Ivermectin Use for COVID-19 Evidence Review - COVID-19 Clinical Advisory Group Update Updated July 27, 2021 - Vitals by ...
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Ivermectin Use for COVID-19 Evidence Review - COVID-19 Clinical Advisory Group Update
Updated July 27, 2021
Ivermectin (IVM) is an antiparasitic drug that is approved by the Food and Drug Administration (FDA) for the treatment of onchocerciasis and
strongyloidiasis. Ivermectin is not FDA-approved for the treatment of any viral infection. In general, the drug is well tolerated. It is currently being
evaluated as a potential treatment for COVID-19.
Clinical Data
Updated: Two meta-analysis14,15 published in July 2021. See summary of analysis in the meta-analysis table below.
The results of several randomized trials and retrospective cohort studies of IVM use in patients with COVID-19 have been published in peer-
reviewed journals or made available as preliminary, non-peer-reviewed reports. There are no well-designed controlled trials that have been
published to date. However, pilot studies, or retrospective chart review of patients treated with IVM show a trend to benefit viral load reduction or
overall decrease in mortality. The evidence table summarizes studies that have reported shorter time to resolution of disease manifestations
attributed to COVID-19, greater reduction in inflammatory markers, shorter time to viral clearance, or lower mortality rates in patients who received
ivermectin than in patients who received usual care or placebo.
Ivermectin was widely distributed among 8 states in Peru. Peru has reported a dramatic decrease in case fatality rates, especially among patients
over 60 years old.6 These data, despite studied as part of controlled trial, resulted in the Peruvian government approving IVM use by decree on in
May 2020. As a result of this, in vitro data and small reports, IVM use has created much interest and controversy in the scientific community. See
evidence table for a data analysis (Ref 10) of all countries that deployed prophylactic chemotherapy with ivermectin compared to no ivermectin.
A long-awaited, placebo controlled trial (IVERCOR-COVID-19)16 conducted in Argentina was published in July 2021 that evaluated whether
ivermectin prevents hospitalization in patients who have been diagnosed with early COVID-19. Patients were randomized to treatment vs placebo
within 48 hours of a positive test result. A total of 501 participants were enrolled and randomized. Dosing will be either 12 mg, 18 mg or 24 mg
daily f or 2 days, based on patient’s weight (48-80kg; 81-110kg, or > 110 kg, respectively). Enrollment completion date was in February 2021.
Although the primary endpoint of hospitalization due to COVID was lower in the ivermectin treated group, this was not statistically significant.
Overall low hospitalization was a limitation to this study. There were also no statistically significant differences in secondary endpoints evaluated
(invasive mechanical ventilation, time to hospitalization, and PCR test negativity). The dose used in the study may have been too short duration
and it also did not select for high risk patients.
1
FMCP 07/27/2021; 03/08/2021.lhr
Key points:
• No individual trial published to date is large enough to draw conclusions to incorporate into standard practice.
• Combined data from the controlled trials shows consistent benefit, however possible study bias and variances in standard of care
therapies should be considered.
2
FMCP 07/27/2021; 03/08/2021.lhrNATIONAL GUIDANCE RECOMMENDATIONS SUMMARY:
GROUP (Last Updated) RECOMMENDATION RATIONALE/
KEY POINTS
FDA Statement to consumers • Issued statement against ivermectin use in • The FDA has received multiple reports of patients who
(3/5/2021) COVID-19. have required medical support and been hospitalized
FAQ af ter self-medicating with ivermectin intended for horses.
(4/26/2021) • The FDA has not reviewed clinical data regarding efficacy
and saf ety when ivermectin is taken for prophylaxis or
treatment of COVID-19.
IDSA • The panel suggests against ivermectin in both • The panel determined the certainty of evidence to be low
(2/5/2021) inpatients and outpatients, unless in the and a risk f or bias ad imprecision within published
context of enrollment in clinical trials. studies.
NIH • The COVID-19 Treatment Guidelines Panel • The sample size of most of the trials was small.
(1/14/2021 (the Panel) has determined that currently there • Various doses and schedules of ivermectin were used.
7/8/2021 evidence update) are insufficient data to recommend either for or • Some of the randomized controlled trials were open-label
against the use of ivermectin for the treatment studies in which neither the participants nor the
of COVID-19. Results from adequately investigators were blinded to the treatment arms.
powered, well-designed, and well-conducted • In addition to ivermectin or the comparator drug, in some
clinical trials are needed to provide more studies patients also received various concomitant
specific, evidence-based guidance on the role medications (e.g., doxycycline, hydroxychloroquine,
of ivermectin for the treatment of COVID-19. azithromycin, zinc, corticosteroids), confounding
• In some of the published studies, the authors assessment of the true efficacy or safety of ivermectin.
reported shorter time to resolution of disease • The severity of COVID-19 in the study participants was
manif estations, greater reduction in not always well described.
inf lammatory marker levels, shorter time to viral • The study outcome measures were not always clearly
clearance, or lower mortality rates in the IVM def ined.
group vs a comparator or placebo.
• Some studies have shown no benefit or
worsening of COVID.
• Note the limitations in many of the published
studies
It should be noted that Guidelines Groups of these expert bodies have found ivermectin (compare to placebo or control) to reduce mortality based
on > 15 clinical trials or reports. Since the quality of available evidence graded is low or very low and there are no large well designed, RCTs
published, IVM prescribing for COVID-19 is discouraged outside of a clinical trial.
3
FMCP 07/27/2021; 03/08/2021.lhrMETA-ANALYSIS
On July 20, 2021, the pre-print publisher of Research Square, retracted the largest, long-awaited Egyptian study enrolling because of data set
anomalies found and plagiarism. The study was one of the largest ivermectin trials (400-patients) in the world, and had been included in two
recent meta-analyses (Bryant et al. and Hill et al.) that received much attention for their positive results. The authors of the meta-analysis plan to
re-evaluate their analysis, withdrawing the retracted study from the studies included.
AUTHORS/Country DATA REVIEW AND METHODS RESULTS CONCLUSION/ COMMENT
Bryant A, et al14 24 RCT met inclusion involving 3,406 participants Mortality was decreased with IVM with a RR of 62% vs no IVM NOTE: Differing doses used in studies
2021 Avg risk ration 0.38, 95% CI 0.19-0.73). was not evaluated or concluded.
ITT data was used for all analysis These results were consistent among mild, moderate, and severe
disease. Authors found that most of the studies
Authors of individual trials were contacted for Total of 15 trials included to assess mortality risk were self- funded by clinicians in the
clarity Moderate certainty field. No obvious biases except
potential bias in 2 trials total.
Mortality Evaluation: 15 Trials were included in Prophylaxis with IVM reduced COVID infection by an average of 86%
the meta-analysis (95% CI 79%-91%) – Low certainty Overall, evidence suggests that early
Grade approach; Only 3trials IVM use may reduce morbidity and
Results confirmed by trial sequential analysis mortality from COVID-19 based on 1)
Improvement/Deterioration – very low certainty reduction in infections when IVM is
Cochrane effective practice and organization of Lack of benefit with IVM for need of mech ventilation used for prophylaxis, 2) more favorable
care guidance to interpret the evidence. Overall improvement favored IVM when IVM used for mild to moderate
disease for any cause of death, 3) less
A total of 10 trials were felt to have adequate ADRS/Safety – rare among participants deterioration.
blinding
16 trials included for mild to moderate disease Controlled observational studies (mostly HCW, n=738) in Bangledash,
6 trials included for severe disease Argentina, India – Control groups had an infection rate of approx. 50%
while the transmission in the treated group was low to 0%
Most of the trials reviewed compared IVM
treatment to placebo
Hill, et al15 , 2021 PRISMA Guidelines for literature review Individual report on inflammatory markers (5 trials)
4/5 trials – sig reduction in CRP vs control
Primary: all-cause mortality (ITT- follow-up) 1 trial reported sig reduced ferritin levels in the severe pt population/ no
Secondary: time to viral clearance, PCR negative difference in mild to moderate disease. Another trial showed decreased
at day 7; time to clinical recovery, mech vent; ferritin on day 10. Two trials did not show a significant reduction in ferritin
progress to hospitalization; days hospitalized. D-dimer2 studies showed significant decrease in d-dimer; one study did
not (smaller sample size).
Included 24 RCTs. Total participants 3328.
Viral clearance:
Dosing variations: Appears to be a dose-dependent relationship with viral clearance.
Single dose: 9 trials Studies that gave only on dose/day IVM had lower viral clearances.
4
FMCP 07/27/2021; 03/08/2021.lhrMulti day dosing up to 7 days: 15 trials Most pronounced when IVM is given for 5 days or more and a dose of 0.4
mg/kg.
Mild to moderate disease: 15 trials Mortality:
70% increased survival in the mild-moderate disease
Blinded (single or double sided) – 18 trials No difference in mortality in participants with severe disease. It was noted
Open – 6 trials that the number of deaths were small.
There were only 128 deaths reported in 11 clinical trials.
EVIDENCE
There are additional studies that have been conducted that are not included below – either because of design, or not published in full. The following studies are either most recent,
most quoted or designed well enough to include.
AUTHORS/Country STUDY DESIGN AND REGIMEN RESULTS CONCLUSION/ COMMENT
Lopez-Medina 13 RCT, DB single site in Cali, Columbia. Median time to resolution: Authors conclude that a 5-day course of
Columbia IVM gp: 10 days (9-13) ivermectin compared with placebo, did
Participants identified by random sampling from Placebo gp: 12 days (9-13) not significantly improve time to
the state’s health dept electronic database of Hazard ratio 1.07 (95% CI 0.87-1.32) P=0.53 resolution of symptoms for the
laboratory confirmed, COVID-19 and symptoms. treatment of mild COVID-19.
Time period: July 15-Nov 30, 2020 Resolution of symptoms by day 21:
IVM gp: 82% Usual ivermectin dose is 150-200
Total of 476 adult patients identified who had Placebo 79% mcg/kg 1. Other studies vary
• Mild disease continuation for 2-5 days; or repeat x 1
• Symptoms ≤ 7 days Headache was the most common solicited adverse event reported in over at day 7.
• Inpatient or outpatient 50% of patients.
Patient self-administered treatment vs
Ivermectin dose 300 mcg/kg of body weight daily Serious adverse event was multiorgan failure – occurring in 4 patients placebo and contacted by telephone for
for 5 days total, 2 patients in each treatment group. assessment. Reliability questionable.
After enrollment by study nurse, patients were
contacted by telephone for assessment and Ivermectin effect on decreasing viral
given treatment or identical placebo at home load was not evaluated
Primary Endpoint: time to resolution of symptoms
within 21-day follow-up.
Solicited ADR and serious ADRS also collected.
Hellwig MD, Maia A. GOAL: Collect data from countries that routinely Countries with routine mass drug administration of prophylactic Ivermectin has the ability to inhibit
10 deploy prophylactic chemotherapy (PCT) and chemotherapy that included ivermectin have a significantly lower replication of SARS-CoV-2 but the
World Database determine if there is a correlation with SARS- incidence of COVID-19 (p< 0.05) concentrations needed in humans
Collection CoV-2 incidence and ivermectin PCT. doesn’t correlate with efficacy/safety.
The authors hypothesize that there is
Observational Study - Data retrieval from an unknown mechanism that is
efficacious at lower, safe dosages don’t
5
FMCP 07/27/2021; 03/08/2021.lhrAUTHORS/Country STUDY DESIGN AND REGIMEN RESULTS CONCLUSION/ COMMENT
• Prophylactic Chemotherapy (PCT) databank correlate with efficacy. Other
(WHO) mechanism(s) are probable.
• Worldometer (Johns Hopkins) – count of
COVID cases obtained Some countries used ivermectin prior to
this pandemic and still had low rates.
3 Groups – noted that the sizes of the three Might be indicative of a residual effect.
groups vary greatly
• PCT deployed in countries, ivermectin The hypothesis of ivermectin
included prophylaxis is a correlation however
• PCT deployed in countries, ivermectin NOT becoming increasingly stronger.
included
• PCT not deployed in country
Time Prophylactic use of ivermectin against parasitic infections is most
April 2020; Because SARS-CoV-2 was being common in Africa and these data show that the reported correlation is
detected in new countries almost daily, highly significant both when compared among African nations as well as
calculations were updated and new countries in a worldwide context (p=0.017).
affected were added several times throughout
May 2021.
Individual dosages generally varied between 150 μg and 200 μg per
kilogram of body weight, there seemed to be no notable difference in
COVID-19 incidence among recipients of different dosages.
Ahmed S, et al. 1 RCT, DB, Virological clearance occurred earliest in the ivermectin x 5 days group The results provide potential benefit of
2020 in Dhaka, (9.7 days) compared to early intervention with ivermectin in
Bangladesh Goal: to evaluate the rapidity of viral clearance Placebo (12.7 days) p=0.02. adult patients with early COVID-19.
and safety of a 5-day course of The ivermectin + doxy arm virological clearance was not statistically
• ivermectin 12 mg PO daily x 5 days (n=24), vs improved over placebo group p=0.27. Presumably, the faster viral clearance
at disease onset may prevent
significant immune system involvement
6
FMCP 07/27/2021; 03/08/2021.lhrAUTHORS/Country STUDY DESIGN AND REGIMEN RESULTS CONCLUSION/ COMMENT
• A single dose of ivermectin 12 mg + 5-day In all 3 groups Blood biomarkers dropped by day 7, but was statistically and hasten recovery. Additionally,
course of doxycycline 200mg day 1, 100 mg significant in the 5-day ivermectin group for CRP and LDH: clearance of viral load may block further
days 2-5. (n=24). CRP (p=0.02) transmission.
• Placebo (n=24) LDH (p = 0.01)
72 hospitalized patients were evaluated. Procalcitonin One single dose of ivermectin (plus
ferritin doxycycline) did not have a statistically
significant benefit over the placebo
Inclusion: treated group.
• Adult patients (18-65) with mild COVID-19 No severe adverse events noted
• Hospitalized Authors recommend larger randomized
Symptom onset ≤ 7 days trial.
Exclusion:
• Major risk factors for severe disease It should be noted that all patients
received 12 mg. Weight variability
Primary endpoint: time to virological clearance among the subjects was not provided.
(measured by a negative rRT-PCR nasal swab)
Remission of cough and fever by day 7
Secondary endpoints:
• Ability to maintain spO2 ≥ 93%
• Duration of hospitalization
• All-cause mortality
Kory P, et al. 2 2021 Protocol of individual drugs/dose criteria based Authors summarize their protocol of MATH+ and the evidence supporting MATH+ protocol not studied. So many
on severity of disease, O2 requirements, ICU, the efficacy of ivermectin in the prophylaxis and treatment. variables, it is unclear how ivermectin
etc. adds to the other unproven but
MATH: methylprednisolone + ascorbic acid + Most of data are from pilot or case series. Reports show patients who theoretical therapies.
thiamine + heparin+ received early (usually single doses) of 0.4 mg/kg
• Vit D3 5000 IU/day
• atorvastatin
• melatonin
• zinc
• famotidine
• therapeutic plasma exchange
GOAL: to study the efficacy of the MATH+
protocol with “supportive care only”, AND against
other novel proposed treatment approaches
Formation of patient registry
Chaccour C, et al3 RCT, DB, single center, parallel arm • Initially, there was no difference in proportion of PCR positives between A larger trial is warranted to evaluate
2021 the groups for genes E and N in the same order of magnitude. the positive trend in symptom
7
FMCP 07/27/2021; 03/08/2021.lhrAUTHORS/Country STUDY DESIGN AND REGIMEN RESULTS CONCLUSION/ COMMENT
Spain Goal: to evaluate the efficacy of a single • The median viral load for both genes was lower at days 4 and 7 post in improvement in the treatment group
ivermectin dose in reducing transmission of the ivermectin group 3-fold lower at day 4 to around 18-fold lower at compared to placebo.
SARS-CoV-2 when administered early. A day 7,
reduction of at least 50% in proportion of p > 0.05. There is a need to evaluation
positives desired. ivermectin treatment with disease
• There was a marked reduction in anosmia/ hyposmia, reduction in severity, inflammation and antibody
Inclusion: cough titers.
• Patients were not high risk • A trend to lower viral loads, lower IgG
• Non-severe COVID The results raise questions about the
• Onset of symptoms ≤ 72 hours possible mechanism of ivermectin in
COVID-19. Ivermectin may
Exclusion: downregulate the expression of pro-
• High risk co-morbidities inflammatory genes; it may have an
• COVID pneumonia effect on the nicotinic receptor; the
• Antibody positive mechanism may be
immunomodulatory.
1:1 randomization:
• Ivermectin 400 mcg/kg x1 (n=12) Dose given was 2x general
recommended dose but only
• Placebo (n=12)
administered as one-time single dose.
Pt Characteristics:
All had symptoms at enrollment (one or more of
the following: H/A, fever, general malaise, cough)
Symptoms were self-reported for 28 days.
Rajter J C., et al. Retrospective chart review of consecutive Mortality rates : Ivermectin was associated with lower
2021 patients hospitalized at 4 health system Overall the ivermectin gp had significantly lower mortality the usual care mortality as part of treatment of COVID-
FL, USA hospitals. gp (15% vs 25.2%, p=0.03). 19 patients, especially in patients who
required higher inspired O2 or ventilator
Hospital treatment guidelines were available but Ivermectin-tx’d with severe pulmonary involvement Mortality 38.8% vs support.
prescribing was at the discretion of the 80.7%, respectively. P = 0.001).
prescribing physician. Study not powered to detect difference
In a matched cohort, the absolute risk reduction from ivermectin was in mortality from hydroxychloroquine
Total charts = 280 11.2% (95% CI, 0.38%-22.1%). The number need to treat was 8.9 to treatment.
173 tx’d ivermectin prevent one death.
Received at least one dose of 200 mcg/kg, Authors note that there may have been
orally. No difference found in extubation rates. preferential treatment of more severe
A second dose could be prescribed at day 7, patients with ivermectin There may
at the physician’s discretion. have been a treatment timing bias.
107 did not receive ivermectin (usual care)
Appropriate dosing of ivermectin for this
Primary Endpoint indication is not known
All cause in-hospital mortality
8
FMCP 07/27/2021; 03/08/2021.lhrAUTHORS/Country STUDY DESIGN AND REGIMEN RESULTS CONCLUSION/ COMMENT
Secondary Endpoints
• Mortality with pulmonary involvement
• Extubation rates
• LOS
Inclusion
Laboratory confirmed SARS-CoV-2
Enrollment March 15-May 11, 2020
Adult patients only
Usual treatment care may have included:
hydroxychloroquine treatment
Corticosteroids
Azithromycin
Severity of pulmonary involvement assessed
(severe vs non-severe). Severe pulmonary
involvement defined as = FiO2 ≥ 50%, high flow
nasal O2 , noninvasive ventilation , or mechanical
ventilation.
Hashim et al. 2020 RCT Progression: Ivermectin with doxycycline significantly
Iraq COVID-19 pts (n=70) 4.28% of all and 9% (severe) progressed to more severe disease in the reduced the time to recovery. The
ivermectin group vs 10% (all) and 31.8% (severe) in the control group (p> combination also decreased
ARM 1 0.05). In subanalysis, progression was lowered if ivermectin given within progression to more severe disease.
Ivermectin 200 mcg/kg/d x 2-3 days plus the first two days of severe stage. Mortality was also reduced but
doxycycline 100 mg BID x 5-10 days bordering significance.
Mild/moderate (n=48) Mortality: Was 0% in mild-moderate and 18% in severe Covid for the
Severe disease (n=11) ivermectin group vs 0% and 27.3%, respectively (p=0.052)
Critical patients (n=11)
Mean time to recovery:
ARM 2: Usual Care (MATH + regimen above) For the ivermectin group it was 6.34, 20.27 and 24.13 for the mild-
Mild/moderate (n=48) moderate, severe, and critical patients respectively versus 13.7 and 24.25
Severe disease (n=22) in the mild-moderate and severe patients treated with stand care,
Critical patients (n=0) respectively (p < 0.01).
Endpoints:
• Time to recover
• Progression of disease
• Mortality
Abbreviations: DB=double blind; H/A=headache; LOS= length of stay; RCT=randomized controlled trial;tx’d=treated;
9
FMCP 07/27/2021; 03/08/2021.lhrADDITIONAL KEY POINTS TO CONSIDER
Ivermectin (Stromectol®)
• Available as a 3-mg oral tablet.
• Tablets should be taken on an empty stomach with water.
PARISITIC INFECTIONS COVID-19
USUAL A DULT DOSE 150-200 mcg/kg • Ref 1: 12 mg x 1 (with doxycycline);
or 12 mg x 5 days. -
• Ref 3: 400 mcg/kg single dose; may
repeat at day 7
• 200 mcg/kg 2-3 days with doxy 5
days
COMMON A DVERSE EVENTS Varies depending on parasite treated:
From Package Insert of listed side • Skin rash or itching
effects occurring ≥ 3% • Lymph node enlargement /tenderness
• Dizziness
• Diarrhea
• Joint or muscle pain
• Lightheadedness
• Peripheral edema
• tachycardia
PRECAUTION • May make bronchial asthma worse
• Elevation of liver enzymes and
bilirubin
COST • 12 mg x 1 = $13.40 (GPO) 12 mg x 1 dose = $13.40 (GPO);
Repeat in 7 days = $ 27
OR
12 mg x 5 days = $66.65 (GPO)
EFFICACY • Intestinal strongyloidiasis Pilot study in mild Covid-19 may
• Onchocerciasis decrease viral load; may hasten
improvement of anosmia/hyposmia and
cough
For more severe patients, may
decrease overall mortality
10
FMCP 07/27/2021; 03/08/2021.lhrSelect References:
1. Ahmed S, Kharim MM, Rose AG, et al. A five-day course of ivermectin for the treatment of COVID-19 may
reduce the duration of illness. Int J Infect Dis 2020 Dec 2:s doi: 10.1016/j.ijid.2020.11.191.
2. Kory P, Meduri GU, Iglesias J, Varon J, and Marik PE. Clinical and scientific rationale for the MATH+ hospital
treatment protocol for COVID. JInt Care Med 2021. 34(2):135-56. Doi: 10.1177/0885066620973585.
3. Chaccour C, Casellas A, Blanco-Di Matteo A, et al. The effect pf early treatment with ivermectin on viral load,
symptoms and humoral response in patients with non-severe COVID-19: A pilot, double-blind, placebo-
controlled, randomized clinical trial. EClinicalMedicine (2021), https://doi.org/10.1016/j.eclinm.2020.100720.
4. Rajter JCl, Sherman MS, Fatteh N, et al. use of ivermectin is associated with lower mortality in hospitalized
patients with coronavirus disease 2019: the ICO study. Chest 2020;S0012-3692(2034898-4. PMID: 33065103
DOI: 10.1016/j.chest.2020.10.009.
5. Kaur H, Shekhar N, Sharma S, et al. Ivermectin as a potential drug for the treatment of COVID-19: an in-sync
review with clinical and computational attributes. Pharmacol Reports 2021. DOI 10.1007/s43440-020-00195-y.
6. Chamie. Real-world evidence: the case of Peru. Causality between ivermectin and Covid-19 infection fatality
rate. Trial Site News. October 5, 2020.
7. Hashim A, Maulood MF, Rasheed AM, et al. Controlled randomized clinical trial on using ivermectin with
doxycycline for treating COVID-19 patients in Baghdad, IRAQ. MedRXiv preprint
https://doi:0.1101/2020.10.26.20219345.
8. Schmith VD, Zhou JJ, and Lohmer LR. The approved dose of ivermectin alone is not the ideal dose for the
treatment of COVID-19. Clin Pharmacol Ther. 2020; 108(4):762-765. Doi: 10.1002/cpt.1889. Epub 2020 Jun 7.
9. Caly L, Druce JD, Catton MG, et al. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in
vitro. Antiviral Res 2020. PMID 104787.
10. US Food and Drug Administration. Why you should not use ivermectin to treat or prevent COVID-19.
https://www.fda.gov/consumers/consumer-updates/why-you-should-not-use-ivermectin-treat-or-prevent-
covid-19. Current as of 3/5/2021.
11. Hellwig MD, Maia A. A COVID-19 prophylaxis? Lower incidence associated with prophylactic administration of
ivermectin. Int J Antimicrob Ag. Available online at https://doi.org/10.1016/j.ijantimicag.2020.106248
12. Vallejos J, Zoni R, Bangher M, et al. Ivermectin to prevent hospitalizations in patients with COVID-19
(IVERCOR-COVID19): a structured summary of a study protocol for a randomized controlled trial. Trials Open
access. https://doi.org/10.1186/s13063-020-04813-1.
13. Lopez-Medina E, Lopez P, Hurtado IC, et al. Effect of ivermectin on time to resolution of symptoms among
adults with mild COVID-19. A randomized clinical trial. JAMA. Published online March 4, 2021.
https://doi:10.1001/jama.2021.3071.
14. Bryant A, Laurie TA, Dowswell T, et al. Ivermectin for the prevention and treatment of COVID-19 infection: A
systematic review, meta-analysis, and trial sequential analysis to inform clinical guidelines. Am J of
Therapeutics 2021; 28: e434-e460.
15. Hill A, Garratt A, Levi J, et al. Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection.
Open forum Infectious Diseases. Doi/10.1093/ofid/ofab358/6316214.
16. Vallejos, J., Zoni, R., Bangher, M. et al. Ivermectin to prevent hospitalizations in patients with COVID-19
(IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial. BMC Infect Dis 21, 635 (2021).
https://doi.org/10.1186/s12879-021-06348-5
11
FMCP 07/27/2021; 03/08/2021.lhrYou can also read
