Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities: The I-TECH Randomized Clinical Trial

Abstract

Importance:
Ivermectin, an inexpensive and widely available antiparasitic drug, is prescribed to treat COVID-19. Evidence-based data to recommend either for or against the use of ivermectin are needed.

Objective:
To determine the efficacy of ivermectin in preventing progression to severe disease among high-risk patients with COVID-19.

Design, setting, and participants:
The Ivermectin Treatment Efficacy in COVID-19 High-Risk Patients (I-TECH) study was an open-label randomized clinical trial conducted at 20 public hospitals and a COVID-19 quarantine center in Malaysia between May 31 and October 25, 2021. Within the first week of patients' symptom onset, the study enrolled patients 50 years and older with laboratory-confirmed COVID-19, comorbidities, and mild to moderate disease.

Interventions:
Patients were randomized in a 1:1 ratio to receive either oral ivermectin, 0.4 mg/kg body weight daily for 5 days, plus standard of care (n = 241) or standard of care alone (n = 249). The standard of care consisted of symptomatic therapy and monitoring for signs of early deterioration based on clinical findings, laboratory test results, and chest imaging.

Main outcomes and measures:
The primary outcome was the proportion of patients who progressed to severe disease, defined as the hypoxic stage requiring supplemental oxygen to maintain pulse oximetry oxygen saturation of 95% or higher. Secondary outcomes of the trial included the rates of mechanical ventilation, intensive care unit admission, 28-day in-hospital mortality, and adverse events.

Results:
Among 490 patients included in the primary analysis (mean [SD] age, 62.5 [8.7] years; 267 women [54.5%]), 52 of 241 patients (21.6%) in the ivermectin group and 43 of 249 patients (17.3%) in the control group progressed to severe disease (relative risk [RR], 1.25; 95% CI, 0.87-1.80; P = .25). For all prespecified secondary outcomes, there were no significant differences between groups. Mechanical ventilation occurred in 4 (1.7%) vs 10 (4.0%) (RR, 0.41; 95% CI, 0.13-1.30; P = .17), intensive care unit admission in 6 (2.4%) vs 8 (3.2%) (RR, 0.78; 95% CI, 0.27-2.20; P = .79), and 28-day in-hospital death in 3 (1.2%) vs 10 (4.0%) (RR, 0.31; 95% CI, 0.09-1.11; P = .09). The most common adverse event reported was diarrhea (14 [5.8%] in the ivermectin group and 4 [1.6%] in the control group).

Conclusions and relevance:
In this randomized clinical trial of high-risk patients with mild to moderate COVID-19, ivermectin treatment during early illness did not prevent progression to severe disease. The study findings do not support the use of ivermectin for patients with COVID-19.

Trial registration:
ClinicalTrials.gov Identifier: NCT04920942.

Full text

Efficacy of Ivermectin Treatment on Disease Progression
Among Adults With Mild to Moderate COVID-19
and Comorbidities
The I-TECH Randomized Clinical Trial
Steven Chee Loon Lim, MRCP; Chee Peng Hor, MSc; Kim Heng Tay, MRCP; Anilawati Mat Jelani, MMed;
Wen Hao Tan, MMed; HongBee Ker, MRCP; Ting Soo Chow, MRCP; Masliza Zaid, MMed; Wee Kooi Cheah, MRCP;
Han Hua Lim, MRCP; Khairil Erwan Khalid, MRCP; Joo Thye Cheng, MRCP; Hazfadzila Mohd Unit, MRCP;
Noralfazita An, MMed; Azraai Bahari Nasruddin, MRCP; Lee Lee Low, MRCP; Song Weng Ryan Khoo, MRCP;
Jia Hui Loh, MRCP; Nor Zaila Zaidan, MMed; Suhaila Ab Wahab, MMed; Li Herng Song, MD;
Hui Moon Koh, MClinPharm; Teck Long King, BPharm; Nai Ming Lai, MRCPCH;
Suresh Kumar Chidambaram, MRCP; Kalaiarasu M. Peariasamy, MSc; for the I-TECH Study Group
IMPORTANCE Ivermectin, an inexpensive and widely available antiparasitic drug, is
prescribed to treat COVID-19. Evidence-based data to recommend either for or against
the use of ivermectin are needed.
OBJECTIVE To determine the efficacy of ivermectin in preventing progression to severe
disease among high-risk patients with COVID-19.
DESIGN, SETTING, AND PARTICIPANTS The Ivermectin Treatment Efficacy in COVID-19
High-Risk Patients (I-TECH) study was an open-label randomized clinical trial conducted
at 20 public hospitals and a COVID-19 quarantine center in Malaysia between May 31 and
October 25, 2021. Within the first week of patients’ symptom onset, the study enrolled
patients 50 years and older with laboratory-confirmed COVID-19, comorbidities, and mild
to moderate disease.
INTERVENTIONS Patients were randomized in a 1:1 ratio to receive either oral ivermectin,
0.4 mg/kg body weight daily for 5 days, plus standard of care (n = 241) or standard of care
alone (n = 249). The standard of care consisted of symptomatic therapy and monitoring
for signs of early deterioration based on clinical findings, laboratory test results, and
chest imaging.
MAIN OUTCOMES AND MEASURES The primary outcome was the proportion of patients who
progressed to severe disease, defined as the hypoxic stage requiring supplemental oxygen
to maintain pulse oximetry oxygen saturation of 95% or higher. Secondary outcomes of
the trial included the rates of mechanical ventilation, intensive care unit admission, 28-day
in-hospital mortality, and adverse events.
RESULTS Among 490 patients included in the primary analysis (mean [SD] age, 62.5 [8.7]
years; 267 women [54.5%]), 52 of 241 patients (21.6%) in the ivermectin group and 43 of
249 patients (17.3%) in the control group progressed to severe disease (relative risk [RR],
1.25; 95% CI, 0.87-1.80; P= .25). For all prespecified secondary outcomes, there were
no significant differences between groups. Mechanical ventilation occurred in 4 (1.7%) vs
10 (4.0%) (RR, 0.41; 95% CI, 0.13-1.30; P= .17), intensive care unit admission in 6 (2.4%)
vs 8 (3.2%) (RR, 0.78; 95% CI, 0.27-2.20; P= .79), and 28-day in-hospital death in 3 (1.2%)
vs 10 (4.0%) (RR, 0.31; 95% CI, 0.09-1.11; P= .09). The most common adverse event
reported was diarrhea (14 [5.8%] in the ivermectin group and 4 [1.6%] in the control group).
CONCLUSIONS AND RELEVANCE In this randomized clinical trial of high-risk patients with mild
to moderate COVID-19, ivermectin treatment during early illness did not prevent progression
to severe disease. The study findings do not support the use of ivermectin for patients with
COVID-19.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04920942
JAMA Intern Med. doi:10.1001/jamainternmed.2022.0189
Published online February 18, 2022.
Visual Abstract
Related article
Supplemental content
Author Affiliations: Author
affiliations are listed at the end of this
article.
Group Information: The members
of the I-TECH Study Group appear
in Supplement 3.
Corresponding Author: Steven Chee
Loon Lim, MRCP, Department of
Medicine, Raja Permaisuri Bainun
Hospital, Jalan Raja Ashman Shah,
30450 Ipoh, Perak, Malaysia
(stevenlimcl@gmail.com).
Research
JAMA Internal Medicine | Original Investigation
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Despite the success of COVID-19 vaccines and the imple-
mentation of nonpharmaceutical public health mea-
sures, there is an enormous global need for effective
therapeutics for SARS-CoV-2 infection. At present, repur-
posed anti-inflammatory drugs (dexamethasone, tocili-
zumab, and sarilumab),
1-3
monoclonal antibodies,
4-6
and an-
tivirals (remdesivir, molnupiravir,and nirmatrelvir/ritonavir)
7-9
have demonstrated treatment benefits at different stages of
COVID-19.
10
In Malaysia, about 95% of patients with COVID-19 pre-
sent early with mild disease, and less than 5% progress to a
hypoxic state requiring oxygen supplementation. Notably,
patients 50 years and older with comorbidities are at high risk
for severe disease.
11
Potentially, an antiviral therapy adminis-
tered during the early viral replication phase could avert the
deterioration. Although molnupiravir and nirmatrelvir/
ritonavir have shown efficacy in the early treatment of
COVID-19,
8,9
they can be too expensive for widespread use in
resource-limited settings.
Ivermectin, an inexpensive,easy-to-administer, and widely
available antiparasitic drug, has been used as an oral therapy
for COVID-19. An in vitro study demonstrated inhibitory ef-
fects of ivermectin against SARS-CoV-2.
12
Although some early
clinical studies suggested the potential efficacy of ivermectin
in the treatment and prevention of COVID-19,
13,14
these stud-
ies had methodologic weaknesses.
15
In 2021, 2 randomized clinical trials from Colombia
16
and
Argentina
17
found no significant effect of ivermectin on symp-
tom resolution and hospitalization rates for patients with
COVID-19. A Cochrane meta-analysis
18
also found insuffi-
cient evidence to support the use of ivermectin for the treat-
ment or prevention of COVID-19.
These findings notwithstanding, ivermectin is widely pre-
scribed for COVID-19, contrary to the World Health Organiza-
tion (WHO) recommendation to restrict use of the drug to
clinical trials.
19
In the present randomized clinical trial, we
studied the efficacy of ivermectin for preventing progression
to severe disease among high-risk patients with COVID-19
in Malaysia.
Methods
Trial Design and Patients
The Ivermectin Treatment Efficacy in COVID-19 High-Risk
Patients (I-TECH) study was a multicenter, open-label, ran-
domized clinical trial conducted at 20 government hospitals
and a COVID-19 quarantine center in Malaysia between May
31 and October 25, 2021. The study was approved by the local
Medical Research and Ethics Committee (NMRR-21-155-
58433) and registered in ClinicalTrials.gov (NCT04920942).
This trial was conducted in accordance with the Declaration
of Helsinki and the Malaysian Good Clinical Practice Guideline.
All participants provided written informed consent. This study
followed the Consolidated Standards of Reporting Trials
(CONSORT) reporting guidelines.
In Malaysia, mandatory notification to public health
authorities applies to all COVID-19 cases. Patients with mild
to moderate disease at risk of disease progression are
referred for hospitalization or admitted to a COVID-19 quar-
antine center to allow close monitoring for 10 or more days
from symptom onset and timely intervention in the event of
deterioration.
The study enrolled patients with reverse transcriptase–
polymerase chain reaction (RT-PCR) test–confirmed or anti-
gen test–confirmed COVID-19 who were 50 yearsor older with
at least 1 comorbidity and presented with mild to moderate
illness (Malaysian COVID-19 clinical severity stage 2 or 3; WHO
clinical progression scale 2-4)
20,21
within 7 days from symp-
tom onset. Patients were excluded if they were asymptom-
atic, required supplemental oxygen,or had pulse oximetry oxy-
gen saturation (SpO
2
) level less than 95% at rest. Other exclusion
criteria were severe hepatic impairment (alanine transami-
nase level >10 times of upper normal limit), acute medical or
surgical emergency, concomitant viral infection, pregnancy
or breastfeeding, warfarin therapy, and histor y of taking iver-
mectin or any antiviral drugs with reported activity against
COVID-19 (favipiravir, hydroxychloroquine, lopinavir, and
remdesivir) within 7 days before enrollment. Eligibility crite-
ria are detailed in the study protocol (Supplement 1). Study
investigators collected information on ethnicity based on the
patient’s Malaysian identification card or passport (for non-
Malaysian citizens).
All patients with COVID-19 were managed in accordance
with the national COVID-19 Management Guidelines,
20
devel-
oped by a local expert panel based on consensus, WHO rec-
ommendations, and the US National Institutes of Health guide-
lines. High-risk patients were defined as those aged 50 years
or older with comorbidity. Patients were staged according to
clinical severity at presentation and disease progression: stage
1, asymptomatic; stage 2, symptomatic without evidence of
pneumonia; stage 3, evidence of pneumonia without hy-
poxia; stage 4, pneumonia with hypoxia requiring oxygen
supplementation; and stage 5, critically ill with multiorgan in-
volvement. Stages 2 and 3 were classified as mild and moder-
ate diseases (WHO scale 2-4), while stages 4 and 5 were re-
ferred to as severe diseases (WHO scale 5-9). The standard
of care for patients with mild to moderate disease consisted
of symptomatic therapy and monitoring for signs of early de-
terioration based on clinical findings, laboratory test results,
and chest imaging.
Key Points
Question Does adding ivermectin, an inexpensive and widely
available antiparasitic drug, to the standard of care reduce the risk
of severe disease in patients with COVID-19 and comorbidities?
Findings In this open-label randomized clinical trial of high-risk
patients with COVID-19 in Malaysia, a 5-day course of oral
ivermectin administered during the first week of illness did not
reduce the risk of developing severe disease compared with
standard of care alone.
Meaning The study findings do not support the use of ivermectin
for patients with COVID-19.
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Randomization and Data Collection
All study data were recorded in case report form and tran-
scribed into the REDCap (Research Electronic Data Capture)
platform.
22,23
Patients were randomized in a 1:1 ratio to either
the intervention group receiving oral ivermectin (0.4 mg/kg
body weight daily for 5 days) plus standard of care or the con-
trol group receiving the standard of care alone (Figure). The
randomization was based on an investigator-blinded random-
ization list uploaded to REDCap, which allocated the patients
via a central, computer-generated randomization scheme
across all study sites during enrollment. The randomization
list was generated independently using random permuted
block sizes 2 to 6. The randomization was not stratified by site.
Intervention
The ivermectin dosage for each patient in the interventionarm
was calculated to the nearest 6-mg or 12-mg whole tablets (dos-
ing table in the study protocol, Supplement 1). The first dose
of ivermectin was administered after randomization on day 1
of enrollment, followed by 4 doses on days 2 through 5. Pa-
tients were encouraged to take ivermectin with food or after
meals to improve drug absorption. Storage, dispensary, and
administration of ivermectin were handled by trained study
investigators, pharmacists, and nurses.
Outcome Measures
The primary outcome was the proportion of patients who pro-
gressed to severe COVID-19, defined as the hypoxic stage re-
quiring supplemental oxygento maintain SpO
2
95%orgreater
(Malaysian COVID-19 clinical severity stages 4 or 5; WHO clini-
cal progression scale 5-9). The SpO
2
was measured using a cali-
brated pulse oximeter per the clinical monitoring protocol.
Secondary outcomes were time of progression to severe
disease, 28-day in-hospital all-cause mortality, mechanical ven-
tilation rate, intensive care unit admission, and length of hos-
pital stay after enrollment. Patientswere also assessed on day
5 of enrollment for symptom resolution, changes in labora-
tory test results, and chest radiography findings. Adverse
events (AEs) and serious AEs (SAEs) wereevaluated and graded
according to Common Terminology Criteriafor Adverse Events,
Figure. Screening, Enrollment, Randomization, and Treatment Assignment
Prescreening of patients done by
attending physicians at study sitesa
Suitable patients were counseled by
investigators about study participationb
501 Patients provided written informed
consent and were screened for
study eligibility
1Excluded after progression
to severe stage of COVID-19
prior to randomization
500 Patients randomized
241 Received ≥1 dose of ivermectin
232
4
1
2
2
Completed 5 doses
Received 4 doses
Received 3 doses
Received 2 doses
Received 1 dose
250 Randomized to intervention
arm (5-d oral ivermectin
plus standard of care)
250 Randomized to control arm
(standard of care only)
3Excluded
6Withdrew informed consent
prior to initiation of ivermectin
2
1
Did not fulfill inclusion criteriac
Met exclusion criteria identified
after randomizationd
1Excluded due to exclusion
criteria identified after
randomizatione
241 Included in modified intention-
to-treat analysisf
3Withdrew from study owing
to adverse events after
taking ivermectin
249 Included in modified
intention-to-treat analysis
a
The study inclusion and exclusion
criteria were made known to
physicians at study sites to facilitate
prescreening of patients.
b
The number of patients counseled
by study investigators was not
collected.
c
One patient had onset of COVID-19
symptoms 8 days prior to
randomization, which exceeded
the first 7 days of illness inclusion
criterion. Another patient had a
COVID-19 rapid test antigen positive
result but polymerase chain
reaction negative result. This was
before a protocol amendment that
included positive COVID-19 antigen
test result as alternative inclusion
criteria if polymerase chain reaction
testing was not done or was
negative.
d
Patient was found to have acute
coronary syndrome after
randomization but before
commencement of ivermectin
therapy.Acute medical emergency
was an exclusion criterion.
e
Patient was diagnosed of dengue
fever with NS-1 antigen positive.
Concomitant viral infection was
an exclusion criterion.
f
In the intervention arm, only
patients who received at least
1 dose of ivermectin were included
in the modified intention-to-treat
analysis.
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Table 1. Baseline Demographicand Clinical Characteristics of Patients in Primary Analysis Population
Characteristic
No. (%)
Difference (95% CI)Ivermectin Control
No. 241 249 NA
Demographics
Age, mean (SD), y 63.0 (8.9) 62.0 (8.4) 0.9 (−0.6 to 2.5)
a
Sex
Female 130 (53.9) 137 (55.0) −1.08 (−9.90 to 7.74)
b
Male 111 (46.1) 112 (45.0) 1.08 (−7.74 to 9.90)
b
Ethnicity
Chinese 37 (15.4) 32 (12.9) 2.50 (−3.66 to 8.67)
b
Indian 38 (15.8) 30 (12.0) 3.72 (−2.41 to 9.84)
b
Malay 153 (63.5) 172 (69.1) −5.59 (−13.95 to 2.77)
b
Other
c
13 (5.4) 15 (6.0) −0.63 (−4.74 to 3.48)
b
Anthropometrics
Weight, mean (SD), kg 68.0 (14.5) 68.7 (14.6) −0.7 (−3.2 to 1.9)
a
BMI, mean (SD) 26.8 (5.2) 26.9 (5.4) −0.1 (−1.0 to 0.9)
a
COVID-19–related history
COVID-19 vaccination
Not vaccinated 75 (31.1) 84 (33.7) −2.61 (−10.90 to 5.67)
b
Received 1 dose of vaccine 42 (17.4) 35 (14.1) 3.37 (−3.08 to 9.82)
b
Completed 2 doses of vaccine 124 (51.5) 130 (52.2) −0.76 (−9.61 to 8.09)
b
Disease severity at enrollment (WHO scale 2-4)
Mild 83 (34.4) 84 (33.7) 0.71 (−7.69 to 9.10)
b
Moderate 158 (65.6) 165 (66.3) −0.71 (−9.10 to 7.69)
b
Day of symptoms at enrollment, mean (SD) 5.1 (1.3) 5.1 (1.3) 0 (−0.2 to 0.3)
a
Comorbidity
Hypertension 178 (73.9) 191 (76.7) −2.85 (−10.49 to 4.79)
b
Diabetes mellitus 131 (54.4) 131 (52.6) 1.75 (−7.09 to 10.58)
b
Dyslipidemia 102 (42.3) 82 (32.9) 9.39 (0.85 to 17.94)
b
Obesity 56 (23.2) 61 (24.5) −1.26 (−8.81 to 6.29)
b
Chronic disease
Kidney 28 (11.6) 43 (17.3) −5.65 (−11.85 to 0.55)
b
Cardiac 37 (15.4) 20 (8.0) 7.32 (1.65 to 12.99)
b
Pulmonary 17 (7.1) 21 (8.4) −1.38 (−6.11 to 3.35)
b
Active smoker 13 (5.4) 7 (2.8) 2.59 (−0.93 to 6.10)
b
Cerebrovascular disease 10 (4.1) 9 (3.6) 0.53 (−2.89 to 3.96)
b
Malignant neoplasm 5 (2.1) 9 (3.6) −1.54 (−4.47 to 1.40)
b
Gout 8 (3.3) 5 (2.0) 1.31 (−1.76 to 4.61)
b
Thyroid disease 5 (2.1) 6 (2.4) 0.33 (−2.96 to 2.29)
b
Chronic disorder
Neurological 4 (1.7) 4 (1.6) 0.05 (−2.19 to 2.30)
b
Liver 3 (1.2) 2 (0.8) 0.44 (−1.34 to 2.23)
b
Autoimmune disease 2 (0.8) 2 (0.8) 0.02 (−1.57 to 1.62)
b
Immunosuppressive therapy 0 1 (0.4) −0.40 (−1.19 to 3.84)
b
Symptom
Cough 183 (75.9) 195 (78.3) −2.38 (−9.82 to 5.06)
b
Fever 112 (46.5) 125 (50.2) −3.73 (−12.57 to 5.11)
b
Runny nose 67 (27.8) 82 (32.9) −5.13 (−13.26 to 3.00)
b
Sore throat 30 (12.4) 45 (18.1) −5.62 (−11.97 to 0.72)
b
Lethargy 35 (14.5) 31 (12.4) 2.07 (−3.98 to 8.12)
b
Anosmia 30 (12.4) 31 (12.4) 0 (−5.85 to 5.85)
b
Diarrhea 28 (11.6) 24 (9.6) −1.98 (−3.48 to 7.44)
b
Exertional dyspnea 24 (10.0) 27 (10.8) −0.88 (−6.29 to 4.52)
b
Headache 22 (9.1) 19 (7.6) 1.50 (−3.41 to 6.41)
b
(continued)
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version 5.0.
24
All outcomes were captured from randomiza-
tion until discharge from study sites or day 28 of enrollment,
whichever was earlier.
Subgroup Analyses
Subgroup analyses were predetermined according to COVID-19
vaccination status, age, clinical staging, duration of illness
at enrollment, and common comorbidities.
Procedures
Patients’ clinical history,anthropometric measurements, blood
samples for complete blood cell count, kidney and liver pro-
files, C-reactive protein levels, and chest radiography were
obtained at baseline. Blood sampling and chest radiography
were repeated on day 5 of enrollment. Study investigators
followed up patients for all outcome assessments and AEs.
All study-related AEs were reviewed by an independent Data
and Safety Monitoring Board.
Sample Size Calculation
The sample size was calculated based on a superiority trial
design and primary outcome measure. The expected rate of
primary outcome was 17.5% in the control group, according
to previous local data of high-risk patients who presented
with mild to moderate disease.
11
A 50% reduction of pri-
mary outcome, or a 9% rate difference between interven-
tion and control groups, was considered clinically important.
This trial required 462 patients to be adequately powered.
This sample size provided a level of significance at 5% with
80% power for 2-sided tests. Considering potential dropouts,
a total of 500 patients (250 patients for each group) were
recruited.
Table 1. Baseline Demographicand Clinical Characteristics of Patients in Primary Analysis Population (continued)
Characteristic
No. (%)
Difference (95% CI)Ivermectin Control
Myalgia 22 (9.1) 14 (5.6) 3.51 (−1.12 to 8.13)
b
Ageusia 21 (8.7) 12 (4.8) 3.89 (−0.55 to 8.34)
b
Vomiting 9 (3.7) 12 (4.8) −1.08 (−4.66 to 2.49)
b
Anorexia 6 (2.5) 7 (2.8) −0.32 (−3.17 to 2.52)
b
Nausea 6 (2.5) 4 (1.6) 0.88 (−1.63 to 3.39)
b
Imaging and laboratory parameters at enrollment
Presence of any COVID-19 lung changes
(chest radiography)
158 (65.6) 165 (66.3) −0.70 (−9.10 to 7.69)
b
Absolute count, mean (SD), cells/μL
Lymphocyte 1803 (799) 1778 (775) 26 (−114 to 166)
a
Neutrophil 3961 (1879) 3859 (1835) 103 (−227 to 432)
a
Neutrophil to lymphocyte ratio, mean (SD) 2.6 (1.7) 2.6 (2.0) 0 (−0.4 to 0.3)
a
Creatinine, median (IQR), mg/dL 0.97 (0.50) 1.01 (0.64) −0.03 (−0.11 to 0.05)
d
Alanine transaminase, mean (SD), U/L 30.3 (21.8) 30.1 (22.0) 0.3 (−3.6 to 4.2)
a
C-reactive protein, mean (SD), mg/dL 2.81 (3.66) 2.79 (3.88) 0.02 (−0.65 to 0.69)
a
Medications given within 7 d before enrollment
Antibiotics 19 (7.9) 7 (2.8) 5.07 (1.10 to 9.05)
b
Systemic anticoagulation 18 (7.5) 9 (3.6) 3.85 (−0.19 to 7.90)
b
Corticosteroids 2 (0.8) 6 (2.4) −1.58 (−3.80 to 0.64)
b
Other antivirals (not for COVID-19) 0 1 (0.4) −0.40 (−1.19 to 0.38)
b
Concomitant medications given during study period
No. 238
e
249 NA
Corticosteroids 64 (26.9) 66 (26.5) 0.38 (−7.48 to 8.25)
b
Antibiotics 55 (23.1) 54 (21.7) 1.42 (−5.99 to 8.83)
b
Systemic anticoagulation 68 (28.6) 57 (22.9) 5.68 (−2.08 to 13.44)
b
Baricitinib 4 (1.7) 7 (2.8) −1.13 (−3.75 to 1.49)
b
Tocilizumab 2 (0.8) 2 (0.8) 0.03 (−1.57 to 1.64)
b
Other antivirals (not for COVID-19) 0 1 (0.4) −0.40 (−1.18 to 0.38)
b
Abbreviations: BMI, body mass index, calculated as weight in kilograms divided
by height in meters squared; NA, not applicable; WHO, World Health
Organization.
SI conversion factors: Toconvert alanine transaminase to μkat/L , multiply
by 0.0167; C-reactive protein to mg/L, multiply by 10; creatinine to μmol/L,
multiply by 88.4; lymphocyte and neutrophil count to ×10
9
/L, multiply
by 0.001.
a
Mean difference (mean of ivermectin group minus mean of the control group)
with 95% CI.
b
Absolute difference in proportion.
c
Other refers to Indigenous ethnic groups in Peninsular Malaysia, Sabah, and
Sarawak, individuals of mixed race, and foreigners residing in Malaysia.
d
The 95% CI was estimated by bootstrap sampling for median differenceby
using confintr R package.
e
Three patients in the ivermectin group withdrew from the study after taking
1 or more doses of ivermectin, and data on these variables were not captured.
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Statistical Analyses
Primary analyses were performed based on the modified in-
tention-to-treat principle, whereby randomized patients in the
intervention group who received atleast 1 ivermectin dose and
all patients in the control group would be followed and evalu-
ated for efficacy and safety. In addition, sensitivity analyses
were performed on all eligible randomized patients, includ-
ing those in the intervention group who did not receive iver-
mectin (intention-to-treat population).
Descriptive data were expressed as means and SDs un-
less otherwise stated. Categorical data were analyzed using the
Fisher exact test. Continuous variables were tested using
the t-test or Mann-Whitney Utest. The primary and categori-
cal secondary outcome measures were estimated using rela-
tive risk (RR). The absolute difference of means of time of pro-
gression to severe disease and lengths of hospitalization
between the study groups were determined with a 95% CI.
Mixed analysis of variance was used to determine whether the
changes of laboratory investigations were the result of inter-
actions between the study groups (between-patients factor)
and times (within-patient factor), and P< .05 was considered
statistically significant. Statistical analyses were performed
using IBM SPSS Statistics for Windows, version22.0 (IBM Corp).
Interim analyses were conducted on the first 150 and 300
patients, with outcome data retrieved on July 13 and August
30, 2021, respectively. The overall level of significance was
maintained at P< .05, calculated according to the O’Brien-
Fleming stopping boundaries. Early stopping would be con-
sidered if P< .003 for efficacy data. The results were pre-
sented to the Data and Safety Monitoring Board, which
recommended continuing the study given no signal for early
termination.
Results
Between May 31 and October 9, 2021, 500 patients were en-
rolled and randomized. The last patient completed follow-up
on October 25, 2021. Four patients were excluded after ran-
domization. One patient in the control arm was diagnosed with
dengue coinfection; in the intervention arm, 2 failed to meet
inclusion criteria owing to symptom duration greater than
7 days and negative COVID-19 RT-PCR test result, while 1 had
acute coronary syndrome before ivermectin initiation. In ad-
dition, 6 patients in the intervention arm withdrew consent
before taking a dose of ivermectin. The modified intention-
to-treat population for the primary analysis included 490 pa-
tients (98% of those enrolled), with 241 in the intervention
group and 249 in the control group (Figure). Drug compli-
ance analysis showed that 232 patients (96.3%) in the inter-
vention group completed 5 doses of ivermectin.
Baseline demographics and characteristics of patients were
well balanced between groups (Table 1). The mean (SD) age was
62.5 (8.7) years,w ith 267 women(5 4.5%); 254 patients(51.8%)
were fully vaccinated with 2 doses of COVID-19 vaccines. All
major ethnic groups in Malaysia were well represented in the
study population. The majority had hypertension (369 [75.3%]),
followed by diabetes mellitus (262 [53.5%]), dyslipidemia
(184 [37.6%]), and obesity (117 [23.9%]).
The mean (SD) duration of symptoms at enrollment was
5.1 (1.3) days. The most common symptoms were cough (378
[77.1%]), fever (237 [48.4%]), and runny nose (149 [30.4%]).
Approximately two-thirds of patients had moderate disease.
The average baseline neutrophil-lymphocyte ratio and se-
rum C-reactive protein level were similar between groups.
Table 2. Outcomes in the Primary Analysis Population
Outcomes
a
No. (%) Absolute difference
(95% CI)
Relative risk
(95% CI) PvalueIvermectin Control
No. 241 249 NA NA NA
Primary outcome
Progression to severe disease
(WHO scale 5-9)
52 (21.6) 43 (17.3) 4.31 (−2.69 to 11.31)
b
1.25 (0.87 to 1.80) .25
Secondary outcomes
Time of progression to severe
disease, mean (SD), d
3.2 (2.4) 2.9 (1.8) 0.3 (−0.6 to 1.2)
c
NA .51
Patients who had mechanical
ventilation
4 (1.7) 10 (4.0) −2.36 (−5.28 to 0.57)
b
0.41 (0.13 to 1.30) .17
Patients admitted to ICU 6 (2.5) 8 (3.2) −0.72 (−3.67 to 2.22)
b
0.78 (0.27 to 2.20) .79
All-cause in-hospital mortality 3 (1.2) 10 (4.0) −2.77 (−5.58 to 0.04)
b
0.31 (0.09 to 1.11) .09
Length of stay, mean (SD), d 7.7 (4.4) 7.3 (4.3) 0.4 (−0.4 to 1.3)
c
NA .38
Clinical outcome at day 5
No. 238
d
247
e
NA NA NA
Complete symptom resolution 122 (51.3) 131 (53.0) −1.78 (−10.70 to 7.12)
b
0.97 (0.82 to 1.15) .72
Normal chest radiography
f
61 (25.6) 61 (24.9) 0.73 (−7.02 to 8.48)
b
1.03 (0.76 to 1.40) .92
Abbreviations: ICU, intensive care unit; NA, not applicable; WHO, WorldHealth
Organization.
a
All outcomes were captured from randomization until discharge from study
sites or day 28 of enrollment, whichever was earlier.
b
Absolute difference in proportion.
c
Mean difference (mean of ivermectin group minus mean of the control group)
with 95% CI.
d
Three patients withdrew from the study before day 5 after taking at least
1 dose of ivermectin.
e
Two patients died before follow-upon day 5.
f
Two patients missed chest radiographyon day 5 (n = 245 for control arm).
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There were no significant differences in the concomitant medi-
cations prescribed for both groups. In sensitivity analyses, base-
line characteristics were similar in the intention-to-treat popu-
lation (eTable 1 in Supplement 2).
Primary Outcome
Among the 490 patients, 95 (19.4%) progressed to severe dis-
ease during the study period; 52 of 241 (21.6%) received iver-
mectin plus standard of care, and 43 of 249 (17.3%)received stan-
dard of care alone (RR, 1.25; 95% CI, 0.87-1.80; P= .25) (Table 2).
Similar results were observed in the intention-to-treat popula-
tion in the sensitivity analyses (eTable 2 in Supplement 2).
Secondary Outcomes
There were no significant differences between ivermectin and
control groups for all the prespecified secondary outcomes
Table 3. Subgroups Analyses forPatients With Severe Disease (WHO Scale 5-9)
in Primary Analysis Population
Subgroup Ivermectin Control
Relative risk
(95% CI)
P
value
Pvalue for
interaction
a
No. 52
b
43
c
NA NA NA
Ethnicity
Chinese 8 (21.6) 5 (15.6) 1.38 (0.50-3.81) .56
.87
Indian 4 (10.5) 1 (3.3) 3.16 (0.37-26.80) .37
Malay 36 (23.5) 33 (19.2) 1.23 (0.81-1.86) .35
Other
d
4 (30.8) 4 (26.7) 1.15 (0.36-3.72) >.99
Sex
Female 26 (20.3) 27 (19.7) 1.01 (0.63-1.64) >.99
.21
Male 26 (23.4) 16 (14.3) 1.64 (0.93-2.88) .09
Age, y
≤60 21 (20.0) 17 (14.3) 1.40 (0.78-2.51) .29
.61
>60 31 (22.8) 26 (20.0) 1.14 (0.72-1.81) .65
COVID-19 vaccination
Complete
e
22 (17.7) 12 (9.2) 1.92 (0.99-3.71) .06
.11
Partial or
unvaccinated
30 (25.6) 31 (26.1) 0.98 (0.64-1.52) >.99
Disease severity
at enrollment
Mild 14 (16.9) 11 (13.1) 1.29 (0.62-2.67) .52
.97
Moderate 38 (24.1) 32 (19.4) 1.24 (0.82-1.88) .35
Day of symptom at
enrollment
≤5 d 33 (23.4) 21 (14.4) 1.63 (0.99-2.67) .07
.11
>5 d 19 (19.0) 22 (21.4) 0.89 (0.51-1.54) .73
Hypertension
Yes 38 (21.3) 37 (19.4) 1.10 (0.74-1.65) .70
.18
No 14 (22.2) 6 (10.3) 2.15 (0.88-5.22) .09
Diabetes mellitus
Yes 31 (23.7) 26 (19.8) 1.19 (0.75-1.89) .55
.81
No 21 (19.1) 17 (14.4) 1.33 (0.74-2.38) .38
Dyslipidemia
Yes 25 (24.5) 14 (17.1) 1.44 (0.80-2.58) .28
.50
No 27 (19.4) 29 (17.4) 1.12 (0.70-1.80) .67
BMI
<30 32 (17.3) 31 (16.5) 1.05 (0.67-1.65) .89
.13
≥30 20 (35.7) 12 (19.7) 1.82 (0.98-3.36) .06
Chronic disease
Cardiac
Yes 7 (18.9) 3 (15.0) 1.26 (0.37-4.35) >.99
.99
No 45 (22.1) 40 (17.5) 1.26 (0.86-1.85) .28
Kidney
Yes 8 (28.6) 6 (14.0) 2.05 (0.80-5.27) .22
.27
No 44 (20.7) 37 (18.0) 1.15 (0.78-1.70) .54
Abbreviations: BMI, body mass index,
calculated as weight in kilograms
divided by height in meters squared;
NA, not applicable; WHO, World
Health Organization.
a
Pvalues were obtained from an
interaction term between the
treatment groups and the
prognostic factor for severe disease
in a logistic regression analysis.
b
Total number of patients from the
ivermectin group included in
the analyses was 52 of 241.
c
Total number of patients from the
control group included in the
analyses was 43 of 249.
d
Other refers to Indigenous ethnic
groups in Peninsular Malaysia,
Sabah, and Sarawak, individuals of
mixed race, and foreigners residing
in Malaysia.
e
Received 2 doses of COVID-19
vaccines.
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(Table 2). Among patients who progressed to severe disease,
the time from study enrollment to the onset of deterioration
was similar across ivermectin and control groups (mean [SD],
3.2 [2.4] days vs 2.9 [1.8] days; mean difference, 0.3; 95% CI,
−0.6 to 1.2; P= .51). Mechanical ventilation occurred in 4 pa-
tients (1.7%) in the ivermectin group vs 10 (4.0%) in the con-
trol group (RR, 0.41; 95% CI, 0.13 to 1.30; P= .17) and inten-
sive care unit admission in 6 (2.5%) vs 8 (3.2%) (RR, 0.78; 95%
CI, 0.27 to 2.20; P= .79).The 28-day in-hospital mortality rate
was similar for the ivermectin and control groups (3 [1.2%] vs
10 [4.0%]; RR, 0.31; 95% CI, 0.09 to 1.11; P= .09), as was the
length of hospital stay after enrollment (mean [SD], 7.7 [4.4]
days vs 7.3 [4.3] days; mean difference, 0.4; 95% CI, −0.4 to
1.3; P= .38).
By day 5 of enrollment, the proportion of patients who
achieved complete symptom resolution was comparable
between both groups (RR, 0.97; 95% CI, 0.82-1.15; P= .72).
Findings of chest radiography without pneumonic changes
or with resolution by day 5 were also similar (RR, 1.03; 95%
CI, 0.76-1.40; P= .92). No marked variation was noted in
blood parameters (eTable 3 in Supplement 2). There was no
significant difference in the incidence of disease complica-
tions and highest oxygen requirement (eTables 4 and 5 in
Supplement 2).
Subgroup Analyses
Subgroup analyses for patients with severe disease were un-
remarkable (Table 3). Among fully vaccinated patients, 22
(17.7%) in the ivermectin group and 12 (9.2%) in the control
group developed severe disease (RR, 1.92; 95% CI, 0.99-3.71;
P= .06). Post hoc analyses on clinical outcomes by vaccina-
tion status showed that fully vaccinated patients in the con-
Table 4.Summar y of AdverseEvents (AEs) and Serious AEs (SAEs) in the Primary Analysis Population
AE
No.
Total Ivermectin Control
No. 490 241 249
Patients who had ≥1 AE/SAE, No. (%) 44 (9.0) 33 (13.7) 11 (4.4)
Total nonserious AE 50 38 12
Diarrhea 18 14 4
Acute kidney injury 4 3 1
Acidosis 3 2 1
Alanine aminotransferase increased 2 2 0
Dizziness 2 2 0
Hypertension 2 1 1
Hyperglycemia 2 1 1
Hypoglycemia 1 1 0
Headache 1 1 0
Abdominal pain 1 1 0
Nausea 1 1 0
Constipation 1 1 0
Fever 1 1 0
Epistaxis 1 0 1
Conjunctivitis 1 1 0
Urticaria 1 1 0
Rash, maculopapular 1 0 1
Myalgia 1 1 0
Noncardiac chest pain 1 1 0
Palpitation 1 1 0
Sinus tachycardia 1 1 0
Muscle weakness, upper limb 1 0 1
Vascular access complication
a
11 0
Fall 1 0 1
Total SAE 5 4 1
Myocardial infarction 2 2 0
Arterial injury
b
10 1
Anemia
c
11 0
Hypotension
d
11 0
Severity by CTCAE grading
130237
21183
3862
4651
Abbreviation: CTCAE, Common
Terminology Criteria for Adverse
Events.
a
Bleeding from brachiocephalic
fistula after hemodialysis.
b
Inferior epigastric arterial bleeding.
c
Severe anemia precipitating an
acute coronary syndrome.
d
Hypovolemic shock due to severe
diarrhea.
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trol group had a significantly lower rate of severe disease
(P= .002; supporting data in eTable 6 in Supplement 2).
Adverse Events
A total of 55 AEs occurred in 44 patients (9.0%) (Table 4).
Among them, 33 were from the ivermectin group, with diar-
rhea being the most common AE (14 [5.8%]). Five events were
classified as SAEs, with 4 in the ivermectin group (2 patients
had myocardial infarction, 1 had severe anemia, and 1 devel-
oped hypovolemic shock secondary to severe diarrhea), and
1 in the control group had inferior epigastric arterial bleeding.
Six patients discontinued ivermectin, and 3 withdrew from
the study owing to AEs. The majority of AEs were grade 1 and
resolved within the study period.
Among the 13 deaths, severe COVID-19 pneumonia was
the principal direct cause (9 deaths [69.2%]). Four patients in
the control group died from nosocomial sepsis. None of the
deaths were attributed to ivermectin treatment.
Discussion
In this randomized clinical trial of early ivermectin treatment
for adults with mild to moderate COVID-19 and comorbidi-
ties, we found no evidence that ivermectin was efficacious in
reducing the risk of severe disease. Our findings are consis-
tent with the results of the IVERCOR-COVID19 trial,
17
which
found that ivermectin was ineffective in reducing the risk
of hospitalization.
Prior randomized clinical trials of ivermectin treatment
for patients with COVID-19 and with 400 or more patientsen-
rolled focused on outpatients.
16,17
In contrast, the patients in
our trial were hospitalized, which permitted the observed
administration of ivermectin with a high adherence rate. Fur-
thermore, we used clearly defined criteria for ascertaining pro-
gression to severe disease.
Before the trial started, the case fatality rate in Malaysia
from COVID-19 was about 1%,
25
a rate too low for mortality to
be the primary end point in our study. Even in a high-risk co-
hort, there were 13 deaths (2.7%). A recent meta-analysis of
8 randomized clinical trials of ivermectin to treat SARS-
CoV-2 infection, involving 1848 patients with 71 deaths (3.8%),
showed that treatment with the drug had no significant ef-
fect on survival.
26
The pharmacokinetics of ivermectin for treating COVID-19
has been a contentious issue. The plasma inhibitory concen-
trations of ivermectin for SARS-CoV-2 are high; thus, establish-
ing an effective ivermectin dose regimen without causing
toxic effects in patients is difficult.
27,28
The dose regimens
that produced favorable results against COVID-19 ranged from
a 0.2-mg/kg single dose to 0.6 mg/kg/d for 5 days
29-32
; a con-
centration-dependent antiviral effect was demonstrated by
Krolewiecki et al.
29
Pharmacokinetic studies have suggested
that a single dose of up to 120 mg of ivermectin can be safe and
well tolerated.
33
Considering the peak of SARS-CoV-2 viral load
during the first week of illness and its prolongation in severe
disease,
34
our trial used an ivermectin dose of 0.4 mg/kg of body
weight daily for 5 days. The notably higher incidence of AEs in
the ivermectin group raises concerns about the use of this drug
outside of trial settings and without medical supervision.
Limitations
Our study has limitations. First, the open-label trial design
might contribute to the underreporting of adverse events in
the control group while overestimatingthe drug effects of iver-
mectin. Second, our study was not designed to assess the ef-
fects of ivermectin on mortality from COVID-19. Finally, the
generalizability of our findings may be limited by the older
study population, although younger and healthier individu-
als with low risk of severe disease are less likely to benefit from
specific COVID-19 treatments.
Conclusions
In this randomized clinical trial of high-risk patients with mild
to moderate COVID-19, ivermectin treatment during early ill-
ness did not prevent progression to severe disease. The study
findings do not support the use of ivermectin for patients with
COVID-19.
ARTICLE INFORMATION
Accepted for Publication: January 22, 2022.
Published Online: February 18, 2022.
doi:10.1001/jamainternmed.2022.0189
Author Affiliations: Department of Medicine,
Raja Permaisuri Bainun Hospital, Perak, Malaysia
(S. C. L. Lim, Ker); Department of Medicine, Kepala
Batas Hospital, Penang, Malaysia (Hor,Cheng );
Clinical Research Centre, Seberang Jaya Hospital,
Penang, Malaysia (Hor); Department of Medicine,
Sungai Buloh Hospital, Selangor, Malaysia (Tay,
Chidambaram); Department of Medicine, Tumpat
Hospital, Kelantan, Malaysia (Mat Jelani);
Department of Medicine, Taiping Hospital, Perak,
Malaysia (Tan, Cheah); Department of Medicine,
Penang Hospital, Penang, Malaysia (Chow);
Department of Medicine, Sultanah Aminah
Hospital, Johor, Malaysia (Zaid); Department of
Medicine, Sarawak General Hospital, Sarawak,
Malaysia (H. H. Lim); Department of Medicine,
Kuala Lumpur Hospital, Kuala Lumpur, Malaysia
(Khalid); Department of Medicine, Sultanah Nur
Zahirah Hospital, Terengganu, Malaysia(Mohd
Unit); Department of Medicine, Sultan Abdul Halim
Hospital, Kedah, Malaysia (An); Department of
Medicine, Putrajaya Hospital, Putrajaya, Malaysia
(Nasruddin); Department of Medicine, Sultanah
Bahiyah Hospital, Kedah, Malaysia (Low);
Department of Medicine, Lahad Datu Hospital,
Sabah, Malaysia (Khoo); Department of Medicine,
Duchess of Kent Hospital, Sabah, Malaysia (Loh);
Department of Medicine, Melaka Hospital, Malacca,
Malaysia (Zaidan); Department of Medicine, Tuanku
Fauziah Hospital, Perlis, Malaysia (Ab Wahab);
Clinical Research Centre, Raja Permaisuri Bainun
Hospital, Perak, Malaysia (Song); Department of
Pharmacy, Sungai Buloh Hospital, Selangor,
Malaysia (Koh); Clinical Research Centre, Sarawak
General Hospital, Sarawak, Malaysia (King);
School of Medicine, Taylor’sUniversity, Selangor,
Malaysia (Lai); Institute for Clinical Research,
National Institutes of Health, Selangor, Malaysia
(Peariasamy).
Author Contributions: Dr S. Lim and Mr King had
full access to all of the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: S. Lim, Tan,Chow, Cheah,
Cheng, An, Low,Song, Chidambaram, Peariasamy.
Acquisition, analysis, or interpretation of data:
S. Lim, Hor, Tay, Mat Jelani, Tan, Ker, Zaid, Cheah,
H. Lim, Khalid, Mohd Unit, An, Nasruddin, Khoo,
Loh, Zaidan, Ab Wahab, Koh,King, Lai.
Drafting of the manuscript: S. Lim, Hor,Tay,
Mat Jelani, Tan, Zaid, H. Lim, An, Low, Ab Wahab,
King, Peariasamy.
Critical revision of the manuscript for important
intellectual content: S. Lim, Hor, Tan, Ker, Chow,
Cheah, Khalid, Cheng, Mohd Unit, An, Nasruddin,
Efficacy of Ivermectin on Disease Progression in Patients With COVID-19 Original Investigation Research
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Khoo, Loh, Zaidan, Song, Koh, King, Lai,
Chidambaram.
Statistical analysis: S. Lim, Hor,Tan, King, Lai.
Administrative, technical, or material support:
S. Lim, Hor, Tay, Mat Jelani, Tan, Ker, Chow, Zaid,
Cheah, H. Lim, Khalid, Low,Khoo, Loh, Zaidan,
Ab Wahab, Song, Koh, Chidambaram.
Supervision: S. Lim, Tan, Ker, Chow, Zaid, Cheng,
Khoo, Loh, Song, Peariasamy.
Conflict of Interest Disclosures: None reported.
The I-TECH Study Group: Members of the I-TECH
Study Group are listed in Supplement 3.
Data Sharing Statement: See Supplement 4.
Additional Contributions: The authors thank all
the investigators at the 21 study sites and the
Institute for Clinical Research, Ministry of Health
Malaysia, for their immense contribution and
support. In addition, we are grateful for the
participation of the patients enrolled in this study.
We also thank the members of the independent
Data and Safety Monitoring Board, namely Petrick
Periyasamy, MMed, National University Medical
Centre, Malaysia; Lai Hui Pang, BPharm, Institute
for Clinical Research, Malaysia; Mohamad Adam
Bujang, PhD, Institute for Clinical Research,
Malaysia; Wei Hong Lai, PhD, Institute for Clinical
Research, Malaysia; and Nurakmal Baharum, BSc,
Institute for Clinical Research, Malaysia. They did
not receive compensation for their contribution to
this study.We also thank Noor Hisham Abdullah,
M Surg, Director-General of Health Malaysia, for his
permission to publish this study.
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