti-viral properties of anti-parasitic drugs to combat SARS-CoV-2?
TLR Agonists as Mediators of Trained Immunity: Mechanistic Insight and Immunotherapeutic Potential to Combat Infection
Evidence-Based Guidelines Should Be Used To Inform COVID-19 Management
Bringing evidence from press release to the clinic in the era of COVID-19
Modalities and Mechanisms of Treatment for Coronavirus Disease 2019
Effectiveness of Antiviral and Immunomodulatory Agents in the Treatment of COVID-19: A Systematic Review
Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19
Pregnancy and COVID ‐19: pharmacologic considerations
Reporting and design of randomized controlled trials for COVID-19: A systematic review
Assessing QT interval in COVID-19 patients:safety of hydroxychloroquine-azithromycin combination regimen
Lessons Learned From Conducting Internet-Based Randomized Clinical Trials During a Global Pandemic
The Rheumatology Drugs for COVID-19 Management: Which and When?
High SARS-CoV-2 load in the nasopharynx of patients with a mild form of COVID-19 is associated with clinical deterioration regardless of the hydroxychloroquine administration
Hydroxychloroquine with or without Azithromycin in Covid-19
Acute severe respiratory syndrome coronavirus-2 treatment overview for pediatrics
Hydroxychloroquine and COVID-19: a Rheumatologist's Take on the Lessons Learned
COVID-19: What Do Rheumatologists Need to Know?
Antimalarial drugs (and lupus)
Lines of Treatment of COVID-19 Infection
Effect of pre-exposure use of hydroxychloroquine on COVID-19 mortality: a population-based cohort study in patients with rheumatoid arthritis or systemic lupus erythematosus using the OpenSAFELY platform
Hydroxychloroquine in the prevention of COVID-19 mortality
Prevention and treatment of COVID-19: Focus on interferons, chloroquine/hydroxychloroquine, azithromycin, and vaccine
COVID-19: A review of therapeutic strategies and vaccine candidates
How useful is serology for COVID-19?
Combining Antivirals and Immunomodulators to Fight COVID-19
Efficacy of chloroquine or hydroxychloroquine in COVID-19 patients: a systematic review and meta-analysis
COVID-19 and Solid Organ Transplantation: A Review Article
Let's do better: public representations of COVID-19 science
Potential Anti-Coronavirus Agents and the Pharmacologic Mechanisms
Experimental Pharmacotherapy for COVID-19: The Latest Advances
Balancing Healthcare and Economy Amidst the COVID-19 Pandemic: An Indian Experience
Chloroquine and Hydroxychloroquine for the Prevention and Treatment of COVID-19: A Fiction, Hope or Hype? An Updated Review
Bots and Misinformation Spread on Social Media: Implications for COVID-19
Actualización del manejo clínico de COVID-19 en pediatría: a un año de pandemia
Revised Korean Society of Infectious Diseases/National Evidence-based Healthcarea Collaborating Agency Guidelines on the Treatment of Patients with COVID-19
A literature review of consent declines and consent withdrawals in randomized controlled trials conducted during the COVID-19 pandemic
COVID-19 Outbreak in Italy: Report on the First 124 Consecutive Patients Treated at Home
The predictive role of lymphocyte subsets and laboratory measurements in COVID-19 disease: a retrospective study
Emergence of Ethnomedical COVID-19 Treatment: A Literature Review
Hydroxychloroquine for the treatment and prophylaxis of COVID-19: The journey so far and the road ahead
Japanese rapid/living recommendations on drug management for COVID‐19
Re: 'Effect of hydroxychloroquine with or without azithromycin on the mortality of COVID-19 patients' by Fiolet et al.
Effect of hydroxychloroquine with or without azithromycin on the mortality of COVID-19 patients: authors' response
Has the door closed on hydroxychloroquine for SARS-COV-2?
Rational for meta-analysis and randomized treatment: the COVID-19 example
Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis
Prescription, over-the-counter (OTC), herbal, and other treatments and preventive uses for COVID-19
Management of symptomatic patients with suspected mild-moderate COVID-19 in general practice. What was published within the first year of the pandemic? A scoping review
Comparative efficacy and safety of pharmacological interventions for the treatment of COVID-19: A systematic review and network meta-analysis
Multidisciplinary Approach to the Diagnosis and In-Hospital Management of COVID-19 Infection: A Narrative Review
Update Alert 3: Hydroxychloroquine or Chloroquine for the Treatment or Prophylaxis of COVID-19
Adrian V. Hernandez, MD, PhD,
Yuani M. Roman, MD, MPH,
Vinay Pasupuleti, MD, MS, PhD,
Joshuan J. Barboza, MSc,
C. Michael White, PharmD
Rise and Fall: Hydroxychloroquine and COVID‐19 Global Trends: Interest, Political Influence, and Potential Implications
Low-dose radiotherapy for COVID-19 pneumonia treatment: case report, procedure, and literature review
Randomized double-blinded placebo-controlled trial of hydroxychloroquine with or without azithromycin for virologic cure of non-severe Covid-19
Efficacy and safety of hydroxychloroquine in healthcare professionals with mild SARS-CoV-2 infection: Prospective, non-randomized trial
Use of hydroxychloroquine and chloroquine in COVID-19: How good is the quality of randomized controlled trials?
Natural history of COVID-19 and therapeutic options
Is Machine Learning a Better Way to Identify COVID-19 Patients Who Might Benefit from Hydroxychloroquine Treatment?—The IDENTIFY Trial
Practical Experience of Using Riamilovir in Treatment of Patients with Moderate COVID-19
A Note From the Editors
Hydroxychloroquine in Hospitalized Patients with COVID‐19: Real‐World Experience Assessing Mortality
Coronavirus disease 2019 (COVID-19): Immunological approaches and emerging pharmacologic treatments
It is time to drop hydroxychloroquine from our COVID-19 armamentarium
Hydroxychloroquine is effective, and consistently so when provided early, for COVID-19: a systematic review
Safety of Hydroxychloroquine Among Outpatient Clinical Trial Participants for COVID-19
Recent Clinical and Preclinical Studies of Hydroxychloroquine on RNA Viruses and Chronic Diseases: A Systematic Review
The association of treatment with hydroxychloroquine and hospital mortality in COVID-19 patients
Mild or Moderate Covid-19
Neil W. Schluger, MD
Hydroxychloroquine in COVID-19: Potential Mechanism of Action Against SARS-CoV-2
Azithromycin for severe COVID-19
Antiviral monotherapy for hospitalised patients with COVID-19 is not enough
Data on chloroquine/hydroxychloroquine content in compounded oral suspension after filtration and centrifugation
Controversies over hydroxychloroquine in the prevention of SARS-CoV-2 infection put rheumatologists on the frontline
The Pipeline of Therapeutics Testing During the Emergency Phase of the COVID-19 Outbreak
Therapeutic Options Against the New Coronavirus: Updated Clinical and Laboratory Evidences
Combination therapy at an early stage of the novel coronavirus infection (COVID-19). Case series and design of the clinical trial "BromhexIne and Spironolactone for CoronаvirUs Infection requiring hospiTalization (BISCUIT)"
Cytokine Storm in COVID-19: "When You Come Out of the Storm, You Won't Be the Same Person Who Walked in"
Oxidative Stress, Proton Fluxes, and Chloroquine/Hydroxychloroquine Treatment for COVID-19
The Model for Early COvid-19 Recognition (MECOR) Score: A Proof-of-Concept for a Simple and Low-Cost Tool to Recognize a Possible Viral Etiology in Community-Acquired Pneumonia Patients during COVID-19 Outbreak
Coronavirus Antiviral Research Database (CoV-RDB): An Online Database Designed to Facilitate Comparisons between Candidate Anti-Coronavirus Compounds
Review of current clinical management guidelines for COVID-19 with special reference to India
Antirheumatic drugs, B cell depletion and critical COVID-19: correspondence on 'Clinical course of coronavirus disease 2019 (COVID-19) in a series of 17 patients with systemic lupus erythematosus under long-term treatment with hydroxychloroquine' by Mathian et al
Quality Assessment of the Chinese Clinical Trial Protocols Regarding Treatments for Coronavirus Disease 2019
Response to: 'Correspondence on ' Festina lente : hydroxychloroquine, COVID-19and the role of the rheumatologist' by Graef et al ' by Lo et al
COVID-19 Therapeutic Options Under Investigation
Dual-histamine receptor blockade with cetirizine - famotidine reduces pulmonary symptoms in COVID-19 patients
A Focus on the Nowadays Potential Antiviral Strategies in Early Phase of Coronavirus Disease 2019 (Covid-19): A Narrative Review
Drug treatments for covid-19: living systematic review and network meta-analysis
Hydroxychloroquine and COVID-19: Lack of Efficacy and the Social Construction of Plausibility
The Landscape of Emerging Randomized Clinical Trial Evidence for COVID-19 Disease Stages: A Systematic Review of Global Trial Registries
COVID-19—Practicing prevention in the workplace
20 October 2020Volume 173, Issue 8
Page: 623-631
ePublished: 16 July 2020
Issue Published: 20 October 2020
Copyright © 2020 by American College of Physicians. All Rights Reserved.
Close Figure Viewer
Browse All FiguresReturn to Figure Change zoom level
Previous FigureNext Figure
Contributors must reveal any conflict of interest. Comments are moderated. Please see our information for authorsregarding comments on an Annals publication.
*All comments submitted after October 1, 2021 and selected for publication will be published online only.
Name (if multiple authors, separate names by comma) Name field is required
Comment Title Title field is required
Affiliation & Institution (max characters: 200) Affiliations field is required
Comment field is required
Please disclose any conflicts of interest or leave the box unchecked if you have none
Disclosure of Any Conflicts of Interest
ACP Journals home
Print ISSN: 0003-4819 | Online ISSN: 1539-3704
Personae (Cover Photo)
Junior Investigator Awards
Annals in the News
Institutions / Libraries / Agencies
Online ISSN: 2767-7664 | Print ISSN: 2767-7672
Copyright © 2022 American College of Physicians. All Rights Reserved.