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

Authors:
  • Kepala Batas Hospital & Seberang Jaya Hospital, Penang, Malaysia

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.
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
(Reprinted) E1
© 2022 American Medical Association. All rights reserved.
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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.
Research Original Investigation Efficacy of Ivermectin on Disease Progression in 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.
Efficacy of Ivermectin on Disease Progression in Patients With COVID-19 Original Investigation Research
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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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Research Original Investigation Efficacy of Ivermectin on Disease Progression in Patients With COVID-19
E10 JAMA Internal Medicine Published online February 18, 2022 (Reprinted) jamainternalmedicine.com
© 2022 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by Steven Lim on 02/18/2022
... Six randomised control trials, published in high impact journals, have been cited as evidence against the use of ivermectin in the treatment of COVID-19 [87][88][89][90][91][92]. Four of these tested ivermectin monotherapy against placebo [89][90][91][92] so the results are not relevant to the multidrug treatment protocols used by practicing doctors. ...
... The I-Tech study [88] is interesting because it recruited high-risk patients with age ≥ 50 and at least one comorbidity, the treatment group was treated with a realistic multidrug protocol combining ivermectin with corticosteroids, antibiotics, and anticoagulants with 1.2% mortality rate, the control group was treated only with corticosteroids, antibiotics, and anticoagulants, with 4.0% mortality rate. The authors claim that this was a negative result due to p-value p = 0.09, and also due to negative results in irrelevant soft endpoints other than hospitalisation and death. ...
... The study allowed a 7-day window from the beginning of symptoms before initiating treatment, however Fazio et al [93] showed that the ideal window of opportunity for the outpatient treatment of COVID-19 is approximately 3 days from the beginning of symptoms. Thus, we can expect stronger results if the protocol used in the I-Tech study [88] is initiated within the 3-day window from the onset of symptoms. ...
... Multiple clinical trials have been conducted to evaluate clinical outcomes [19][20][21][22][23][24][25][26], with contradictory outcomes, and some of these studies have been withdrawn or retracted for fear of serious data inconsistencies or research fraud [27][28][29]. It is imperative to synthesize evidence for clinicians and communities. ...
... COVID-19 disease severity was asymptomatic/mild in 12 randomized controlled trials, moderate in 1, mild and moderate in 17, severe in 2, and moderate and severe in 1. Studies were done in 19 countries: Argentina (n = 3 studies) [58][59][60], Bangladesh (n = 2) [61,62], Brazil (n = 1) [10], China (n = 1) [63], Colombia (n = 1) Z. Song et al. [64], Egypt (n = 3) [23,65,66], India (n = 3) [67][68][69], Iran (n = 3) [26,70,71], Israel (n = 1) [72], Italy (n = 1) [22], Japan, (n = 1) [73], Malaysia (n = 1) [24], Mexico (n = 2) [74,75], Nigeria (n = 1) [76], Pakistan (n = 2) [77,78], Spain (n = 1) [79], Thailand (n = 2) [25,80], Turkey (n = 1) [81], and USA (n = 3) [21,82,83]. Of all 33 studies, 7 had an overall high risk of bias, 13 had some concerns of bias, and 13 had a low risk ( Supplementary Fig. 1). ...
... Twenty-nine of the thirty-three studies reported on all-cause mortality rate (n = 8738 participants) [10,[21][22][23][24][25][26][59][60][61][62][63][64][65][68][69][70][71][72][73][74][75][76][77][79][80][81][82][83]. There was no significant difference in all-cause mortality rate between IVM and controls (RR 0.95, 95% CI 0.75-1.21, ...
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The effect of ivermectin (IVM) in treating coronavirus disease 2019 (COVID-19) is still controversial, yet the drug has been widely used in the world. The aim of this review was to systematically evaluate the clinical outcomes of IVM in patients with COVID-19. From inception to June 22, 2023, the PubMed, EMBASE, Web of Science (WOS), and scopus databases were searched for relevant observational studies on the risk of RA in migraineurs. We searched PubMed/Medline, EMBASE, the Cochrane Library, Web of Science, medRxiv, and bioRxiv to collect all relevant publications from inception to June 22, 2023. Primary outcomes were all-cause mortality rate, mechanical ventilation (MV) requirement, PCR negative conversion, and adverse events (AEs). Revman 5.4 was used to assess the risk of bias (RoB) and quality of evidence. Thirty-three RCTs (n = 10,489) were included. No significant difference in all-cause mortality rates or PCR negative conversion between IVM and controls. There were significant differences in MV requirement (RR 0.67, 95% CI 0.47–0.96) and AEs (RR 0.87, 95% CI 0.80–0.95) between the two groups. Ivermectin could reduce the risk of MV requirement and AEs in patients with COVID-19, without increasing other risks. In the absence of a better alternative, clinicians could use it with caution.
... Initial repurposing was based on non-peer-review observational evidence [8]. Later there were many randomised controlled trials and several meta-analyses giving varying conclusions on efficacy (beneficial [9][10][11][12], inconclusive [12] or non-beneficial [13][14][15][16][17][18]. A Cochrane review concluded that they are uncertain about the efficacy and safety (evidence up to April 2022) [19] and WHO recommended its use only in the setting of clinical trials [20]. ...
... This randomised double-blind controlled clinical trial of ivermectin 24 mg daily for 5 days compared to placebo, among patients with mild to moderate Covid-19, admitted to hospitals showed that there was a greater reduction in the viral load in the ivermectin group by Day 10 compared to placebo. However, there was no significant difference in clinical outcomes with ivermectin on the clinical progression and symptoms in the two groups, in keeping with most other recently reported well-conducted large-scale clinical trials [13][14][15][16]. This study provided data on certain important outcomes and aspects which were not subjected to investigation in initially reported trials. ...
Article
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Background Evidence on ivermectin as a treatment for Covid-19 is controversial. A Cochrane review concluded that the efficacy and safety of ivermectin is uncertain (evidence up to April 2022) and WHO recommended its use only in the setting of clinical trials. This study aimed to assess the efficacy and safety of oral ivermectin in hospitalized patients with mild to moderate Covid-19. Trial design and methods A double-blind, randomized placebo-controlled clinical trial was conducted among RT-PCR-confirmed, adults, hospitalised within the first four days of symptoms. Patients received oral ivermectin 24 mg or placebo daily for five days. RT-PCR was repeated on days five and ten. Clinical progression was monitored using the World Health Organization Clinical Progression Scale. Serum ivermectin levels were measured on days three, five, and seven. The primary outcome was the difference in the viral load between day zero and ten in the two groups. Results Out of 1699 patients screened, 249 underwent randomization and 127 received ivermectin, and 122 placebo. D10 median viral load for E gene (IQR) was 2,000 copies/mL (100 − 20,500) with ivermectin (n = 80) and 4,100 copies/mL (1,000–65,600) with placebo (n = 81, p = 0.028), per protocol analysis. The difference in Log viral load between day zero and ten between ivermectin and placebo was 3.72 and 2.97 respectively (p = 0.022). There was no significant difference in the WHO clinical progression scale or the adverse effects. Ivermectin blood levels taken before or with meals were not significantly different. Only 7 and 17 patients achieved blood levels above 160ng/ML and 100ng/ML respectively and they did not achieve a significantly lower viral load. Conclusion Although ivermectin resulted in statistically significant lower viral load in patients with mild to moderate Covid-19, it had no significant effect on clinical symptoms. Trial registration number SLCTR/2021/020, Sri Lanka Clinical Trials Registry. 19/07/2021.
... These underlying conditions in COVID-19 patients can significantly compromise the body's ability to combat the SARS-CoV-2 virus. This weakened immunity may result in prolonged viral presence [19,20], delayed and less effective immune responses, impaired immune cell function [21], dysregulated inflammation leading to cytokine storms [22], and compromised immunological memory. Additionally, COVID-19 patients with comorbidities may be more susceptible to secondary infections, further complicating the disease course. ...
Article
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Introduction The COVID-19 infection as an inflammatory disease has posed significant challenges to global public health due to multi-factor risks associated with it leading to disease severity and mortality. Understanding the effect of age and comorbidities on overall disease progression is crucial to identify highly susceptible individuals and to develop effective disease management strategies in a resource limited country like Pakistan. Methodology A retrospective study was conducted on hospitalized COVID-19 patients to assess the prevalence of various comorbidities among different age groups and their effect on disease severity and mortality rate. Results In this retrospective study, a cohort of 618 hospitalized COVID-19 patients was analyzed, consisting of 387 males (62.6 %) and 231 females (37.4 %). Notably, the young age group (15–24 years), had the lowest frequency of hospitalized COVID-19 patients, while no case was observed in children (≤14 years) showing a significant association (p < 0.001) of age and disease prevalence. Comorbidities were observed in 63.9 % of COVID-19 patients including hypertension (HTN), diabetes mellitus (DM), ischemic heart diseases (IHD), asthma, chronic kidney disease (CKD) and tuberculosis (TB). The most common comorbidities were HTN (42.1 %) followed by DM (33.8 %), IHD (16.5 %), asthma (11.2 %), CKD (7.9 %) and TB (1.9 %). Furthermore, the study revealed a significant association between comorbidities, age groups, and the need for non-invasive ventilation (NIV) (p < 0.001), mechanical ventilation (MV) (p < 0.001), and intensive care unit (ICU) admission (p < 0.001). Patients with specific comorbidities and those in the older age group (≥65 years) demonstrated a higher need for these interventions. However, patients without any comorbidity consistently exhibited the highest cumulative proportion of survival at each time point, indicating better overall survival outcomes. In contrast, patients with multimorbidities of DM/HTN/IHD, HTN/IHD, and DM/HTN/CKD had comparatively lower survival rates and higher mortality rates (p < 0.001). Conclusion This research highlights the significant impact of age, comorbidities and multimorbidities on the severity and mortality of COVID-19 patients. It highlights the importance of considering these factors in tailoring effective management strategies for patients with COVID-19 or other infectious respiratory diseases.
... Vários estudos de revisão sistemática e meta-análise concluíram que não há evidências confiáveis disponíveis que suportam o uso de ivermectina para tratamento de Covid-19 (Popp et al., 2021;Reis et al., 2022;Lim et al., 2022). No início da pandemia, com a propagação de um novo vírus, os profissionais de saúde foram pressionados a enfrentar um desafio duplo, buscar conhecimento científico constantemente e oferecer uma resposta satisfatória e em tempo hábil à população (Modesto, 2022). ...
Article
Full-text available
Resumo O objetivo do estudo foi avaliar o uso de medicamentos associados à Covid-19 por usuários da Atenção Primária à Saúde (APS). Trata-se de um estudo transversal com coleta de dados nas unidades de Estratégia Saúde da Família do município de Rondonópolis, MT, Brasil. Os dados foram obtidos com aplicação de um formulário semiestruturado. Dentre os participantes, 36% afirmaram ter consumido fármacos para prevenção da Covid-19, como ivermectina (89,58%), vitamina D (13,88%) e azitromicina (6,94%). Residir em domicílio em que duas ou mais pessoas precisaram sair para trabalhar na pandemia foi associado ao uso de medicamentos preventivos da Covid-19 (OR: 1,7; IC95%: 1,09 - 2,60). Os resultados indicam a necessidade de realizar ações para a promoção do uso racional de medicamentos nos territórios da APS, com vistas a capacitação profissional, educação popular em saúde e combate à desinformação.
... Rapidly launched clinical trials focused on SARS-CoV-2 generated key pharmacotherapeutic information to guide practice around the world [10][11][12][13][14][15][16]. Pre-existing and newly developed adaptive platform trials allowed simultaneous comparison of multiple intervention groups against a single control group, thereby facilitating rapid therapeutic discoveries [17]. ...
Article
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Background During the COVID-19 pandemic, many intensive care units (ICUs) halted research to focus on COVID-19-specific studies. Objective To describe the conduct of an international randomized trial of stress ulcer prophylaxis (Re-Evaluating the Inhibition of Stress Erosions in the ICU [REVISE]) during the pandemic, addressing enrolment patterns, center engagement, informed consent processes, data collection, a COVID-specific substudy, patient transfers, and data monitoring. Methods REVISE is a randomized trial among mechanically ventilated patients, comparing pantoprazole 40 mg IV to placebo on the primary efficacy outcome of clinically important upper gastrointestinal bleeding and the primary safety outcome of 90-day mortality. We documented protocol implementation status from March 11th 2020-August 30th 2022. Results The Steering Committee did not change the scientific protocol. From the first enrolment on July 9th 2019 to March 10th 2020 (8 months preceding the pandemic), 267 patients were enrolled in 18 centers. From March 11th 2020-August 30th 2022 (30 months thereafter), 41 new centers joined; 59 were participating by August 30th 2022 which enrolled 2961 patients. During a total of 1235 enrolment-months in the pandemic phase, enrolment paused for 106 (8.6%) months in aggregate (median 3 months, interquartile range 2;6). Protocol implementation involved a shift from the a priori consent model pre-pandemic (188, 58.8%) to the consent to continue model (1615, 54.1%, p < 0.01). In one new center, an opt-out model was approved. The informed consent rate increased slightly (80.7% to 85.0%, p = 0.05). Telephone consent encounters increased (16.6% to 68.2%, p < 0.001). Surge capacity necessitated intra-institutional transfers; receiving centers continued protocol implementation whenever possible. We developed a nested COVID-19 substudy. The Methods Centers continued central statistical monitoring of trial metrics. Site monitoring was initially remote, then in-person when restrictions lifted. Conclusion Protocol implementation adaptations during the pandemic included a shift in the consent model, a sustained high consent rate, and launch of a COVID-19 substudy. Recruitment increased as new centers joined, patient transfers were optimized, and monitoring methods were adapted.
... Furthermore, according to the findings of Lim, et al (2022), where patients 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, among 241 patients who received ivermectin, 52 developed severe COVID-19, compared to 43 of 249 patients who did not take the drug. ...
Preprint
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Clinical trials are critical for discovering new treatments for diseases such as coronavirus disease 19 (COVID-19), a highly contagious and pathogenic viral infection. Ivermectin, an antiparasitic drug, was thought to be a potential treatment for COVID-19. Scoping review of ivermectin use in the treatment of coronavirus disease is essential to uncover conclusions on whether or not this drug can be effective in treating it. This will also help to identify what studies need to be performed in order to effectively treat COVID-19 using Ivermectin. The researches utilize the meta-analysis method type of research a collective results of previous published researches to systematically review and assesses the effectiveness of ivermectin in treating patients with COVID-19. Through the use of PRISMA model in collecting data the researches have collected a total of 12 studies from Google Scholar, sciencedirect, Frontiers, American Journal of Therapeutics, and National Library of Medicine to determine its efficacy. The researchers divided the studies in three: asympotomatic-to-mild patients, mild-to-moderate, and moderate-to-severe patients. The result gathered shows that Ivermectin is effective in treating asymptomatic –to- mild patients only with the collected studies. However in treating mild-to-moderate and moderate-to-severe, study findings do not support the use of ivermectin for patients with COVID‐19 as it shows progression to more critical state, death, longer hospitalization, multi-organ failure and need for mechanical ventilation. Overall, the evidence available does not support the use of ivermectin for treatment or prevention of COVID‐19 outside of well‐designed WHO administered clinical trials. Further meta-analysis following the WHO's Solidarity 2022 trial, assessing other anti-parasitic drugs besides ivermectin, and a study combining antiviral agents and ivermectin are recommended. Keywords: antiparasitic, clinical trials, coronavirus, ivermectin, metaanalysis How to Cite: Dacumos RO, Baobaoen AS, Flores RMT, Galvez DRO, Aban JL (2024). Effectiveness of ivermectin to prevent and treat covid-19: a meta analysis study. A Research Output in Microbiology. pp 1-32.
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Background: During the coronavirus disease (COVID)-19 pandemic several drugs were used to manage the patients mainly those with a severe phenotype. Potential drugs were used off-label and major concerns arose from their applicability to managing the health crisis highlighting the importance of clinical trials. In this context, we described the mechanisms of the three repurposed drugs [Ivermectin-antiparasitic drug, Chloroquine/Hydroxychloroquine-antimalarial drugs, and Azithromycin-antimicrobial drug]; and, based on this description, the study evaluated the clinical efficacy of those drugs published in clinical trials. The use of these drugs reflects the period of uncertainty that marked the beginning of the COVID-19 pandemic, which made them a possible treatment for COVID-19. Methods: In our review, we evaluated phase III randomized controlled clinical trials (RCTs) that analyzed the efficacy of these drugs published from the COVID-19 pandemic onset to 2023. We included eight RCTs published for Ivermectin, 11 RCTs for Chloroquine/Hydroxychloroquine, and three RCTs for Azithromycin. The research question (PICOT) accounted for P—hospitalized patients with confirmed or suspected COVID-19; I—use of oral or intravenous Ivermectin OR Chloroquine/Hydroxychloroquine OR Azithromycin; C—placebo or no placebo (standard of care); O—mortality OR hospitalization OR viral clearance OR need for mechanical ventilation OR clinical improvement; and T—phase III RCTs. Results: While studying these drugs’ respective mechanisms of action, the reasons for which they were thought to be useful became apparent and are as follows: Ivermectin binds to insulin-like growth factor and prevents nuclear transportation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), therefore preventing cell entrance, induces apoptosis, and osmotic cell death and disrupts viral replication. Chloroquine/Hydroxychloroquine blocks the movement of SARS-CoV-2 from early endosomes to lysosomes inside the cell, also, this drug blocks the binding between SARS-CoV-2 and Angiotensin-Converting Enzyme (ACE)-2 inhibiting the interaction between the virus spike proteins and the cell membrane and this drug can also inhibit SARS-CoV-2 viral replication causing, ultimately, the reduction in viral infection as well as the potential to progression for a higher severity phenotype culminating with a higher chance of death. Azithromycin exerts a down-regulating effect on the inflammatory cascade, attenuating the excessive production of cytokines and inducing phagocytic activity, and acts interfering with the viral replication cycle. Ivermectin, when compared to standard care or placebo, did not reduce the disease severity, need for mechanical ventilation, need for intensive care unit, or in-hospital mortality. Only one study demonstrated that Ivermectin may improve viral clearance compared to placebo. Individuals who received Chloroquine/Hydroxychloroquine did not present a lower incidence of death, improved clinical status, or higher chance of respiratory deterioration compared to those who received usual care or placebo. Also, some studies demonstrated that Chloroquine/Hydroxychloroquine resulted in worse outcomes and side-effects included severe ones. Adding Azithromycin to a standard of care did not result in clinical improvement in hospitalized COVID-19 participants. In brief, COVID-19 was one of the deadliest pandemics in modern human history. Due to the potential health catastrophe caused by SARS-CoV-2, a global effort was made to evaluate treatments for COVID-19 to attenuate its impact on the human species. Unfortunately, several countries prematurely justified the emergency use of drugs that showed only in vitro effects against SARS-CoV-2, with a dearth of evidence supporting efficacy in humans. In this context, we reviewed the mechanisms of several drugs proposed to treat COVID-19, including Ivermectin, Chloroquine/Hydroxychloroquine, and Azithromycin, as well as the phase III clinical trials that evaluated the efficacy of these drugs for treating patients with this respiratory disease. Conclusions: As the main finding, although Ivermectin, Chloroquine/Hydroxychloroquine, and Azithromycin might have mechanistic effects against SARS-CoV-2 infection, most phase III clinical trials observed no treatment benefit in patients with COVID-19, underscoring the need for robust phase III clinical trials.
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Background: The efficacy of the viral clearance and clinical outcomes of favipiravir (FPV) in outpatients being treated for coronavirus disease 2019 (COVID-19) is unclear. Ivermectin (IVM), niclosamide (NCL), and FPV demonstrated synergistic effects in vitro for exceed 78% inhibiting severe acute respiratory syndrome- coronavirus-2 (SARS-CoV-2) replication. Methods: A phase 2, open-label, 1:1, randomized, controlled trial was conducted on Thai patients with mild- to-moderate COVID-19 who received either combination FPV/IVM/NCL therapy or FPV alone to assess the rate of viral clearance among individuals with mild-to-moderate COVID-19. Results: Sixty non-high-risk comorbid patients with mild-to-moderate COVID-19 were randomized; 30 received FPV/IVM/NCL, and 30 received FPV alone. Mixed-effects multiple linear regression analysis of the cycle threshold value from SARS-CoV-2 PCR demonstrated no statistically significant differences in viral clearance rates between the combined FPV/IVM/NCL therapy group and the FPV-alone group. World Health Organization Clinical Progression scores and symptomatic improvement did not differ between arms on days 3, 6, and 10, and no adverse events were reported. No patients required hospitalization, intensive care unit admission, or supplemental oxygen or died within 28 days. C-reactive protein on day 3 was lower in the FPV/IVM/NCL group. Conclusion: Viral clearance rates did not differ significantly between the FPV/IVM/NCL combination therapy and FPV-alone groups of individuals with mild-to-moderate COVID-19, although the combined regimen demonstrated a synergistic effect in vitro. No discernible clinical benefit was observed. Further research is required to explore the potential benefits of FVP beyond its antiviral effects.
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The COVID-19 pandemic is one of the greatest threats to human health in the 21st century with more than 257 million cases and over 5.17 million deaths reported worldwide (as of November 23, 2021. Various agents were initially proclaimed to be effective against SARS-CoV-2, the etiological agent of COVID-19. Hydroxychloroquine, lopinavir/ritonavir, and ribavirin are all examples of therapeutic agents, whose efficacy against COVID-19 was later disproved. Meanwhile, concentrated efforts of researchers and clinicians worldwide have led to the identification of novel therapeutic options to control the disease including PAXLOVID™ (PF-07321332). Although COVID-19 cases are currently treated using a comprehensive approach of anticoagulants, oxygen, and antibiotics, the novel Pfizer agent PAXLOVID™ (PF-07321332), an investigational COVID-19 oral antiviral candidate, significantly reduced hospitalization time and death rates, based on an interim analysis of the phase 2/3 EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) randomized, double-blind study of non-hospitalized adult patients with COVID-19, who are at high risk of progressing to severe illness. The scheduled interim analysis demonstrated an 89% reduction in risk of COVID-19-related hospitalization or death from any cause compared to placebo in patients treated within three days of symptom onset (primary endpoint). However, there still exists a great need for the development of additional treatments, as the recommended therapeutic options are insufficient in many cases. Thus far, mRNA and vector vaccines appear to be the most effective modalities to control the pandemic. In the current review, we provide an update on the progress that has been made since April 2020 in clinical trials concerning the effectiveness of therapies available to combat COVID-19. We focus on currently recommended therapeutic agents, including steroids, various monoclonal antibodies, remdesivir, baricitinib, anticoagulants and PAXLOVID™ summarizing the latest original studies and meta-analyses. Moreover, we aim to discuss other currently and previously studied agents targeting COVID-19 that either show no or only limited therapeutic activity. The results of recent studies report that hydroxychloroquine and convalescent plasma demonstrate no efficacy against SARS-CoV-2 infection. Lastly, we summarize the studies on various drugs with incoherent or insufficient data concerning their effectiveness, such as amantadine, ivermectin, or niclosamide.
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Background: Coronavirus disease 2019 (Covid-19) disproportionately results in hospitalization or death in older patients and those with underlying conditions. Sotrovimab is a pan-sarbecovirus monoclonal antibody that was designed to prevent progression of Covid-19 in high-risk patients early in the course of disease. Methods: In this ongoing, multicenter, double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, nonhospitalized patients with symptomatic Covid-19 (≤5 days after the onset of symptoms) and at least one risk factor for disease progression to receive a single infusion of sotrovimab at a dose of 500 mg or placebo. The primary efficacy outcome was hospitalization (for >24 hours) for any cause or death within 29 days after randomization. Results: In this prespecified interim analysis, which included an intention-to-treat population of 583 patients (291 in the sotrovimab group and 292 in the placebo group), 3 patients (1%) in the sotrovimab group, as compared with 21 patients (7%) in the placebo group, had disease progression leading to hospitalization or death (relative risk reduction, 85%; 97.24% confidence interval, 44 to 96; P = 0.002). In the placebo group, 5 patients were admitted to the intensive care unit, including 1 who died by day 29. Safety was assessed in 868 patients (430 in the sotrovimab group and 438 in the placebo group). Adverse events were reported by 17% of the patients in the sotrovimab group and 19% of those in the placebo group; serious adverse events were less common with sotrovimab than with placebo (in 2% and 6% of the patients, respectively). Conclusions: Among high-risk patients with mild-to-moderate Covid-19, sotrovimab reduced the risk of disease progression. No safety signals were identified. (Funded by Vir Biotechnology and GlaxoSmithKline; COMET-ICE ClinicalTrials.gov number, NCT04545060.).
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Background: Ivermectin, an antiparasitic agent used to treat parasitic infestations, inhibits the replication of viruses in vitro. The molecular hypothesis of ivermectin's antiviral mode of action suggests an inhibitory effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in the early stages of infection. Currently, evidence on efficacy and safety of ivermectin for prevention of SARS-CoV-2 infection and COVID-19 treatment is conflicting. Objectives: To assess the efficacy and safety of ivermectin compared to no treatment, standard of care, placebo, or any other proven intervention for people with COVID-19 receiving treatment as inpatients or outpatients, and for prevention of an infection with SARS-CoV-2 (postexposure prophylaxis). Search methods: We searched the Cochrane COVID-19 Study Register, Web of Science (Emerging Citation Index and Science Citation Index), medRxiv, and Research Square, identifying completed and ongoing studies without language restrictions to 26 May 2021. Selection criteria: We included randomized controlled trials (RCTs) comparing ivermectin to no treatment, standard of care, placebo, or another proven intervention for treatment of people with confirmed COVID-19 diagnosis, irrespective of disease severity, treated in inpatient or outpatient settings, and for prevention of SARS-CoV-2 infection. Co-interventions had to be the same in both study arms. We excluded studies comparing ivermectin to other pharmacological interventions with unproven efficacy. Data collection and analysis: We assessed RCTs for bias, using the Cochrane risk of bias 2 tool. The primary analysis excluded studies with high risk of bias. We used GRADE to rate the certainty of evidence for the following outcomes 1. to treat inpatients with moderate-to-severe COVID-19: mortality, clinical worsening or improvement, adverse events, quality of life, duration of hospitalization, and viral clearance; 2. to treat outpatients with mild COVID-19: mortality, clinical worsening or improvement, admission to hospital, adverse events, quality of life, and viral clearance; (3) to prevent SARS-CoV-2 infection: SARS-CoV-2 infection, development of COVID-19 symptoms, adverse events, mortality, admission to hospital, and quality of life. Main results: We found 14 studies with 1678 participants investigating ivermectin compared to no treatment, placebo, or standard of care. No study compared ivermectin to an intervention with proven efficacy. There were nine studies treating participants with moderate COVID-19 in inpatient settings and four treating mild COVID-19 cases in outpatient settings. One study investigated ivermectin for prevention of SARS-CoV-2 infection. Eight studies had an open-label design, six were double-blind and placebo-controlled. Of the 41 study results contributed by included studies, about one third were at overall high risk of bias. Ivermectin doses and treatment duration varied among included studies. We identified 31 ongoing and 18 studies awaiting classification until publication of results or clarification of inconsistencies. Ivermectin compared to placebo or standard of care for inpatient COVID-19 treatment We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.14 to 2.51; 2 studies, 185 participants; very low-certainty evidence) and clinical worsening up to day 28 assessed as need for invasive mechanical ventilation (IMV) (RR 0.55, 95% CI 0.11 to 2.59; 2 studies, 185 participants; very low-certainty evidence) or need for supplemental oxygen (0 participants required supplemental oxygen; 1 study, 45 participants; very low-certainty evidence), adverse events within 28 days (RR 1.21, 95% CI 0.50 to 2.97; 1 study, 152 participants; very low-certainty evidence), and viral clearance at day seven (RR 1.82, 95% CI 0.51 to 6.48; 2 studies, 159 participants; very low-certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on clinical improvement up to 28 days (RR 1.03, 95% CI 0.78 to 1.35; 1 study; 73 participants; low-certainty evidence) and duration of hospitalization (mean difference (MD) -0.10 days, 95% CI -2.43 to 2.23; 1 study; 45 participants; low-certainty evidence). No study reported quality of life up to 28 days. Ivermectin compared to placebo or standard of care for outpatient COVID-19 treatment We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality up to 28 days (RR 0.33, 95% CI 0.01 to 8.05; 2 studies, 422 participants; very low-certainty evidence) and clinical worsening up to 14 days assessed as need for IMV (RR 2.97, 95% CI 0.12 to 72.47; 1 study, 398 participants; very low-certainty evidence) or non-IMV or high flow oxygen requirement (0 participants required non-IMV or high flow; 1 study, 398 participants; very low-certainty evidence). We are uncertain whether ivermectin compared to placebo reduces or increases viral clearance at seven days (RR 3.00, 95% CI 0.13 to 67.06; 1 study, 24 participants; low-certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on the number of participants with symptoms resolved up to 14 days (RR 1.04, 95% CI 0.89 to 1.21; 1 study, 398 participants; low-certainty evidence) and adverse events within 28 days (RR 0.95, 95% CI 0.86 to 1.05; 2 studies, 422 participants; low-certainty evidence). None of the studies reporting duration of symptoms were eligible for primary analysis. No study reported hospital admission or quality of life up to 14 days. Ivermectin compared to no treatment for prevention of SARS-CoV-2 infection We found one study. Mortality up to 28 days was the only outcome eligible for primary analysis. We are uncertain whether ivermectin reduces or increases mortality compared to no treatment (0 participants died; 1 study, 304 participants; very low-certainty evidence). The study reported results for development of COVID-19 symptoms and adverse events up to 14 days that were included in a secondary analysis due to high risk of bias. No study reported SARS-CoV-2 infection, hospital admission, and quality of life up to 14 days. Authors' conclusions: Based on the current very low- to low-certainty evidence, we are uncertain about the efficacy and safety of ivermectin used to treat or prevent COVID-19. The completed studies are small and few are considered high quality. Several studies are underway that may produce clearer answers in review updates. Overall, the reliable evidence available does not support the use ivermectin for treatment or prevention of COVID-19 outside of well-designed randomized trials.
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Ivermectin is an antiparasitic drug being investigated for repurposing against SARS-CoV-2. Ivermectin showed in-vitro activity against SARS-COV-2 at high concentrations. This meta-analysis investigated ivermectin in 24 randomized clinical trials (3328 patients) identified through systematic searches of PUBMED, EMBASE, MedRxiv and trial registries. Ivermectin was associated with reduced inflammatory markers (C-Reactive Protein, d-dimer and ferritin) and faster viral clearance by PCR. Viral clearance was treatment dose- and duration-dependent. In 11 randomized trials of moderate/severe infection, there was a 56% reduction in mortality (Relative Risk 0.44 [95%CI 0.25-0.77]; p=0.004; 35/1064 (3%) deaths on ivermectin; 93/1063 (9%) deaths in controls) with favorable clinical recovery and reduced hospitalization. Many studies included were not peer reviewed and a wide range of doses were evaluated. Currently, WHO recommends the use of ivermectin only inside clinical trials. A network of large clinical trials is in progress to validate the results seen to date.
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Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has changed our lives. The scientific community has been investigating re-purposed treatments to prevent disease progression in coronavirus disease (COVID-19) patients. Objective To determine whether ivermectin treatment can prevent hospitalization in individuals with early COVID-19. Design, setting and participants: A randomized, double-blind, placebo-controlled study was conducted in non-hospitalized individuals with COVID-19 in Corrientes, Argentina. Patients with SARS-CoV-2 positive nasal swabs were contacted within 48 h by telephone to invite them to participate. The trial randomized 501 patients between August 19th 2020 and February 22nd 2021. Intervention Patients were randomized to ivermectin (N = 250) or placebo (N = 251) arms in a staggered dose, according to the patient’s weight, for 2 days. Main outcomes and measures The efficacy of ivermectin to prevent hospitalizations was evaluated as primary outcome. We evaluated secondary outcomes in relationship to safety and other efficacy end points. Results The mean age was 42 years (SD ± 15.5) and the median time since symptom onset to the inclusion was 4 days [interquartile range 3–6]. The primary outcome of hospitalization was met in 14/250 (5.6%) individuals in ivermectin group and 21/251 (8.4%) in placebo group (odds ratio 0.65; 95% confidence interval, 0.32–1.31; p = 0.227). Time to hospitalization was not statistically different between groups. The mean time from study enrollment to invasive mechanical ventilatory support (MVS) was 5.25 days (SD ± 1.71) in ivermectin group and 10 days (SD ± 2) in placebo group, (p = 0.019). There were no statistically significant differences in the other secondary outcomes including polymerase chain reaction test negativity and safety outcomes. Limitations Low percentage of hospitalization events, dose of ivermectin and not including only high-risk population. Conclusion Ivermectin had no significant effect on preventing hospitalization of patients with COVID-19. Patients who received ivermectin required invasive MVS earlier in their treatment. No significant differences were observed in any of the other secondary outcomes. Trial registration ClinicalTrials.gov NCT04529525.
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Background: Repurposed medicines may have a role against the SARS-CoV-2 virus. The antiparasitic ivermectin, with antiviral and anti-inflammatory properties, has now been tested in numerous clinical trials. Areas of uncertainty: We assessed the efficacy of ivermectin treatment in reducing mortality, in secondary outcomes, and in chemoprophylaxis, among people with, or at high risk of, COVID-19 infection. Data sources: We searched bibliographic databases up to April 25, 2021. Two review authors sifted for studies, extracted data, and assessed risk of bias. Meta-analyses were conducted and certainty of the evidence was assessed using the GRADE approach and additionally in trial sequential analyses for mortality. Twenty-four randomized controlled trials involving 3406 participants met review inclusion. Therapeutic advances: Meta-analysis of 15 trials found that ivermectin reduced risk of death compared with no ivermectin (average risk ratio 0.38, 95% confidence interval 0.19-0.73; n = 2438; I2 = 49%; moderate-certainty evidence). This result was confirmed in a trial sequential analysis using the same DerSimonian-Laird method that underpinned the unadjusted analysis. This was also robust against a trial sequential analysis using the Biggerstaff-Tweedie method. Low-certainty evidence found that ivermectin prophylaxis reduced COVID-19 infection by an average 86% (95% confidence interval 79%-91%). Secondary outcomes provided less certain evidence. Low-certainty evidence suggested that there may be no benefit with ivermectin for "need for mechanical ventilation," whereas effect estimates for "improvement" and "deterioration" clearly favored ivermectin use. Severe adverse events were rare among treatment trials and evidence of no difference was assessed as low certainty. Evidence on other secondary outcomes was very low certainty. Conclusions: Moderate-certainty evidence finds that large reductions in COVID-19 deaths are possible using ivermectin. Using ivermectin early in the clinical course may reduce numbers progressing to severe disease. The apparent safety and low cost suggest that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic globally.
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Background Patients with underlying medical conditions are at increased risk for severe coronavirus disease 2019 (Covid-19). Whereas vaccine-derived immunity develops over time, neutralizing monoclonal-antibody treatment provides immediate, passive immunity and may limit disease progression and complications. Methods In this phase 3 trial, we randomly assigned, in a 1:1 ratio, a cohort of ambulatory patients with mild or moderate Covid-19 who were at high risk for progression to severe disease to receive a single intravenous infusion of either a neutralizing monoclonal-antibody combination agent (2800 mg of bamlanivimab and 2800 mg of etesevimab, administered together) or placebo within 3 days after a laboratory diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The primary outcome was the overall clinical status of the patients, defined as Covid-19–related hospitalization or death from any cause by day 29. Results A total of 1035 patients underwent randomization and received an infusion of bamlanivimab–etesevimab or placebo. The mean (±SD) age of the patients was 53.8±16.8 years, and 52.0% were adolescent girls or women. By day 29, a total of 11 of 518 patients (2.1%) in the bamlanivimab–etesevimab group had a Covid-19–related hospitalization or death from any cause, as compared with 36 of 517 patients (7.0%) in the placebo group (absolute risk difference, −4.8 percentage points; 95% confidence interval [CI], −7.4 to −2.3; relative risk difference, 70%; P<0.001). No deaths occurred in the bamlanivimab–etesevimab group; in the placebo group, 10 deaths occurred, 9 of which were designated by the trial investigators as Covid-19–related. At day 7, a greater reduction from baseline in the log viral load was observed among patients who received bamlanivimab plus etesevimab than among those who received placebo (difference from placebo in the change from baseline, −1.20; 95% CI, −1.46 to −0.94; P<0.001). Conclusions Among high-risk ambulatory patients, bamlanivimab plus etesevimab led to a lower incidence of Covid-19–related hospitalization and death than did placebo and accelerated the decline in the SARS-CoV-2 viral load. (Funded by Eli Lilly; BLAZE-1 ClinicalTrials.gov number, NCT04427501.)