Research

JAMA | Original Investigation

Effect of Higher-Dose Ivermectin for 6 Days vs Placebo

on Time to Sustained Recovery in Outpatients With COVID-19
A Randomized Clinical Trial
Susanna Naggie, MD, MHS; David R. Boulware, MD, MPH; Christopher J. Lindsell, PhD; Thomas G. Stewart, PhD;
Alex J. Slandzicki, MD; Stephen C. Lim, MD; Jonathan Cohen, MD; David Kavtaradze, MD; Arch P. Amon, MD;
Ahab Gabriel, MD; Nina Gentile, MD; G. Michael Felker, MD, MHS; Dushyantha Jayaweera, MD;
Matthew W. McCarthy, MD; Mark Sulkowski, MD; Russell L. Rothman, MD, DPP; Sybil Wilson, RN;
Allison DeLong, BS; April Remaly, BA; Rhonda Wilder, MS; Sean Collins, MD, MSci; Sarah E. Dunsmore, PhD;
Stacey J. Adam, PhD; Florence Thicklin; George J. Hanna, MD; Adit A. Ginde, MD, MPH; Mario Castro, MD, MPH;
Kathleen McTigue, MD, MPH, MS; Elizabeth Shenkman, PhD; Adrian F. Hernandez, MD, MHS;
for the Accelerating Covid-19 Therapeutic Interventions and Vaccines (ACTIV)-6 Study Group and Investigators

Visual Abstract
IMPORTANCE It is unknown whether ivermectin, with a maximum targeted dose of Editorial and Editor's Note
600 μg/kg, shortens symptom duration or prevents hospitalization among outpatients with
mild to moderate COVID-19. Supplemental content

OBJECTIVE To evaluate the effectiveness of ivermectin at a maximum targeted dose

of 600 μg/kg daily for 6 days, compared with placebo, for the treatment of early mild to
moderate COVID-19.

DESIGN, SETTING, AND PARTICIPANTS The ongoing Accelerating COVID-19 Therapeutic

Interventions and Vaccines 6 (ACTIV-6) platform randomized clinical trial was designed to
evaluate repurposed therapies among outpatients with mild to moderate COVID-19.
A total of 1206 participants older than 30 years with confirmed COVID-19 experiencing
at least 2 symptoms of acute infection for less than or equal to 7 days were enrolled at 93
sites in the US from February 16, 2022, through July 22, 2022, with follow-up data through
November 10, 2022.

INTERVENTIONS Participants were randomly assigned to receive ivermectin, with a maximum

targeted dose of 600 μg/kg (n = 602) daily, or placebo (n = 604) for 6 days.

MAIN OUTCOMES AND MEASURES The primary outcome was time to sustained recovery,
defined as at least 3 consecutive days without symptoms. The 7 secondary outcomes
included a composite of hospitalization, death, or urgent/emergent care utilization by day 28.

RESULTS Among 1206 randomized participants who received study medication or placebo,
the median (IQR) age was 48 (38-58) years, 713 (59.1%) were women, and 1008 (83.5%)
reported receiving at least 2 SARS-CoV-2 vaccine doses. The median (IQR) time to sustained
recovery was 11 (11-12) days in the ivermectin group and 11 (11-12) days in the placebo group.
The hazard ratio (posterior probability of benefit) for improvement in time to recovery was
1.02 (95% credible interval, 0.92-1.13; P = .68). Among those receiving ivermectin, 34 (5.7%)
were hospitalized, died, or had urgent or emergency care visits compared with 36 (6.0%)
receiving placebo (hazard ratio, 1.0 [95% credible interval, 0.6-1.5]; P = .53). In the ivermectin
group, 1 participant died and 4 were hospitalized (0.8%); 2 participants (0.3%) were
hospitalized in the placebo group and there were no deaths. Adverse events were uncommon Author Affiliations: Author
in both groups. affiliations are listed at the end of this
article.
CONCLUSIONS AND RELEVANCE Among outpatients with mild to moderate COVID-19,
Group Information: A complete list
treatment with ivermectin, with a maximum targeted dose of 600 μg/kg daily for 6 days, of the members of the Accelerating
compared with placebo did not improve time to sustained recovery. These findings do not Covid-19 Therapeutic Interventions
support the use of ivermectin in patients with mild to moderate COVID-19. and Vaccines (ACTIV)-6 Study Group
and Investigators appears in
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04885530 Supplement 4.
Corresponding Author: Susanna
Naggie, MD, MHS, Duke Clinical
Research Institute, Duke University
School of Medicine, 300 W Morgan St,
JAMA. doi:10.1001/jama.2023.1650 Ste 800, Durham, NC 27701 (susanna.
Published online February 20, 2023. naggie@duke.edu).

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 Research Original Investigation Higher-Dose Ivermectin vs Placebo and Time to Sustained Recovery in Outpatients With COVID-19

D
espite treatment advances for COVID-19, the evolu-
tion of SARS-CoV-2 variants and subvariants has Key Points
shifted therapeutic options, including the recent loss
Question Does ivermectin, with a maximum targeted dose of
of effectiveness of monoclonal antibodies. Novel oral antivi- 600 μg/kg daily for 6 days, compared with placebo, shorten
rals have been authorized for high-risk individuals in high- symptom duration among adult (ⱖ30 years) outpatients with
income countries.1,2 However, efficacy of these antivirals in symptomatic mild to moderate COVID-19?
those vaccinated or with prior SARS-CoV-2 infection remains
Findings In this double-blind, randomized, placebo-controlled
unclear. Interest remains for the potential of repurposed platform trial including 1206 US adults with COVID-19 during
drugs to improve symptoms and clinical outcomes among February 2022 to July 2022, the median time to sustained
patients with COVID-19. recovery was 11 days in the ivermectin group and 11 days in the
Numerous repurposed drugs have been investigated for placebo group. In this largely vaccinated (84%) population, the
COVID-19 management, with several large randomized out- posterior probability that ivermectin reduced symptom duration
by more than 1 day was less than 0.1%.
patient trials published.3-5 Trial results have been mixed. Trials
of some drugs suggest possible benefit by reducing emer- Meaning These findings do not support the use of ivermectin
gency department (ED) visits or hospitalizations, including among outpatients with COVID-19.
fluvoxamine dosed at 100 mg twice daily3 and immediate-
release metformin.6 Others have failed to show a reduction in ized), double-blind, randomized placebo-controlled plat-
ED visits or hospitalizations, such as fluvoxamine 50 mg twice form trial investigating repurposed drugs for the treatment of
daily.6,7 Although recently completed trials benefit from the mild to moderate COVID-19 in the outpatient setting. The plat-
increasing representation of vaccinated people, which is more form protocol is designed to be flexible, allowing enrollment
relevant to the pandemic’s current state, the results have not across a wide range of settings within health care systems
affected treatment guidelines largely due to study design limi- and the community, as well as virtually. The platform enrolls
tations, including definitions of outcomes that were of un- outpatients with mild to moderate COVID-19 with a con-
clear significance in the US health care setting.8-10 firmed positive SARS-CoV-2 test result. The full trial protocol
Ivermectin, an antiparasitic drug used worldwide for on- and statistical analysis plan are available in Supplement 1 and
chocerciasis and strongyloidiasis, emerged in 2020 as a po- Supplement 2.
tential repurposed drug for COVID-19 initially informed by an The trial protocol was approved by each site’s institu-
in vitro study suggesting possible antiviral activity.11 The in- tional review board. Participants provided informed consent
terest for ivermectin as a therapy for COVID-19 has remained either via written consent or an electronic consent process. An
high and, although there have been numerous ivermectin independent data monitoring committee oversaw partici-
studies, its use has become controversial due to a lack of high- pant safety and trial conduct.
quality adequately powered randomized trials and article re-
tractions of some of the earlier and most positive studies.12-15 Participants
Three large randomized outpatient trials of people with symp- Recruitment into the platform trial opened on June 11, 2021,
tomatic mild or moderate COVID-19 failed to identify a clini- and ivermectin 600 μg/kg was included on the platform be-
cal benefit of ivermectin when dosed at 400 μg/kg daily for 3 ginning on February 16, 2022. Enrollment into the ivermec-
days.16-18 One possibility is that the dose and duration stud- tin 600 μg/kg group was stopped on July 22, 2022, when 1206
ied were too low and too short, missing the therapeutic win- participants had received their study drug, identical matched
dow for ivermectin. A combination of modeling studies and a placebo, or contributing placebo. Participants were either iden-
proof-of-concept clinical study have suggested doses up to tified by sites or self-identified by contacting a central study
600 μg/kg daily may achieve system levels sufficient for in vitro telephone hotline or website.
antiviral activity.18,19 For this reason we tested ivermectin, with Study staff verified eligibility criteria including age of 30
a maximum targeted dose of 600 μg/kg daily, for 6 days from years or older, SARS-CoV-2 infection within 10 days (positive
February 16, 2022, through July 22, 2022. This report de- polymerase chain reaction or antigen test result, including
scribes the effectiveness of this dose and duration of ivermec- home-based tests), and experiencing at least 2 symptoms of
tin compared with placebo for the treatment of early mild to acute COVID-19 for no more than 7 days from enrollment. The
moderate COVID-19. The primary outcome was time to sus- protocol defined “mild to moderate” as having symptoms as
tained recovery, defined as at least 3 consecutive days with- noted above self-reported at the time of enrollment, and symp-
out symptoms, and secondary outcomes included a compos- toms were graded by participants as none, mild, moderate, or
ite of hospitalization, death, or urgent/emergent care utilization severe. Symptoms included fatigue, dyspnea, fever, cough,
by day 28. nausea, vomiting, diarrhea, body aches, chills, headache, sore
throat, nasal symptoms, and new loss of sense of taste or smell.
Exclusion criteria included hospitalization, ivermectin use
within 14 days, and known allergy or contraindication to the
Methods
study drug (Supplement 1). Vaccination against SARS-CoV-2
Trial Design and Oversight was allowable, as was concurrent use of standard therapies for
Accelerating COVID-19 Therapeutic Interventions and COVID-19 available under US Food and Drug Administration
Vaccines 6 (ACTIV-6) is an ongoing, fully remote (decentral- Emergency Use Authorization or approval.

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 Higher-Dose Ivermectin vs Placebo and Time to Sustained Recovery in Outpatients With COVID-19 Original Investigation Research

Figure 1. Participant Flow in a Trial of Higher-Dose Ivermectin for Mild to Moderate COVID-19

18 525 Self-identified nonhospitalized adults with test-

demonstrated COVID-19 assessed for eligibility

13 296 Did not proceed to the ivermectin group

7834 Did not return a consent form
5157 Consented to inclusion in at least 1
study group not including ivermectin
305 Returned a consent form but declined
to participate in any study group
3017 Presented outside the ivermectin window

2212 Met inclusion criteria and consented

to receive ivermectin

596 Excluded because ineligible for receipt

of ivermectin
265 Eligible but elected not to continue
192 Did not complete screening information
30 Did not meet inclusion criteriaa
23 COVID-19 symptoms for ≥10 d
19 Current or planned use of
contraindicated medications
16 Current/recent COVID-19 hospitalization
11 Receiving warfarin
10 Drug allergy to ivermectin
9 Hospitalized in last 10 d
8 Participated in another COVID-19 trial
7 Current use of ivermectin
3 Pregnant, possibly pregnant, or breastfeeding
3 Kidney disease

a
1616 Eligible to receive ivermectin and randomizedb After consent, test results, birth
date and pre-enrollment symptoms
were reviewed. Patients whose test
282 Randomized to an alternative active result date was found to be 10 days
study drug in the platform trial
prior, who had less than 2
symptoms, whose date of symptom
onset was more than 7 days prior, or
1334 Randomized who was younger than 30 years did
not proceed because they did not
meet baseline inclusion criteria.
668 Randomized to receive ivermectin 676 Randomized to receive placebo b
In this platform trial with multiple
543 Randomized to receive a placebo
matching ivermectin study drugs, participants were able
61 Randomized to receive a placebo to choose what agents they were
matching an alternative active willing to be randomized to receive.
study drug Participants were first randomized
in a ratio of m:1, where m is the
66 Did not receive study 72 Did not receive study
number of study drugs for which
medication in the mail medication in the mail the participant was eligible. After
and were excluded and were excluded randomization to receive an active
agent vs placebo, participants were
randomized with equal probability
602 Included in the primary analysis 604 Included in the primary analysis
among the study drugs for which
they were eligible.

Randomization ized with equal probability among the study drugs for which
Participants were randomized using a random number genera- they were eligible. The more study drugs a participant was eli-
tor in a 2-step process (Figure 1). First, participants were ran- gible for, the greater the chance of receiving an active agent. Par-
domized to receive an active agent or placebo in a ratio of m:1, ticipants who were eligible to receive both ivermectin and
where m is the number of study drugs for which the partici- fluvoxamine 50 mg but were randomized to the fluvoxamine-
pant was eligible; the other study drug under investigation dur- matched placebo group were included in and contributed to the
ing this period was fluvoxamine 50 mg twice daily for 10 days. placebo group for ivermectin.
Participants could choose to opt out of specific study drug groups
during the consent process if they or the site investigator did Interventions
not feel there was equipoise or if there was a contraindication A central pharmacy supplied ivermectin or placebo to partici-
to any study drug on the platform. After randomization to re- pants via direct home delivery. Ivermectin was supplied as
ceive an active agent vs placebo, participants were random- a bottle of 7-mg tablets. Participants were instructed to take

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 Research Original Investigation Higher-Dose Ivermectin vs Placebo and Time to Sustained Recovery in Outpatients With COVID-19

a prespecified number of tablets for 6 consecutive days based pants completed assessments. Supplement 1 presents survey
on their weight for a maximum targeted daily dose of details. Additional details of participant monitoring during fol-
approximately 600 μg/kg. The dosing schedule was based on low-up are available in Supplement 3.
weight ranges as follows: those weighing 35 to 52 kg received
a 21-mg daily dose; 53 to 69 kg, 28-mg daily dose; 70 to 89 kg, Statistical Analysis Plan
42-mg daily dose; 90 to 109 kg, 49-mg daily dose; 110 to This platform trial was designed to be analyzed accepting the
129 kg, 56-mg daily dose; and more than 129 kg, 70-mg daily possibility of adding and dropping groups as the trial pro-
dose. This schedule resulted in a range of doses from 400 to gressed. The general analytical approach was regression mod-
600 μg/kg (eFigure 1 in Supplement 3) and a median (IQR) eling. Proportional hazard regression was used for time-to-
dose of 498 (465-532) μg/kg per day. The median daily dose event analyses and cumulative probability ordinal regression
was calculated among participants randomized to receive models were used for ordinal outcomes. In addition, the mean
ivermectin. Packaging for the matched placebo was identical time spent unwell was estimated using a longitudinal ordinal
to ivermectin and packaging for the contributing placebos regression model as a quantification of benefit.
was identical to that of the associated study drug, which in The complete statistical analysis plan is provided in Supple-
this case was fluvoxamine 50 mg twice daily. ment 2. Briefly, the planned primary end point analysis was a
bayesian proportional hazards model for time to sustained re-
Outcome Measures covery. The primary inferential (decision-making) quantity was
The primary measure of effectiveness was time to sustained the posterior distribution for the treatment assignment haz-
recovery, defined as the number of days between study drug ard ratio (HR), with HR greater than 1 indicating faster recov-
receipt and the third of 3 consecutive days without symp- ery. Decision thresholds and modeling parameters are as pre-
toms. This outcome was selected a priori from among the 2 viously described16 and provided in Supplement 2. The study
co–primary end points that remain available to other study design was estimated to have 80% power to detect an HR of
drugs in the platform (Supplement 2). The key secondary 1.2 in the primary end point with approximately 1200 partici-
outcome was the composite of hospitalization or death by pants. To achieve this sample size in an ongoing platform trial,
day 28. Other secondary outcomes included mean time once 1200 participants had been randomized to the study
unwell, estimated from a longitudinal ordinal model; group or matching placebo and had received the study drug,
COVID-19 Clinical Progression Scale score on days 7, 14, and the study group became unavailable for new participants ex-
28; mortality through day 28; and the composite of urgent or pressing interest in the platform. Some participants had al-
emergency care visits, hospitalizations, or death through day ready consented to participate but had not yet been random-
28. The final secondary outcome, the Patient-Reported Out- ized or received the study drug at the time of group closure,
comes Measurement Information System 29 profile, was to and these participants were allowed to continue as assigned.
be assessed through day 90 and is not reported in this article The primary end point–adjusted model included the fol-
because of the longer follow-up. lowing predictor variables in addition to randomization
assignment: age (as restricted cubic spline), sex, duration of
Trial Procedures symptoms at study drug receipt, calendar time (as restricted
The study was designed as a fully remote, or decentralized, cubic spline, surrogate for SARS-CoV-2 variant/subvariant),
trial. Screening and eligibility confirmation were participant- vaccination status (no vaccination vs ≥1 dose), geographic
reported and site-confirmed. A positive SARS-CoV-2 poly- region (Northeast, Midwest, South, West), call center indica-
merase chain reaction or antigen test result was verified prior tor, and day 1 symptom severity. This adjusted model was
to randomization via uploading into the participant portal and prespecified. The proportional hazards assumption of the
reviewal by the site. At screening, participant-reported demo- primary end point was evaluated by generating visual diag-
graphic information was collected and included race and eth- nostics, such as the log-log plot and plots of time-dependent
nicity, eligibility criteria, medical history, concomitant medi- regression coefficients for each predictor in the model, a
cations, symptom reporting, and quality-of-life questionnaires. diagnostic that indicates deviations from proportionality if
A central investigational pharmacy distributed the study the time-dependent coefficients are not constant in time.
drug (either active or placebo) using a next-day priority ship- Secondary end points were analyzed with bayesian
ping service. Delivery was tracked and participants needed regression models (either proportional hazards or propor-
to have received the study drug within 7 days of enrollment tional odds) using noninformative priors for all parameters.
to be included. Confirmation that the study drug was deliv- Secondary end points were not used for formal decision-
ered to the participant’s address was required for the partici- making, and no decision threshold was selected. Due to an
pant to be included in the analysis. Receipt of study drug was increased potential for type I error due to multiple compari-
defined as study day 1. sons, secondary end points should be interpreted as explor-
Participants were asked to complete daily assessments and atory. The same covariates used in the primary end point
report adverse events through day 14. Assessments included model were used in the adjusted analysis of secondary end
symptoms and severity, health care visits, and medications. points, provided that the end point accrued enough events to
If symptoms were still ongoing at day 14, daily surveys con- be analyzed with covariate adjustment.
tinued until participants experienced 3 consecutive days with- As a platform trial, the primary analysis is implemented
out symptoms or until day 28. At days 28 and 90, all partici- separately for each study drug, where the placebo group

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 Higher-Dose Ivermectin vs Placebo and Time to Sustained Recovery in Outpatients With COVID-19 Original Investigation Research

Table 1. Baseline Characteristics in a Trial of Higher-Dose Ivermectin Table 1. Baseline Characteristics in a Trial of Higher-Dose Ivermectin
for Mild to Moderate COVID-19 for Mild to Moderate COVID-19 (continued)

No. (%) No. (%)

Ivermectin Placebo Ivermectin Placebo
Variable (n = 602) (n = 604) Variable (n = 602) (n = 604)
Age, median (IQR), y 47.0 (38.0-58.0) 48.0 (39.0-58.0) Symptom burden on study day 1f n = 584 n = 593
>50 y 272 (45.2) 279 (46.2) No symptoms 37 (6.3) 32 (5.4)
Sexa Mild 362 (62.0) 341 (57.5)
Women 350 (58.1) 363 (60.1) Moderate 170 (29.1) 210 (35.4)
Men 249 (41.4) 240 (39.7) Severe 15 (2.6) 10 (1.7)
Undifferentiated 3 (0.5) 0 Allowable COVID-19 medications
Prefer not to answer 0 1 (0.2) Monoclonal antibodies 25 (4.2) 22 (3.6)
Race (not mutually exclusive)b Nirmatrelvir and ritonavir (Paxlovid) 15 (2.5) 26 (4.3)
American Indian 9 (1.5) 11 (1.8) Molnupiravir 1 (0.2) 5 (0.8)
or Alaska Native
Remdesivir 0 0
Asian 52 (8.6) 44 (7.3)
Black or African American 45 (7.5) 48 (8.0) Abbreviations: BMI, body mass index (calculated as weight in kilograms divided
by height in meters squared); COPD, chronic obstructive pulmonary disease.
Middle Eastern or North African 14 (2.3) 15 (2.5) a
Participants also had the option to select “unknown,” although no participant
Native Hawaiian 2 (0.3) 6 (1.0) selected this option.
or Other Pacific Islander
b
Participants may have selected any combination of the race descriptors,
White 448 (74.4) 461 (76.3)
including “prefer not to answer.” Consequently, the sum of counts over all race
None of the above 31 (5.2) 22 (3.6) categories will not match the column total.
Prefer not to answer 14 (2.3) 14 (2.3) c
The following state groups define each region: Northeast includes
Ethnicity Connecticut, Maine, Massachusetts, New Hampshire, Rhode Island, Vermont,
New Jersey, New York, and Pennsylvania; Midwest includes Indiana, Illinois,
Hispanic/Latino 136 (22.6) 124 (20.5)
Michigan, Ohio, Wisconsin, Iowa, Kansas, Minnesota, Missouri, Nebraska,
Not Hispanic/Latino 466 (77.4) 480 (79.5) North Dakota, and South Dakota; South includes Delaware, District of
Regionc Columbia, Florida, Georgia, Maryland, North Carolina, South Carolina, Virginia,
West Virginia, Alabama, Kentucky, Mississippi, Tennessee, Arkansas, Louisiana,
Midwest 112 (18.6) 111 (18.4)
Oklahoma, and Texas; and West includes Arizona, Colorado, Idaho,
Northeast 56 (9.3) 49 (8.1) New Mexico, Montana, Utah, Nevada, Wyoming, Alaska, California, Hawaii,
South 285 (47.3) 297 (49.2) Oregon, and Washington.
d
West 149 (24.8) 147 (24.3) Patients may have alternatively been recruited at local clinical sites.
e
Recruited via call center d
61 (10.1) 42 (7.0) Medical history was provided by participants responding to the following
prompts: “Has a doctor told you that you have any of the following?” and
BMI, median (IQR) 28.4 (24.5-32.8) 28.2 (24.9-32.5) “Have you ever experienced any of the following (select all that apply)”
>30 236 (39.2) 223 (36.9) and “Have you ever smoked tobacco products?”
f
Weight, median (IQR), kg 81.6 (70.3-97.5) 80.7 (69.4-93.0) Each day, participants were asked to “Please choose the response that best
>88 kg 233 (38.7) 212 (35.1) describes the severity of your COVID-19 symptoms today” with the response
options being “no symptoms,” “mild,” “moderate,” and “severe.”
Medical history,
No./total No. (%)e
Hypertension 150/593 (25.3) 167/591 (28.3)
Smoking (past year) 89/593 (15.0) 69/591 (11.7) consists of contemporaneously randomized participants who
Asthma 77/593 (13.0) 94/591 (15.9) met the eligibility criteria for that study drug; this includes both
Diabetes 56/593 (9.4) 53/591 (9.0) matched and contributing placebo. For this trial, the modi-
Heart disease 27/593 (4.6) 20/591 (3.4) fied intention-to-treat analysis set for the primary analyses in-
COPD 13/593 (2.2) 13/591 (2.2) cluded all participants who received the study drug, and par-
Cancer 11/588 (1.9) 13/589 (2.2) ticipants were analyzed as assigned. All available data were
Chronic kidney disease 5/593 (0.8) 6/591 (1.0)
used to compare ivermectin vs placebo, regardless of postran-
domization study drug treatment adherence. In both the pri-
COVID-19 vaccine status
mary and secondary end point analyses, missing data among
Vaccinated
covariates used for adjustment were addressed with condi-
≥2 doses 499 (82.9) 509 (84.3)
tional mean imputation because the amount of missing co-
1 dose 3 (0.5) 3 (0.5)
variate data was minimal (<4%).
Not vaccinated 100 (16.6) 92 (15.2)
A prespecified analysis tested for differential treatment ef-
Time between symptom onset 5 (3-7) [n = 600] 5 (3-7) [n = 603]
and receipt of drug, fects as a function of preexisting participant characteristics.
median (IQR), d Analysis of heterogeneity of treatment effect included age,
Time between symptom onset 3 (2-5) [n = 599] 3 (2-5) [n = 602] symptom duration, body mass index (BMI), symptom sever-
and enrollment,
median (IQR), d ity on day 1, calendar time (surrogate for SARS-CoV-2 vari-
ant), sex, and vaccination status; continuous variables were
(continued)
modeled as such without creating subgroups.

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 Research Original Investigation Higher-Dose Ivermectin vs Placebo and Time to Sustained Recovery in Outpatients With COVID-19

Table 2. Primary and Secondary Outcomes in a Trial of Higher-Dose Ivermectin for Mild to Moderate COVID-19

No. (%) Posterior

Ivermectin Placebo Adjusted HR P value
End point (n = 602) (n = 604) (95% CrI)a (efficacy)
Primary
Time to recoveryb
Skeptical prior (primary analysis) 1.02 (0.92 to 1.13) .68
Skeptical prior (matched/unmatched placebos) 1.03 (0.93 to 1.14) .70
Noninformative prior (sensitivity analysis) 1.03 (0.91 to 1.17) .69
No prior (sensitivity analysis) 1.03 (0.91 to 1.17) NEc
Secondary
Mortality at day 28 1 (0.17) 0
Hospitalization or death through day 28 5 (0.83) 2 (0.33) 2.51 (0.49 to 12.96)c
Hospitalization, urgent care, ED visit, or death through day 28 34 (5.65) 36 (5.96) 1.0 (0.6 to 1.5) .53
Clinical progression ordinal outcome scaled
Day 7 (n = 1206) OR, 1.61 (0.87 to 2.46) .04
Day 14 (n = 1175) OR, 2.14 (0.87 to 3.77) .03
Day 28 (n = 1206) OR, 2.61 (0.77 to 4.80) .02
Time unwell, mean (95% CrI), de 11.21 (11.01 to 11.41) 11.35 (11.16 to 11.54) Difference, −0.14 (−0.51 to 0.24) .77
Days of benefit, mean (95% CrI), df 3.42 (3.18 to 3.64) 3.26 (3.03 to 3.48) Difference, 0.16 (−0.28 to 0.61) .77
Abbreviations: CrI, credible interval; ED, emergency department; HR, hazard scale is reported in Supplement 3. Proportional odds was not evaluated
ratio; OR, odds ratio; NE, not estimated. because the vast majority of participants were either at home with limitations
a
Unless otherwise noted, a highest-density credible interval. Adjustment or at home without limitations, resulting in a model that is approximately
variables for time to recovery, mortality, composite clinical endpoints, and a logistic regression.
e
clinical progression in addition to randomization assignment: age (as restricted Adjustment variables for mean time unwell in addition to randomization
cubic spline), sex, duration of symptoms prior to receipt of study drug, assignment include age and calendar time.
calendar time (as restricted cubic spline), vaccination status, geographic f
P(YA better YB| day i) is the probability of a better outcome in the treatment A
region (Northeast, Midwest, South, West), call center indicator, and baseline group on follow-up day i. The days benefit of A is the sum of P(YA better YB|
symptom severity. For time to recovery, HR >1 is favorable for faster recovery day i) over each day of follow-up. For example, if the probability that outcomes
for ivermectin compared with placebo. For the secondary end points, HR <1, in treatment group A were better than treatment group B was 0.8 for each day
OR <1, and difference <0 indicate favorability for ivermectin. of follow-up (eg, 10 days), the days of benefit would be 0.8 × 10 = 8 days.
b
Time to recovery is from receipt of study drug to achieving the third of 3 days Continuing the example, if the probability that outcomes in group B were
of recovery. HR >1.0 is favorable for faster recovery for ivermectin compared better was 0.1 for each day of follow-up, the days of benefit of B would be 1
with placebo. day. The difference in days of benefit is the days of benefit of A minus the days
c
CI rather than CrI because low event rate precluded covariate adjustment. benefit of B. Using the values from the example, the difference in days of
d
benefit (A minus B) would be 8 − 1 = 7 days.
The description of the 8 levels of the clinical progression ordinal outcome

Analyses were performed with R, version 4.1 (R Founda- The median (IQR) age of the participants was 48 (38-58)
tion for Statistical Computing) with primary packages of years and 551 (45.7%) were 50 years or older (Table 1). The popu-
rstanarm, rmsb, and survival.20 Additional details are avail- lation included 713 (59.1%) women and 93 participants (7.7%)
able in Supplement 3. identified as Black or African American, 96 (8.0%) identified
as Asian, and 260 (21.6%) reported being of Latino/Hispanic
ethnicity. Although not required for enrollment, high-risk co-
morbidities included BMI greater than 30 (38.1%), diabetes
Results (9.2%), hypertension (26.8%), asthma (14.4%), and chronic ob-
Study Population structive pulmonary disease (2.2%). Overall, 1008 partici-
Of the 2212 participants who consented for inclusion in the iver- pants (83.6%) reported receiving at least 2 COVID-19 vaccine
mectin group, 1334 were eligible to receive ivermectin and ran- doses. Median (IQR) time from symptom onset to enrollment
domized to receive either ivermectin or placebo and 1206 were was 3 (2-5) days and to study drug receipt was 5 (3-7) days, with
included in the modified intention-to-treat analysis because 60% receiving the study drug within 5 days of symptom on-
they received the study drug. set (eFigure 2 in Supplement 3). eTable 1 in Supplement 3 pre-
Those randomized to receive the active agent in the iver- sents baseline symptom prevalence and severity.
mectin group received the active study drug with a targeted
maximum dose of 600 μg/kg (n = 602); the median (IQR) dose Primary Outcome
of ivermectin was 498 (465-532) μg/kg (eFigure 1 in Supple- The median (IQR) time to recovery was 11 (11-12) days in the
ment 3). Of participants receiving placebo, 543 (90%) re- ivermectin group and 11 (11-12) days in the placebo group. The
ceived matching placebo and 61 (10%) received placebo as part posterior probability for benefit was .68 for the primary out-
of the contributing placebo group (Figure 1). come of time to recovery, with an HR of 1.02 (95% credible

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 Higher-Dose Ivermectin vs Placebo and Time to Sustained Recovery in Outpatients With COVID-19 Original Investigation Research

Figure 2. Time to Sustained Recovery, Hospitalization, Urgent or Emergency Care Visits, or Death, and Mean Time Unwell

A Days to sustained recovery B Days to hospitalization, urgent or emergency C Difference in mean time unwell
care visits, or death
Favors Favors Favors Favors Favors Favors
placebo ivermectin ivermectin placebo ivermectin placebo
8 2.0 2.5

2.0
6 1.5
Posterior density

Posterior density

Posterior density
1.5
4 1.0
1.0

2 0.5
0.5

0 0 0
0.85 0.90 0.95 1 1.05 1.10 1.15 1.20 0.4 0.5 1 1.5 2 –1.0 –0.5 0 0.5 1
Hazard ratio Hazard ratio Difference in mean time unwell, d

Thick vertical lines denote the estimated mean of the posterior distribution. Density is the relative likelihood of posterior probability distribution. Outcomes with
higher density are more likely than outcomes with lower density.

interval [CrI], 0.92-1.13), where HR greater than 1 indicates Figure 3. Primary Outcome of Time to Sustained Recovery
faster symptom resolution with ivermectin (Table 2 and
Figure 2A). This posterior probability was below the prespeci- 1.0

fied threshold of .95 (Supplement 2). The data do not provide Probability of not recovered Ivermectin
evidence of a conclusive treatment benefit when using a bayes- 0.8 Placebo
ian noninformative prior, no prior, with various approaches to
imputing missing symptom data, or when restricting the analy- 0.6

sis to participants who received the drug within 2 or 3 days of

symptom onset and across severity of symptoms reported on 0.4

day 1 (Table 2, Figure 3, and eFigures 3 and 4 in Supple-

0.2
ment 3). The probability that ivermectin reduced symptom du-
ration by 24 hours was less than 0.1%.
0
0 7 14 21 28
Secondary Outcomes Time, d
Hospitalizations and deaths were uncommon, with 5 events (in- No. of patients at risk
cluding 1 death not attributable to COVID-19 or treatment) in the Ivermectin 602 487 232 131 92
Placebo 604 508 244 142 95
ivermectin group and 2 events (no deaths) in the placebo group
(eFigure 5A in Supplement 3). Statistical comparisons were un- Recovery was defined as the third of 3 consecutive days without symptoms.
informative due to the few events. The composite secondary Four participants were censored for nonresponse and all others were followed
up until recovery, death, or the end of short-term 28-day follow-up. Median
outcome of urgent care or ED visits, hospitalizations, or death
(IQR) time to recovery was 11 (11-12) days in the ivermectin group and 11 (11-12)
was not shown to differ with ivermectin compared with pla- days in the placebo group. Shaded regions denote the pointwise 95% CIs.
cebo (5.6% [34/602] vs 6.0% [36/604]; HR, 1.0 [95% CrI, 0.6-
1.5]; P = .53) (Table 2, Figure 2B, and eFigure 5B in Supple-
ment 3). The difference in the amount of time spent feeling ity were not adjusted for multiple comparisons (eFigure 7 in
unwell with COVID-19 was estimated as 3 hours and 20 min- Supplement 3). The overall effect of timing from symptom on-
utes faster with ivermectin (95% CrI, 12 hours better to 6 hours set to receipt of the study drug was not significant (P = .15 for
worse) than placebo (Figure 2C). The COVID Clinical Progres- heterogeneity). Similarly, no evidence existed for a different
sion Scale scores at days 7, 14, and 28 did not meet prespeci- treatment effect of ivermectin compared with placebo for se-
fied thresholds for beneficial treatment effect (Supplement 3). verity of symptoms, sex, age, BMI, calendar time, or vaccina-
For example, by day 7, a total of 532 of 602 participants (88%) tion status (eFigure 8 in Supplement 3).
in the ivermectin group and 549 of 604 (91%) in the placebo
group were not hospitalized and did not report limitation of ac- Adverse Events
tivities (eFigure 6 in Supplement 3). Among participants who reported taking the study drug at least
once, adverse events were similar in both groups (52/566 [9.2%]
Heterogeneity of Treatment Effect Analyses in the ivermectin group and 41/576 [7.1%] in the placebo group
Interaction tests for heterogeneity of treatment effect showed with adverse events) (eTable 2 in Supplement 3). Adverse
no overall influence of the putative treatment effect modifi- events reported more than twice, only in the ivermectin group,
ers, even when all subgroup analyses across symptom sever- included cognitive impairment (n = 4), blurred vision (n = 5),

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 Research Original Investigation Higher-Dose Ivermectin vs Placebo and Time to Sustained Recovery in Outpatients With COVID-19

light sensitivity to eye (n = 5), photophobia (n = 4), dizziness the known self-resolving visual disturbances in the interven-
(n = 5), and asthma (n = 3). Serious adverse events were rare, tion group previously reported with similar doses of ivermec-
with 5 in the ivermectin group and 3 in the placebo group. The tin for parasitic infections.18,19
death in the ivermectin group was reported to be an accident The notable difference in baseline characteristics be-
and not attributable to the study drug or COVID-19. tween these 2 cohorts is the completed vaccination rate, which
was 84% for this study and 47% for the prior ivermectin
400 μg/kg group.16 Hospitalizations and COVID-19–related
clinical events were less common in this largely vaccinated co-
Discussion hort. The incidence of acute care visits, hospitalizations, or
Among a largely vaccinated outpatient population with mild death was similar with ivermectin (5.7%) and placebo (6.0%),
to moderate COVID-19, treatment with ivermectin, with a tar- which was a result also observed in the 2 previous random-
geted maximum dose of 600 μg/kg daily for 6 days, com- ized trials of ivermectin 400 μg/kg in the US.6,16
pared with placebo was not shown to improve time to recov- This trial has several strengths. This was a double-blind,
ery in more than 1200 participants in the US during a period randomized, placebo-controlled nationwide trial with 93 en-
of Omicron variant/subvariant circulation. No evidence of ben- rolling sites and a call center that recruited participants from
efit was observed for secondary clinical outcomes, including all 50 US states. The ivermectin 600 μg/kg group of the plat-
the composite of hospitalization, death, or acute care visits. form trial enrolled rapidly due to ongoing Omicron variant/
Hospitalization and death were uncommon in this largely vac- subvariant surges and largely included vaccinated people, thus
cinated population. These findings do not support the use of representing a highly relevant study population that also ad-
ivermectin in outpatients with COVID-19. dresses a weakness of many other studies that excluded vac-
Multiple large double-blind randomized clinical trials have cinated people. Furthermore, standard-of-care therapies were
failed to identify a clinically meaningful benefit of ivermec- allowable in this study, although utilization was low.
tin when used at a targeted dose of 400 μg/kg daily for 3
days.6,17 This large clinical trial addresses a potential gap in Limitations
knowledge by testing (1) a higher daily dose (targeted maxi- This study has limitations. Due to infrequent hospitalization,
mum dose of 600 μg/kg) and (2) a longer (6-day) duration of this study cannot assess the effect of the intervention on this
ivermectin. Due to the lack of early-phase studies or animal- clinical outcome. Also, due to the remote nature of the trial,
model studies to determine optimal dosing for a therapeutic 60% of participants received the study drug within 5 days of
drug, the appropriate dosing of ivermectin for COVID-19 was symptom onset. Most outpatient COVID-19 antiviral trials have
never determined. Modeling studies and a proof-of-concept limited enrollment to participants within 5 days of symptom
clinical study have suggested that doses up to 600 μg/kg daily onset.1,2 In this trial, no evidence of a differential treatment
may achieve levels sufficient for in vitro antiviral activity18,19; effect was observed based on shorter time to study drug re-
however, a phase 2 trial testing ivermectin, 600 μg/kg daily ceipt. Lastly, the primary end point–adjusted model did not
for 7 days, and assessing a virologic end point of oropharyn- include underlying comorbidities. Treatment effect was pu-
geal SARS-CoV-2 polymerase chain reaction test result did not tatively expected to differ based on age and BMI, and these
show measurable antiviral activity and was stopped for were included as covariates and evaluated for heterogeneity
futility.21 With weight-based dosing, there is additional vari- of treatment effect.
ability in the range for dosing and, in this study, the dosing per
weight strata was targeted to a maximum dose of 600 μg/kg;
thus, the median dose across the study population of approxi-
mately 500 μg/kg is meaningfully higher than that achieved
Conclusions
in studies that targeted a maximum dose of 400 μg/kg. For ex- Among outpatients with mild or moderate COVID-19, treatment
ample, a previous study from the current platform trial that with ivermectin, with a targeted maximum dose of 600 μg/kg
had a maximum targeted dose of ivermectin 400 μg/kg daily for 6 days, was not shown to improve time to sustained re-
achieved a median dose of 343 μg/kg. The 600-μg/kg dose was covery compared with placebo. These findings do not support
safe and generally well tolerated, with a higher prevalence of the use of ivermectin in outpatients with COVID-19.

ARTICLE INFORMATION Minneapolis (Boulware); Vanderbilt University Department of Emergency Medicine, Lewis Katz
Accepted for Publication: February 1, 2023. Medical Center, Nashville, Tennessee (Lindsell, School of Medicine at Temple University,
Rothman, Collins); School of Data Science, Philadelphia, Pennsylvania (Gentile); Department of
Published Online: February 20, 2023. University of Virginia, Charlottesville (Stewart); Medicine, Miller School of Medicine, University of
doi:10.1001/jama.2023.1650 Clinical Trials Center of Middle Tennessee, Franklin Miami, Miami, Florida (Jayaweera); Weill Cornell
Author Affiliations: Duke Clinical Research (Slandzicki); University Medical Center Medicine, New York, New York (McCarthy); Division
Institute, Duke University School of Medicine, New Orleans, Louisiana State University Health of Infectious Diseases, Johns Hopkins University,
Durham, North Carolina (Naggie, Felker, Wilson, Sciences Center, New Orleans (Lim); Jadestone Baltimore, Maryland (Sulkowski); Veterans Affairs
DeLong, Remaly, Wilder, Hernandez); Department Clinical Research, LLC, Silver Spring, Maryland Tennessee Valley Healthcare System, Geriatric
of Medicine, Duke University School of Medicine, (Cohen); David Kavtaradze, Inc, Cordele, Georgia Research, Education and Clinical Center (GRECC),
Durham, North Carolina (Naggie, Felker, (Kavtaradze); Lakeland Regional Medical Center, Nashville (Collins); National Center for Advancing
Hernandez); Division of Infectious Diseases and Lakeland, Florida (Amon); Focus Clinical Research Translational Sciences, Bethesda, Maryland
International Medicine, University of Minnesota, Solutions, Charlotte, North Carolina (Gabriel); (Dunsmore); Foundation for the National Institutes

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 Higher-Dose Ivermectin vs Placebo and Time to Sustained Recovery in Outpatients With COVID-19 Original Investigation Research

of Health, Bethesda, Maryland (Adam); Stakeholder Center; and having stock options in Bioscape Digital Secretary for Preparedness and Response,
Advisory Committee, Pittsburgh, Pennsylvania unrelated to the current work. Dr Stewart reported Biomedical Advanced Research and Development
(Thicklin); Biomedical Advanced Research and receiving grants from Duke University as a Authority (contract No.75A50122C00037). The
Development Authority, Washington, DC (Hanna); subaward for ACTIV-6 from NIH during the conduct Vanderbilt University Medical Center Clinical and
University of Colorado School of Medicine, Aurora of the study and grants from NIH supported by Translational Science Award from NCATS
(Ginde); Division of Pulmonary, Critical Care and grants from NCATS and NIDDK and research (UL1TR002243) supported the REDCap
Sleep Medicine, University of Missouri-Kansas City support from the Abdominal Core Health Quality infrastructure.
School of Medicine, Kansas City (Castro); Collaborative, a 501(c)(3) nonprofit organization, Role of the Funder/Sponsor: NCATS participated
Department of Medicine, University of Pittsburgh outside the submitted work. Dr Lim reported in the design and conduct of the study; collection,
Medical Center, Pittsburgh, Pennsylvania receiving a subaward from NCATS to the institution management, analysis, and interpretation of the
(McTigue); Department of Health Outcomes & during the conduct of the study. Dr Gentile data; preparation, review, or approval of the
Biomedical Informatics, College of Medicine, reported receiving personal fees from Duke manuscript; and decision to submit the manuscript
University of Florida, Gainesville (Shenkman). University for ACTIV-6 protocol development for publication.
Author Contributions: Drs Lindsell and Stewart committee membership during the conduct of the
study. Dr Felker reported receiving grants from NIH Data Sharing Statement: See Supplement 5.
had full access to all of the data in the study and
take responsibility for the integrity of the data and during the conduct of the study. Dr Jayaweera Additional Contributions: We thank Samuel
the accuracy of the data analysis. reported receiving grants from NCATS during the Bozzette, MD, PhD, and Eugene Passamani, MD
Concept and design: Naggie, Boulware, Lindsell, conduct of the study and grants from Gilead, ViiV (National Center for Advancing Translational
Stewart, Kavtaradze, Gentile, Felker, McCarthy, Healthcare, and Janssen and personal fees from Sciences), for their roles in the trial design and
Rothman, Wilson, Remaly, Collins, Thicklin, Ginde, Theratechnologies outside the submitted work. protocol development. We also thank the ACTIV-6
Castro, Hernandez. Dr Sulkowski reported receiving grants to the data monitoring committee and clinical events
Acquisition, analysis, or interpretation of data: institution from Janssen, Vir, and GSK; personal committee members for their contributions: data
Naggie, Boulware, Lindsell, Stewart, Slandzicki, fees for serving on a scientific advisory board from monitoring committee: Clyde Yancy, MD, MSc
Lim, Cohen, Kavtaradze, Amon, Gabriel, Felker, GSK, AbbVie, Antios, Assembly Bio, Atea, Gilead; (Northwestern University Feinberg School of
Jayaweera, Sulkowski, Rothman, DeLong, Wilder, personal fees for serving on a data and safety Medicine); Adaora Adimora, MD (University of
Dunsmore, Adam, Thicklin, Hanna, Castro, McTigue, monitoring board from Precision Bio and North Carolina, Chapel Hill); Susan Ellenberg, PhD
Shenkman, Hernandez. Immunocore; personal fees as an editor for Journal (University of Pennsylvania); Kaleab Abebe, PhD
Drafting of the manuscript: Naggie, Boulware, of Viral Hepatitis; and personal fees from NIH (University of Pittsburgh); Arthur Kim, MD
Lindsell, Stewart, Amon, McCarthy, Thicklin. (K24DA034621) outside the submitted work. Dr (Massachusetts General Hospital); John D. Lantos,
Critical revision of the manuscript for important Rothman reported receiving grants from the NIH MD (Children’s Mercy Hospital); Jennifer
intellectual content: Boulware, Lindsell, Stewart, during the conduct of the study and spouse owning Silvey-Cason (participant representative); Frank
Slandzicki, Lim, Cohen, Kavtaradze, Gabriel, a small amount of stock in Moderna. Dr Wilson Rockhold, PhD (Duke Clinical Research Institute);
Gentile, Felker, Jayaweera, Sulkowski, Rothman, reported receiving grants from NCATS Sean O’Brien, PhD (Duke Clinical Research
Wilson, DeLong, Remaly, Wilder, Collins, Dunsmore, (3U24TR001608) during the conduct of the study. Institute); Frank Harrell, PhD (Vanderbilt University
Adam, Hanna, Ginde, Castro, McTigue, Shenkman, Dr DeLong reported receiving grants from NCATS Medical Center); Zhen Huang, MS (Duke Clinical
Hernandez. (3U24TR001608) during the conduct of the study. Research Institute); clinical events committee:
Statistical analysis: Lindsell, Stewart, McCarthy. Dr Collins reported receiving grants from NCATS Renato Lopes, MD, PhD, MHS; W. Schuyler Jones,
Obtained funding: Naggie, Lindsell, Gabriel, during the conduct of the study and personal fees MD; Antonio Gutierrez, MD; Robert Harrison, MD;
Jayaweera, Collins, Hernandez. from Vir Biotechnology and Enanta David Kong, MD; Robert McGarrah, MD; Michelle
Administrative, technical, or material support: Pharmaceuticals and grants from NHLBI outside the Kelsey, MD; Konstantin Krychtiuk, MD; Vishal Rao,
Naggie, Lindsell, Slandzicki, Lim, Cohen, Amon, submitted work. Dr Adam reported receiving US MD (Duke Clinical Research Institute, Duke
Gabriel, Jayaweera, Wilson, DeLong, Remaly, Government funding through Operation Warp University School of Medicine). Elizabeth E.S. Cook
Wilder, Dunsmore, Adam, Hanna, McTigue, Speed during the conduct of the study. Dr Hanna ( Duke Clinical Research Institute) provided
Hernandez. reported receiving grants from US Biomedical editorial support.
Supervision: Naggie, Lindsell, Kavtaradze, Amon, Advanced Research & Development Authority
Gabriel, Gentile, Felker, Jayaweera, Rothman, contract to Tunnell Government Services for REFERENCES
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