Ivermectin Use for COVID-19 Literature Review - COVID-19 Clinical Advisory Group Update February 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 Literature Review - COVID-19 Clinical Advisory Group Update
February 2021
Ivermectin 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
The results of several randomized trials and retrospective cohort studies of ivermectin 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 ivermectin 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. These data, despite studied as part of controlled trial, resulted in the Peruvian government approving ivermectin use by decree
on in May 2020. As a result of this, in vitro data and small reports, ivermectin use has created much interest and controversy in the scientific
community.
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.
1
FMCP 02/08/2021NATIONAL GUIDANCE RECOMMENDATIONS SUMMARY:
GROUP (Last Updated) RECOMMENDATION RATIONALE/
KEY POINTS
ASHP If ivermectin therapy is considered, the No published data to date from randomized, controlled
(12/17/2020) patient/prescriber are encouraged to seek one trials support the use in the treatment or prevention of
of various clinical trials evaluating ivermectin COVID-19.
for the treatment or prevention of COVID-19
are registered at clinicaltrials.gov
IDSA The panel suggests against ivermectin in both The panel determined the certainty of evidence to be low
(4/5/2021) inpatients and outpatients, unless in the and a risk for 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.
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, patients
clinical trials are needed to provide more also received various concomitant medications (e.g.,
specific, evidence-based guidance on the role doxycycline, hydroxychloroquine, azithromycin, zinc,
of ivermectin for the treatment of COVID-19. corticosteroids), confounding assessment of the true
efficacy or safety of ivermectin.
The severity of COVID-19 in the study participants was
not always well described.
The study outcome measures were not always clearly
defined.
2
FMCP 02/08/2021EVIDENCE
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
Ahmed S, et al. 1 2020 RCT, DB, Virological clearance occurred earliest in the The results provide potential benefit of
in Dhaka, Bangladesh ivermectin x 5 days group (9.7 days) compared to early intervention with ivermectin in adult
Goal: to evaluate the rapidity of viral clearance Placebo (12.7 days) p=0.02. patients with early COVID-19.
and safety of a 5-day course of The ivermectin + doxy arm virological clearance was
ivermectin 12 mg PO daily x 5 days (n=24), not statistically improved over placebo group p=0.27. Presumably, the faster viral clearance at
vs disease onset may prevent significant
single dose of ivermectin 12 mg + 5-day In all 3 groups Blood biomarkers dropped by day 7, immune system involvement and hasten
course of doxycycline 200mg day 1, 100 mg but was statistically significant in the 5-day ivermectin recovery. Additionally, clearance of viral
days 2-5. (n=24). group for CRP and LDH: load may block further transmission.
Placebo (n=24) CRP (p=0.02)
72 hospitalized patients were evaluated. LDH (p = 0.01) One single dose of ivermectin (plus
Procalcitonin doxycycline) did not have a statistically
ferritin significant benefit over the placebo
Inclusion: treated group.
Adult patients (18-65) with mild COVID-19
Hospitalized No severe adverse events noted 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 among
Primary endpoint: time to virological the subjects was not provided.
clearance (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
3
FMCP 02/08/2021AUTHORS/Country STUDY DESIGN AND REGIMEN RESULTS CONCLUSION/ COMMENT
Kory P, et al. 2 2021 Protocol of individual drugs/dose criteria Authors summarize their protocol of MATH+ and the MATH+ protocol not studied. So many
based on severity of disease, O2 evidence supporting the efficacy of ivermectin in the variables, it is unclear how ivermectin
requirements, ICU, etc. prophylaxis and treatment. adds to the other unproven but
MATH: methylprednisolone + ascorbic acid + theoretical therapies.
thiamine + heparin+ Most of data are from pilot or case series. Reports
vit D3 5000 IU/day show patients who received early (usually single
atorvastatin doses) of 0.4 mg/kg
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 2021 RCT, DB, single center, parallel arm Initially, there was no difference in proportion of A larger trial is warranted to evaluate the
Spain PCR positives between the groups for genes E and positive trend in symptom improvement
Goal: to evaluate the efficacy of a single N in the same order of magnitude. in the treatment group compared to
ivermectin dose in reducing transmission of The median viral load for both genes was lower at placebo.
SARS-CoV-2 when administered early. A days 4 and 7 post in the ivermectin group 3-fold
reduction of at least 50% in proportion of lower at day 4 to around 18-fold lower at day 7, There is a need to evaluation ivermectin
positives desired. p > 0.05. treatment with disease severity,
inflammation and antibody titers.
Inclusion: There was a marked reduction in anosmia/
Patients were not high risk hyposmia, reduction in cough The results raise questions about the
Non-severe COVID A trend to lower viral loads, lower IgG possible mechanism of ivermectin in
Onset of symptoms ≤ 72 hours COVID-19. Ivermectin may downregulate
the expression of pro-inflammatory
Exclusion: genes; it may have an effect on the
High risk co-morbidities nicotinic receptor; the mechanism may
COVID pneumonia be immunomodulatory.
Antibody positive
Dose given was 2x general
1:1 randomization: recommended dose but only
Ivermectin 400 mcg/kg x1 (n=12) administered as one-time single dose.
4
FMCP 02/08/2021AUTHORS/Country STUDY DESIGN AND REGIMEN RESULTS CONCLUSION/ COMMENT
Placebo (n=12)
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. 2021 Retrospective chart review of consecutive Mortality rates : Ivermectin was associated with lower
FL, USA patients hospitalized at 4 health system Overall the ivermectin gp had significantly lower mortality as part of treatment of COVID-
hospitals. mortality the usual care 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 Ivermectin-tx’d with severe pulmonary involvement support.
but prescribing was at the discretion of the Mortality 38.8% vs 80.7%, respectively. P = 0.001).
prescribing physician. Study not powered to detect difference in
In a matched cohort, the absolute risk reduction from mortality from hydroxychloroquine
Total charts = 280 ivermectin was 11.2% (95% CI, 0.38%-22.1%). The treatment.
173 tx’d ivermectin number need to treat was 8.9 to 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 patients with ivermectin There may have
7, at the physician’s discretion. 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
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
5
FMCP 02/08/2021AUTHORS/Country STUDY DESIGN AND REGIMEN RESULTS CONCLUSION/ COMMENT
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 reduced the time to recovery. The
severe disease in the ivermectin group vs 10% (all) combination also decreased progression
ARM 1 and 31.8% (severe) in the control group (p> 0.05). In to more severe disease. Mortality was
Ivermectin 200 mcg/kg/d x 2-3 days plus subanalysis, progression was lowered if ivermectin also reduced but bordering significance.
doxycycline 100 mg BID x 5-10 days given within the first two days of severe stage.
Mild/moderate (n=48)
Severe disease (n=11) Mortality: Was 0% in mild-moderate and 18% in
Critical patients (n=11) severe Covid for the ivermectin group vs 0% and
27.3%, respectively (p=0.052)
ARM 2: Usual Care (MATH + regimen above)
Mild/moderate (n=48) Mean time to recovery:
Severe disease (n=22) For the ivermectin group it was 6.34, 20.27 and 24.13
Critical patients (n=0) for the mild-moderate, severe, and critical patients
respectively versus 13.7 and 24.25 in the mild-
Endpoints: moderate and severe patients treated with stand care,
Time to recover respectively (p < 0.01).
Progression of disease
Mortality
Abbreviations: DB=double blind; H/A=headache; LOS= length of stay; RCT=randomized controlled trial;tx’d=treated;
6
FMCP 02/08/2021KEY 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 ADULT 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 ADVERSE 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
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
7
FMCP 02/08/2021Select 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.
8
FMCP 02/08/2021You can also read
