Table 2c. Ivermectin: Selected Clinical Data

Last Updated: July 19, 2021

The Panel has reviewed other clinical studies of IVM for the treatment of COVID-19.1-16 However, those studies have limitations that make them less definitive and informative than the studies discussed here. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations.

Table 2c. Ivermectin: Selected Clinical Data
Study Design Methods Results Limitations and Interpretation
Ivermectin Versus Placebo for Treatment of Mild COVID-1917
Randomized, double-blind, placebo-controlled trial in Cali, Colombia (n = 476) Key Inclusion Criteria:
  • Positive SARS-CoV-2 PCR result or positive antigen test result
  • Symptoms began ≤7 days prior to randomization
  • Mild disease (defined as receiving outpatient or inpatient care, but not receiving HFNC oxygen or mechanical ventilation)

Key Exclusion Criteria:

  • Asymptomatic disease
  • Severe pneumonia
  • Receipt of IVM within previous 5 days
  • Hepatic dysfunction/abnormal liver function tests

Interventions:

  • Oral IVM 300 μg/kg per day in solution for 5 days, taken primarily on an empty stomach
  • Placebo

Primary Endpoints:

  • Time from randomization to resolution of symptoms within the 21-day follow-up period. Resolution of symptoms was defined as the first day a patient reported a score of 0 (no clinical evidence of infection) on an 8-point ordinal scale.
Number of Participants:
  • IVM (n = 200) and placebo (n = 198) in primary analysis

Participant Characteristics:

  • Median age was 37 years; 4% of patients in IVM arm and 8% in placebo arm were aged ≥65 years.
  • 39% of patients in IVM arm and 45% in placebo arm were male.
  • 79% of patients had no known comorbidities; median BMI in both arms was 26.
  • Median time from symptom onset to randomization was 5 days (IQR 4–6 days).
  • 62% of patients in IVM arm and 55% in placebo arm were not hospitalized and had no limitations of activities at baseline (ordinal scale 1); 38% and 44% were not hospitalized but had some limitations on activities, or they were receiving oxygen at home, or both (ordinal scale 2).
  • 1% of patients in both arms were hospitalized at baseline.

Primary Outcomes:

  • No difference in time to resolution of symptoms (median 10 days in IVM arm vs. 12 days in placebo arm; HR 1.07; 95% CI, 0.87–1.32; P = 0.53)
  • Symptoms resolved in 82% of patients in IVM arm and 79% in placebo arm by Day 21.

Other Outcomes:

  • No significant difference between arms in proportion of patients who showed clinical deterioration of ≥2 points on the ordinal scale (3.5% in IVM arm vs. 2.0% in placebo arm; absolute difference -1.5%; 95% CI, -4.8% to 1.7%)
  • No significant difference between arms in the odds of improvement in ordinal scale score and the proportion of patients who sought medical care or required escalation in care.
  • 8% of patients in IVM arm and 3% in placebo arm discontinued treatment due to an AE. None of the reported SAEs were considered to be related to study interventions.
Key Limitations:
  • Relatively small sample size
  • Primary endpoint was modified during the trial due to lower than expected event rates.
  • The first 65 patients received a placebo that smelled and tasted different from IVM.
  • The study enrolled a younger, healthier demographic than those who typically experience more serious cases of COVID-19.
  • Study included 4 hospitalized patients (out of 398).
  • The IVM dose used in this study was higher than the dose that is usually administered (IVM 200 μg/kg per day).

Interpretation:

  • A 5-day course of IVM did not improve time to resolution of symptoms in patients with mild COVID-19.
Ivermectin Versus Ivermectin Plus Doxycycline Versus Placebo for Treatment of COVID-1918
Randomized, double-blind, placebo-controlled trial of hospitalized adults in Dhaka, Bangladesh (n = 72) Key Inclusion Criteria:
  • Aged 18–65 years
  • Laboratory-confirmed SARS-CoV-2 infection with fever, cough, or sore throat
  • Admitted to hospital within previous 7 days

Key Exclusion Criteria:

  • Chronic cardiac, renal, or liver disease

Interventions:

  • IVM 12 mg PO once daily for 5 days
  • Single dose of IVM 12 mg PO plus DOX 200 mg PO on Day 1, then DOX 100 mg every 12 hours for 4 days
  • Placebo

Primary Endpoints:

  • Time to virologic clearance, measured by obtaining an NP swab for SARS-CoV-2 PCR on Days 3, 7, and 14, then weekly until PCR result was negative
  • Resolution of fever and cough within 7 days
Number of Participants:
  • IVM (n = 24; 2 withdrew), IVM plus DOX (n = 24; 1 withdrew), and placebo (n = 24; 1 withdrew)

Participant Characteristics:

  • Mean age was 42 years.
  • 54% of patients were female.
  • Mean time from symptom onset to assessment was 3.83 days.
  • No patients required supplemental oxygen.

Primary Outcomes:

  • Shorter mean time to virologic clearance with IVM than placebo (9.7 days vs. 12.7 days; P = 0.02), but not with IVM plus DOX (11.5 days; P = 0.27).
  • Rates of virologic clearance were greater in IVM arm at Day 7 (HR 4.1; 95% CI, 1.1–14.7; P = 0.03) and at Day 14 (HR 2.7; 95% CI, 1.2–6.0; P = 0.02) compared to placebo, but not in the IVM plus DOX arm (HR 2.3; 95% CI, 0.6–9.0; P = 0.22 and HR 1.7; 95% CI, 0.8–4.0; P = 0.19).
  • No statistically significant difference in time to resolution of fever, cough, or sore throat between IVM and placebo arms (P = 0.35, P = 0.18, and P = 0.35, respectively) or IVM plus DOX and placebo arms (P = 0.09, P = 0.23, and P = 0.09, respectively).

Other Outcomes:

  • Mean values of CRP, LDH, procalcitonin, and ferritin declined in all arms from baseline to Day 7, but there were no between-arm comparisons of the changes.
  • No between-arm differences in duration of hospitalization (P = 0.93).
  • No SAEs recorded.
Key Limitations:
  • Small sample size
  • Unclear whether both IVM and DOX placebos were used.
  • Excluded patients with chronic diseases.
  • Disease appears to have been mild in all patients; thus, the reason for hospitalization is unclear.
  • Absolute changes in inflammatory markers were not presented, but were reportedly significant.
  • PCR results are not a validated surrogate marker for clinical efficacy.

Interpretation:

  • A 5-day course of IVM resulted in faster virologic clearance than placebo, but not a faster time to resolution of symptoms (fever, cough, and sore throat). Because time to virologic clearance is not a validated surrogate marker for clinical efficacy, the clinical efficacy of IVM is unknown.
Effectiveness and Safety of Adding Ivermectin to Treatment in Patients With Severe COVID-1919
Randomized, single-blind trial of hospitalized adults in Turkey (n = 66) Key Inclusion Criteria:
  • Hospitalized with PCR-confirmed SARS-CoV-2 infection
  • ≥1 of the following severity criteria:
    • Tachypnea (≥30 breaths/min), SpO2 <90% on RA, or PaO2/FiO2 <300 mm Hg in patients who were receiving oxygen
    • Presence of “specific” radiologic findings
    • Mechanical ventilation
    • Acute organ dysfunction

Key Exclusion Criteria:

  • Aged <18 years
  • Pregnant or breast feeding
  • Autoimmune disease
  • Chronic liver or kidney disease
  • Immunosuppression
  • SNP mutation in MDR1/ABCB1 gene and/or haplotypes and mutations of the CYP3A4 gene (affects IVM metabolism and toxicity)

Interventions:

  • IVM 200 μg/kg per day for 5 days plus SOC (HCQ plus favipiravir plus AZM)
  • SOC alone

Primary Endpoint:

  • “Clinical response” at Day 5: extubation (in mechanically ventilated patients), respiratory rate <26 breaths/min, SpO2 >90% on RA, PaO2/FiO2 >300 mm Hg (if patient was receiving oxygen), presence of ≥2 of the 2-point reduction criteria in SOFA

Key Secondary Endpoints:

  • Clinical response at Day 10: respiratory rate 22 to 24 breaths/min, SpO2 >95% on RA, absence of oxygen requirement, and no need for intensive care
  • Changes in SpO2, PaO2/FiO2, and levels of CRP, ferritin, and D-dimer
  • Mortality
Number of Participants:
  • IVM (n = 36) and SOC (n = 30)
  • 6 participants in IVM arm were excluded after genotyping.

Participant Characteristics:

  • Mean age was 58 years in IVM arm and 66 years in SOC arm.
  • 70% of patients were male in IVM arm and 63% were male in SOC arm.
  • Comorbidities (IVM vs. SOC): DM (30% vs. 33%), HTN (50% vs. 40%), CAD (17% vs. 27%)

Primary Outcome:

  • Clinical improvement at Day 5: 14 of 30 patients (46.7%) in IVM arm, 11 of 30 (36.7%) in SOC arm (P = 0.43)

Secondary Outcomes:

Between-Arm Comparisons at Day 10:
  • Clinical improvement: 73.3% in IVM arm, 53.3% in SOC arm (P = 0.10)
  • IVM vs. SOC arm SOFA score at Day 10: P = 0.50
  • Mean SpO2: 95.4% in IVM arm, 93.0% in SOC arm (P = 0.032)
  • Mean PaO2/FiO2: 236.3 mm Hg in IVM arm, 220.8 mm Hg in SOC arm (P = 0.39)
  • Serum CRP, ferritin, and D-dimer levels were lower in IVM arm than in SOC arm (P = 0.02, P = 0.005, and P = 0.03, respectively).
Within-Group Changes from Baseline:
  • Change in SOFA score to Day 10: P = 0.009 in IVM arm, P = 0.88 in SOC arm
  • Mean changes in SpO2 to Day 5: 89.9% to 93.5% (P = 0.005) in IVM arm, 89.7% to 93.0% (P = 0.003) in SOC arm
Mortality During Follow-Up Period:
  • 6 patients (20%) in IVM arm and 9 (30%) in SOC arm (P = 0.37).
  • Average length of follow-up was 3 months.
Key Limitations:
  • Small sample size
  • Time from symptom onset to intervention was not reported.
  • Study used nonstandard severity classification for COVID-19.
  • Primary endpoint was difficult to characterize; it was presented in the Methods section as a composite endpoint, but each component was analyzed separately.
  • Power analysis performed for virologic endpoint, not primary endpoint.
  • Only 57% of patients in IVM arm and 27% in SOC arm were evaluated for VL changes.

Interpretation:

  • A 5-day course of IVM in hospitalized patients with severe COVID-19 did not result in clinical improvement at the end of treatment, and no reduction in mortality was observed.
  • Faster improvement of oxygenation and more pronounced reduction in inflammatory markers were observed in IVM arm.
Chloroquine, Hydroxychloroquine, or Ivermectin in Patients With Severe COVID-1920
Randomized, double-blind, Phase 2 trial of hospitalized adults in Brazil (n = 168) Key Inclusion Criteria:
  • Hospitalized with laboratory-confirmed SARS-CoV-2 infection (PCR or IgM positive)
  • ≥1 of the following severity criteria:
    • Dyspnea
    • Tachypnea (>30 breaths/min)
    • SpO2 <93%
    • PaO2/FiO2 <300 mm Hg
    • Involvement of >50% of lungs on CXR or CT

Key Exclusion Criteria:

  • Aged <18 years old
  • Cardiac arrhythmia, including prolonged QT interval
  • Previous use of CQ, HCQ, or IVM for >24 hours

Interventions:

  • CQ 450 mg twice daily on Day 0, then CQ 450 mg once daily for 4 days
  • HCQ 400 mg twice daily on Day 0, then HCQ 400 mg once daily for 4 days
  • IVM 14 mg once daily for 3 days followed by placebo for 2 days

Endpoints:

  • Need for supplemental oxygen, invasive mechanical ventilation, or ICU admission
  • Mortality
Number of Participants:
  • CQ (n = 61), HCQ (n = 54), and IVM (n = 53)

Participant Characteristics:

  • Mean age was 53.4±15.6 years.
  • 58.2% of patients were male.
  • 78.9% of patients were Hispanic.
  • 37.5% of patients had a BMI >30.
  • Most common comorbidities were HTN (43.4% of patients) and DM (28.1%).
  • On admission, 76.5% of patients had respiratory failure, and 42.5% had “pneumonic syndrome.”

Outcomes:

  • No differences between arms in proportion of patients who required supplemental oxygen (88.5% in CQ arm, 90.2% in HCQ arm, and 88.4% in IVM arm) or mean number of days of supplemental oxygenation (7.9 vs. 7.8 vs. 8.1 days)
  • No differences between arms in proportion of patients admitted to the ICU (22.4% in CQ arm, 21.1% in HCQ arm, and 28.0% in IVM arm) or proportion of patients who received invasive mechanical ventilation (20.6% vs. 21.1% vs. 23.5%)
  • No differences between arms in proportion of patients who were receiving concomitant medications, including steroids and anticoagulants
  • No differences between arms in death due to COVID-19 complications (21.3% in CQ arm, 22.2% in HCQ arm, and 23.0% in IVM arm)
  • Baseline characteristics that were associated with mortality included age >60 years (HR 2.44; 95% CI, 1.40–4.30), DM (HR 1.87; 95% CI, 1.02–2.59), BMI >33 (HR 1.95; 95% CI, 1.07–3.09), and SpO2 <90% (HR 5.79; 95% CI, 2.63–12.7).
  • No difference in rates of AEs between arms
Key Limitations:
  • Small sample size
  • No placebo control
  • No clear primary endpoint

Interpretation:

  • Use of IVM did not reduce risk of oxygen requirement, ICU admission, invasive mechanical ventilation, or death in hospitalized patients with severe COVID-19.
Ivermectin Versus Placebo for Outpatients With Mild COVID-1921
Open-label RCT of adult outpatients in Lahore, Pakistan (n = 50) Key Inclusion Criteria:
  • SARS-CoV-2 PCR positive
  • Mild disease

Key Exclusion Criteria:

  • Severe symptoms likely related to cytokine storm
  • Malignancy, chronic kidney disease, or cirrhosis
  • Pregnancy

Interventions:

  • IVM 12 mg PO immediately, followed by 12 mg doses at 12 and 24 hours, plus symptomatic treatment
  • Symptomatic treatment

Primary Endpoint:

  • Symptoms reported on Day 7. Patients were stratified as asymptomatic or symptomatic.
Number of Participants:
  • IVM (n = 25) and control (n = 25)

Participant Characteristics:

  • Mean age was 40.6 years.
  • 62% of patients were male.
  • 40% of patients had diabetes, 30% were smokers, 26% had hypertension, 8% had cardiovascular disease, and 12% had obesity.

Outcomes:

  • Proportion of asymptomatic patients at Day 7 was similar in IVM and control arms (64% vs. 60%; P = 0.500).
  • AEs were attributed to IVM in 8 patients (32%).
Key Limitations:
  • Small sample size
  • Open-label study
  • Authors reported the proportions of patients with certain symptoms and comorbidities but did not provide objective assessment of disease severity. This precludes the ability to compare outcomes between arms.
  • Study classified outcomes at Day 7 as “symptomatic” and “asymptomatic,” but did not account for symptom worsening or improvement.

Interpretation:

  • IVM showed no effect on symptom resolution in patients with mild COVID-19.
Ivermectin in Patients With Mild to Moderate COVID-1922
Open-label, single-center, RCT of outpatients with laboratory-confirmed SARS-CoV-2 infection in Bangladesh (n = 62) Key Inclusion Criteria:
  • Aged ≥18 years
  • Laboratory-confirmed SARS-CoV-2 infection
  • ≤7 days of symptoms
  • Mild or moderate disease

Key Exclusion Criteria:

  • Hypersensitivity to IVM
  • Pregnancy or breastfeeding
  • Use of HCQ or “other antimicrobials”

Interventions:

  • Single dose of IVM 200 µg/kg
  • SOC

Primary Endpoint:

  • Full recovery from all symptoms

Secondary Endpoint:

  • Conversion to negative RT-PCR at Day 10
Number of Participants:
  • IVM (n = 32) and SOC (n = 30)

Participant Characteristics:

  • 71% of patients were male.
  • Mean age was 39.2 years (SD 12.1 years).
  • 81% of patients had mild disease and 19% had moderate disease.
  • Study provided no information on comorbidities.

Outcomes:

  • Mean overall recovery time was 5.3 days (SD 2.5 days) in IVM arm and 6.3 days (SD 4.2 days) in SOC arm. The difference was not statistically significant. Time to resolution of fever, shortness of breath, and fatigue were no shorter in IVM arm.
  • Negative SARS-CoV-2 PCR result at Day 10: 18 of 20 patients (90%) in IVM arm, 19 of 20 (95%) in SOC arm.
Key Limitations:
  • Open-label study
  • Small study
  • Study enrolled young patients with mild disease who were unlikely to progress to severe COVID-19.

Interpretation:

  • Compared to SOC, use of IVM did not lead to faster recovery from mild to moderate COVID-19.
  • The small sample size and large number of comparisons make it difficult to assess the clinical efficacy of IVM in this population.
Ivermectin Plus Doxycycline Versus Hydroxychloroquine Plus Azithromycin for Asymptomatic Patients and Patients With Mild to Moderate COVID-1923

RCT of outpatients with SARS-CoV-2 infection with or without symptoms in Bangladesh (n = 116)

This is a preliminary report that has not yet been peer reviewed.

Key Inclusion Criteria:
  • Laboratory-confirmed SARS-CoV-2 infection by RT-PCR
  • SpO2 ≥95%
  • Normal or near-normal CXR
  • No unstable comorbidities

Interventions

Group A:
  • A single dose of IVM 200 μg/kg plus DOX 100 mg twice daily for 10 days
Group B:
  • HCQ 400 mg on Day 1, then HCQ 200 mg twice daily for 9 days plus AZM 500 mg once daily for 5 days

Primary Endpoints:

  • Time to negative PCR result. Asymptomatic patients were tested starting on Day 5, then every other day until a negative result occurred. Symptomatic patients were tested on their second symptom-free day, then every other day until a negative result occurred.
  • Time to resolution of symptoms
Number of Participants:
  • Group A (n = 60) and Group B (n = 56)

Participant Characteristics:

  • Mean age was 33.9 years.
  • 78% of patients were male.
  • 91 of 116 patients (78.5%) were symptomatic.

Outcomes:

  • PCR became negative in 60 of 60 patients (100%) in Group A and in 54 of 56 patients (96.4%) in Group B.
  • Mean time to negative PCR result: 8.93 days (range 8–13 days) in Group A, 9.33 days (range 5–15 days) in Group B (P = 0.2314).
  • Mean time to symptom recovery: 5.93 days (range 5–10 days) in Group A, 6.99 days (range 4–12 days) in Group B (P = 0.071).
  • In a subgroup analysis of patients who were symptomatic at baseline, the mean time to negative PCR result for Groups A and B were 9.06 days and 9.74 days, respectively (P = 0.0714).
  • Patients who received IVM plus DOX had fewer AEs than those who received HCQ plus AZM (31.7% vs. 46.4%) in the subgroup analysis.
Key Limitations:
  • Small sample size
  • Open-label study
  • No SOC alone group
  • Study enrolled young patients without major risk factors for disease progression.
  • None of the comparative outcome measures were statistically significant.

Interpretation:

  • In this small study with a young population, the authors suggested that IVM plus DOX was superior to HCQ plus AZM despite no statistically significant difference in time from recovery to negative PCR result and symptom recovery between patients who received IVM plus DOX and those who received HCQ plus AZM.
Antiviral Effect of High-Dose Ivermectin in Adults with COVID-1924
Multicenter, randomized, open-label, blinded trial of hospitalized adults with mild to moderate COVID-19 in Argentina (n = 45) Key Inclusion Criteria:
  • Laboratory-confirmed SARS-CoV-2 infection
  • Hospitalized
  • ≤5 days of symptoms

Key Exclusion Criteria:

  • Use of immunomodulators or any agent with potential anti-SARS-CoV-2 activity prior to enrollment
  • Poorly controlled comorbidities

Interventions:

  • IVM 600 μg/kg once daily plus SOC for 5 days
  • SOC

Primary Endpoint:

  • VL reduction at Day 5. VL was quantified by NP swab at baseline, then at 24, 48, and 72 hours and Day 5.

PK Sampling:

  • Performed 4 hours after dose on Days 1, 2, 3, 5, and 7 to assess elimination
Number of Participants:
  • IVM (n = 30) and SOC (n = 15)
  • After excluding patients with poor sample quality, those without a detectable VL at baseline, and those who withdrew, 32 patients (20 IVM, 12 SOC) were included in the viral efficacy analysis population.

Participant Characteristics:

  • Mean age was 42.3±12.8 years in IVM arm and 38.1±11.7 years in SOC arm.
  • 50% of patients were male in IVM arm and 67% were male in SOC arm.

Primary Outcomes:

  • By Day 5, a similar magnitude of VL reduction was seen in both arms.

Other Outcomes:

  • Patients with higher IVM concentrations had greater reductions in VL (r 0.44; P < 0.04).
  • Treated patients were divided into 2 groups based on IVM Cmax: IVM >160 ng/mL (median of 202 ng/mL) and <160 ng/mL (median of 109 ng/mL).
    • Median percentage of VL reduction by Cmax concentration vs. control (P = 0.0096) was 72% (IQR 59% to 77%) in >160 ng/mL group (n = 9), 40% (IQR 21% to 46%) in <160 ng/mL group (n = 11), and 42% (IQR 31% to 73%) in SOC arm.
    • Median viral decay rate (P = 0.04) was 0.64 day-1 in >160 ng/mL group, 0.14 day-1 in <160 ng/mL group, and 0.13 day-1 in SOC arm.
  • Percentages of AEs were similar between the arms (43% in IVM arm, 33% in SOC arm), and AEs were mostly mild.
Key Limitations:
  • Small sample size
  • No clinical response data reported.
  • The Cmax level of 160 ng/mL used in the analysis appears to be arbitrary.

Interpretation:

  • Concentration-dependent virologic response was seen when using a higher-than-usual dose of IVM (600 μg/kg vs. 200 or 400 μg/kg once daily), with minimal associated toxicities.
  • The study results showed large interpatient variation of IVM Cmax. Larger sample sizes are needed to further assess the safety and efficacy of using higher doses of IVM to treat COVID-19.
Effect of Early Treatment With Ivermectin Versus Placebo on Viral Load, Symptoms, and Humoral Response in Patients With Mild COVID-1925
A single-center, randomized, double-blind, placebo-controlled pilot trial in Spain (n = 24) Key Inclusion Criteria:
  • Laboratory-confirmed SARS-CoV-2 infection
  • ≤72 hours of symptoms
  • No risk factors for severe disease or COVID-19 pneumonia

Interventions:

  • Single dose of IVM 400 μg/kg
  • Nonmatching placebo tablet administered by a nurse who did not participate in the patient’s care

Primary Endpoint:

  • Positive SARS-CoV-2 PCR result from an NP swab at Day 7 post-treatment
Number of Participants:
  • IVM (n = 12) and placebo (n = 12)

Participant Characteristics:

  • Mean age was 26 years (range 18–54 years).
  • 50% of patients were male.
  • All patients had symptoms at baseline; 70% had headache, 66% had fever, 58% had malaise, and 25% had cough.
  • Median onset of symptoms was 24 hours in IVM arm and 48 hours in placebo arm.

Outcomes:

  • At Day 7, 12 patients (100%) in both groups had a positive PCR (for gene N), and 11 of 12 who received IVM (92%) and 12 of 12 who received placebo (100%) had a positive PCR (for gene E); P = 1.0 for both comparisons.
  • In a post hoc analysis, the authors reported fewer patient-days of cough and anosmia in the IVM-treated patients, but no differences in the patient-days for fever, general malaise, headache, and nasal congestion.
Key Limitations:
  • Small sample size
  • PCR is not a validated surrogate marker for clinical efficacy.
  • PCR cycle threshold values were higher for patients who received IVM than those who received placebo at some time points, but these comparisons are not statistically significant.
  • Symptom results were not a prespecified outcome and are of unclear statistical and clinical significance.

Interpretation:

  • Patients who received IVM showed no difference in viral clearance compared to those who received placebo.
  • The small sample size and large number of comparisons make it difficult to assess the clinical efficacy of IVM in this population.
Ivermectin Plus Doxycycline Plus Standard Therapy Versus Standard Therapy Alone in Patients With Mild to Moderate COVID-1926

Randomized, unblinded, single-center study of patients with laboratory-confirmed SARS-CoV-2 infection in Baghdad, Iraq (n = 140)

This is a preliminary report that has not yet been peer reviewed.

Key Inclusion Criteria:
  • Diagnosis by clinical, radiological, and PCR testing
  • Outpatients had mild or moderate COVID-19, while inpatients had severe and critical COVID-19.

Interventions:

  • IVM 200 μg/kg PO daily for 2 days. If patient required more time to recover, a third dose was given 7 days after the first dose, plus DOX 100 mg twice daily for 5–10 days plus standard therapy (based on clinical condition).
  • Standard therapy was based on clinical condition and included AZM, acetaminophen, vitamin C, zinc, vitamin D3, dexamethasone 6 mg daily or methylprednisolone 40 mg twice daily if needed, and oxygen or mechanical ventilation if needed.
  • All critically ill patients were assigned to receive IVM plus DOX.
Number of Participants:
  • IVM plus DOX plus standard therapy (n = 70) and standard therapy alone (n = 70)

Participant Characteristics:

  • Median age was 50 years in IVM arm and 47 years in standard therapy arm.
  • 50% of patients were male in IVM arm and 53% were male in standard therapy arm.
  • In IVM arm, 48 patients had mild or moderate COVID-19, 11 had severe COVID-19, and 11 had critical COVID-19.
  • In standard therapy arm, 48 patients had mild or moderate COVID-19, 22 had severe COVID-19, and no patients had critical COVID-19.

Outcomes:

  • Mean recovery time in IVM arm was 10.1 days (SD 5.3 days) vs. 17.9 days (SD 6.8 days) for standard therapy arm (P < 0.0001). This result was only significant for those with mild to moderate disease.
  • Disease progression occurred in 3 of 70 patients (4.3%) in IVM arm and 7 of 70 (10.0%) in standard therapy arm (P = 0.19)
  • 2 of 70 patients (2.85%) in IVM arm and 6 of 70 (8.57%) in standard therapy arm died (P = 0.14)
Key Limitations:
  • Not blinded
  • Patient deaths prevent an accurate comparison of mean recovery time between arms in this study, and the authors did not account for competing mortality risks.
  • Relies heavily on post hoc subgroup comparisons.
  • Substantial imbalance in disease severity at baseline
  • Authors noted that critical patients were not assigned to standard therapy arm; thus, the arms were not truly randomized.
  • Unclear how many patients required corticosteroids.

Interpretation:

  • IVM may shorten the time to recovery for patients with mild or moderate disease, but the lack of control for competing mortality causes in the study limits the ability to interpret the results.
Ivermectin in Patients With Mild to Moderate COVID-1927

Double-blind RCT in patients with mild to moderate COVID-19 in India (n = 157)

Key Inclusion Criteria:
  • Aged ≥18 years
  • Positive SARS-CoV-2 RT-PCR or antigen test
  • Nonsevere COVID-19 (defined as SpO2 >90% on RA and no hypotension or need for mechanical ventilation)

Key Exclusion Criteria:

  • CrCl <30 mL/min
  • Transaminases >5 times ULN
  • MI or heart failure in previous 90 days
  • QTc interval >450 ms
  • Severe comorbidity

Interventions

  • Single dose of IVM 24 mg in alcohol-based elixir prepared by pharmacy
  • Single dose of same elixir with IVM 12 mg
  • Single dose of same elixir without IVM (placebo)
Primary Endpoint:
  • Reduction of SARS-CoV-2 VL as measured by NP and OP swab at Day 5
  • Conversion to negative RT-PCR at Day 5
Key Secondary Endpoints:
  • Qualitative and quantitative RT-PCR on Days 3 and 7
  • Time to clinical resolution
  • Frequency of clinical worsening
  • Clinical status at Day 14
  • Number of hospital-free days at Day 28
Number of Participants:
  • ITT analysis (safety): IVM 24 mg (n = 51), IVM 12 mg (n = 49), and placebo (n = 52)
  • mITT analysis (included only those with positive NP/OP RT-PCR result): IVM 24 mg (n = 40), IVM 12 mg (n = 40), and placebo (n = 45)
  • 64% of patients had mild disease (including asymptomatic disease) and 36% had moderate disease

Participant Characteristics:

  • Mean age was 35.5 years (SD 10.4 years).
  • 88.8% of patients were male.
  • Mean BMI was 25.
  • Median duration of symptoms was similar between the arms (5 days; IQR 3–7 days).
  • 10% of patients received concurrent antivirals (RDV, favipiravir, or HCQ). No difference in use of antivirals between arms.

Primary Outcomes:

  • Proportion of patients with negative RT-PCR result on Day 5: 47.5% in IVM 24 mg arm, 35.0% in IVM 12 mg arm, and 31.1% in placebo arm (P = 0.30)
  • VL at enrollment did not impact conversion to negative RT-PCR on Day 5.
  • No significant difference in VL decline by Day 5 between the arms
  • No difference in VL decline in the mild or moderate disease strata at Day 5

Secondary Outcomes:

  • No difference between arms in mean time to symptom resolution or number of hospital-free days at Day 28
  • Proportions of patients with clinical worsening were similar across the arms: 7.5% in IVM 24 mg arm, 5.0% in IVM 12 mg arm, and 11.1% in placebo arm (P = 0.65)
  • No difference between arms in frequency of AEs or SAEs
Key Limitations:
  • Small sample size

Interpretation:

  • Though the rate of negative RT-PCR results was numerically higher in the IVM arms than in the placebo arm on Day 5, the result was not statistically significant.
  • No difference in clinical outcomes or frequency of AEs.
Efficacy and Safety of Ivermectin and Hydroxychloroquine in Patients With Severe COVID-1928

Randomized, double-blind trial of hospitalized adults with COVID-19 pneumonia in Mexico (n = 106)

This is a preliminary report that has not yet been peer reviewed.

Key Inclusion Criteria:
  • Laboratory-confirmed SARS-CoV-2 infection
  • Pneumonia, diagnosed by CXR or high-resolution chest CT scan
  • Recently established hypoxemic respiratory failure or deterioration of pre-existing lung or heart disease

Key Exclusion Criteria:

  • Receipt of HFNC oxygen or invasive mechanical ventilation
  • Patients with QT intervals ≥500 ms were not eligible for HCQ but were eligible for IVM.

Interventions:

  • HCQ 400 mg twice daily on Day 1, then HCQ 200 mg/kg twice daily for 4 days
  • Single dose of IVM 12 mg (in patients weighing ≤80 kg) or 18 mg (in those weighing >80 kg) plus calcium citrate for subsequent doses
  • Calcium citrate placebo
Primary Endpoint:
  • Time to discharge due to recovery
Number of Participants:
  • HCQ (n = 33), IVM (n = 36), and placebo (n = 37)

Participant Characteristics:

  • Mean age was 53 years (SD 16.9 years).
  • 62% of patients were male.
  • 34% of patients had diabetes, 32% had hypertension, and 72% had any comorbidity.
  • Mean BMI was 29.6 (SD 6.6).

Outcomes:

  • Median time to discharge due to recovery was 7 days (IQR 3–9 days) in HCQ arm, 6 days (IQR 4–11 days) in IVM arm, and 5 days (IQR 4–7 days) in placebo arm. The differences between arms were not statistically significant.
  • Proportion of patients discharged alive: 79% in HCQ arm, 75% in IVM arm, and 73% in placebo arm
  • Mortality: 6% of patients in HCQ arm, 14% in IVM arm, and 16% in placebo arm
Key Limitations:
  • Small study
  • Length of follow-up period is unclear.
  • The study was stopped prior to achieving its target sample size.

Interpretation:

  • In hospitalized patients with COVID-19 pneumonia who were not critically ill, neither IVM nor HCQ decreased the number of in-hospital days, rate of respiratory deterioration, or mortality.
  • The small sample size and large number of comparisons make it difficult to assess the clinical efficacy of IVM in this population.
Ivermectin as Adjunctive Therapy to Hospitalized Patients With COVID-1929

Randomized, double-blind, placebo-controlled, multicenter, Phase 2 clinical trial of hospitalized adults with mild to severe SARS-CoV-2 infection in 5 facilities in Iran (n = 180)

This is a preliminary report that has not yet been peer reviewed.

Key Inclusion Criteria:
  • Symptoms suggestive of COVID-19 pneumonia, with chest CT compatible with mild to severe COVID-19 or positive RT-PCR result for SARS-CoV-2

Key Exclusion Criteria:

  • Severe immunosuppression, malignancy, or chronic kidney disease
  • Pregnancy

Interventions:

  • HCQ 200 mg/kg twice daily alone as SOC (standard arm)
  • SOC plus 1 of the following:
    • Placebo
    • Single dose of IVM 200 μg/kg
    • IVM 200 μg/kg on Days 1, 3, and 5
    • Single dose of IVM 400 μg/kg
    • IVM 400 μg/kg on Day 1, then IVM 200 μg/kg on Days 3 and 5
Primary Endpoint:
  • Clinical recovery within 45 days of enrollment (defined as normal temperature, respiratory rate, and SpO2 >94% for 24 hours)
Number of Participants:
  • All 6 arms (n = 30 in each arm)

Participant Characteristics:

  • Average age was 56 years (range 45–67 years).
  • 50% of patients were male.
  • Disease stratification (based on CT findings): negative (1%), mild (14%), moderate (73%), and severe (12%)
  • Mean SpO2 at baseline was 89%.

Primary Outcomes:

  • Durations of hypoxemia and hospitalization were shorter in IVM arms than placebo arm (P = 0.025 and P = 0.006, respectively), and mortality was lower in the IVM arms (P = 0.001).
  • There was no difference in number of days of tachypnea (P = 0.584) or return to normal temperature (P = 0.102).
  • Significant differences in change from baseline to Day 5 in absolute lymphocyte count, platelet count, erythrocyte sedimentation rate, and CRP.
  • Higher mortality was reported in standard and placebo arms than IVM arms.
Key Limitations:
  • Small study
  • Power estimation is confusing.
  • Mortality was not listed as the primary or secondary outcome.
  • It is unclear whether IVM patients also received HCQ.
  • It is unclear whether the between-group comparisons are between combined IVM groups and placebo plus SOC.
  • Patients were stratified by disease severity based on CT findings. These categorizations are unclear and were not taken into account in outcome comparisons.
  • The post hoc grouping of randomized arms raises risk of false positive findings.

Interpretation:

  • IVM appeared to improve laboratory outcomes and some clinical outcomes (shorter duration of hypoxemia and hospitalization) and lowered mortality.
  • The small size of the study, the unclear treatment arm assignments, and the lack of accounting for disease severity at baseline make it difficult to draw conclusions about the efficacy of using IVM to treat patients with mild COVID-19.
Retrospective Analysis of Ivermectin in Hospitalized Patients With COVID-1930

Retrospective analysis of consecutive patients with laboratory-confirmed SARS-CoV-2 infection who were admitted to 4 Florida hospitals (n = 276)

Key Inclusion Criteria:
  • Positive NP swab with SARS-CoV-2 RNA

Interventions:

  • Single dose of IVM 200 µg/kg, repeated on Day 7 at the doctors’ discretion; 90% of patients also received HCQ.
  • Usual care: 97% of patients received HCQ and most also received AZM.
Primary Endpoint:
  • All-cause, in-hospital mortality
Number of Participants:
  • IVM (n = 173; 160 patients received a single dose, 13 patients received a second dose) and usual care (n = 103)

Participant Characteristics:

  • Mean age was 60.2 years in IVM arm and 58.6 years in usual care arm.
  • 51.4% of patients were male in IVM arm and 58.8% were male in usual care arm.
  • 56.6% of patients were Black in IVM arm and 51.4% were Black in usual care arm.

Outcomes:

  • All-cause mortality was lower in IVM arm than in usual care arm (OR 0.27; 95% CI, 0.09–0.80; P = 0.03); the benefit appeared to be limited to the subgroup of patients with severe disease.
  • No difference in median length of hospital stay between arms (7 days for both) or proportion of mechanically ventilated patients who were successfully extubated (36% in IVM arm vs. 15% in usual care arm; P = 0.07).
Key Limitations:
  • Not randomized
  • Little to no information on SpO2 or radiographic findings
  • Timing of therapeutic interventions was not standardized.
  • Ventilation and hospitalization duration analyses do not appear to account for death as a competing risk.
  • No virologic assessments were performed.

Interpretation:

  • IVM use was associated with lower mortality than usual care. However, the limitations of this retrospective analysis make it difficult to draw conclusions about the efficacy of using IVM to treat patients with COVID-19.
Observational Study on the Effectiveness of Hydroxychloroquine, Azithromycin, and Ivermectin Among Hospitalized Patients With COVID-1931

Retrospective cohort study of hospitalized adults with COVID-19 in Peru (n = 5,683)

This is a preliminary report that has not yet been peer reviewed.

Key Inclusion Criteria:
  • Aged ≥18 years
  • Symptomatic
  • Laboratory-confirmed SARS-CoV-2 infection
  • No life-threatening illness at admission

Key Exclusion Criteria:

  • Required oxygen at admission
  • Use of tocilizumab, LPV/RTV, or RDV

Interventions:

  • One of the following interventions administered within 48 hours of admission:
    • HCQ or CQ alone
    • IVM alone
    • AZM alone
    • HCQ or CQ plus AZM
    • IVM plus AZM
    • SOC (e.g., supportive care, antipyretics, hydration)
Primary Endpoint:
  • All-cause mortality
Secondary Endpoint:
  • All-cause mortality and/or transfer to ICU
Number of Participants:
  • HCQ or CQ alone (n = 200), IVM alone (n = 203), AZM alone (n = 1,600), HCQ or CQ plus AZM (n = 692), IVM plus AZM (n = 358), and SOC (n = 2,630)

Participant Characteristics:

  • 63% of patients were male.
  • Mean age was 59.4 years (range 18–104 years).
  • All patients had mild or moderate disease.

Outcomes:

  • Median follow-up time was 7 days. Mortality rate was 18.9% at the end of follow-up.
  • IVM alone was associated with increased risk of death and/or ICU transfer compared to SOC (wHR 1.58; 95% CI, 1.11–2.25).
  • IVM plus AZM did not have an effect on deaths or any secondary outcomes (all-cause death and/or ICU transfer, all-cause death and/or oxygen prescription) compared to SOC.
  • HCQ or CQ plus AZM was associated with a higher risk of death (wHR 1.84; 95% CI, 1.12–3.02), death and/or ICU transfer (wHR 1.49; 95% CI, 1.01–2.19), and death and/or oxygen prescription (wHR 1.70; 95% CI, 1.07–2.69) compared to SOC.
Key Limitations:
  • Not randomized
  • Unclear whether all patients received IVM or other medications according to Peruvian guidelines referred to in the manuscript.
  • Dosing and timing of administration are unclear.

Interpretation:

  • Compared to SOC, IVM alone was associated with increased risk of death and/or ICU admission. Using IVM in combination with AZM was not associated with effects on mortality, ICU transfer, or oxygen prescription compared to SOC.
Retrospective Study of Ivermectin Versus Standard of Care in Patients With COVID-1932

Retrospective study of consecutive adult patients hospitalized in Bangladesh with laboratory-confirmed SARS-CoV-2 infection (n = 248)

This is a preliminary report that has not yet been peer-reviewed.

Key Inclusion Criteria:
  • Aged ≥18 years
  • Positive NP swab with SARS-CoV-2 RNA
  • “Free from any other serious pathological conditions”

Interventions:

  • Single dose of IVM 12 mg within 24 hours of hospital admission
  • SOC

Primary Endpoint:

  • Not specified
Number of Participants:
  • IVM (n = 115) and SOC (n = 133)

Participant Characteristics:

  • Median age in IVM arm was 34 years; 70% of patients were male.
  • Median age in SOC arm was 35 years; 52% of patients were male.
  • All patients had mild or moderate disease.
  • 12% of patients had hypertension in both arms.
  • 17% of patients in IVM arm and 12% in SOC arm had DM.

Outcomes:

  • Fewer patients in IVM arm had evidence of disease progression compared to SOC arm (P < 0.001): moderate respiratory distress (2.6% vs. 15.8%), pneumonia (0% vs. 9.8%), ischemic stroke (0% vs. 1.5%).
  • Fewer patients in IVM arm required intensive care management compared to SOC arm (0.9% vs. 8.8%; P < 0.001).
  • Fewer patients in IVM arm required antibiotic therapy (15.7% vs. 60.2%; P < 0.001) or supplemental oxygen (9.6% vs. 45.9%; P < 0.001) compared to SOC arm.
  • Shorter median duration of viral clearance in IVM arm compared to SOC arm (4 vs. 15 days; P < 0.001).
  • Shorter median duration of hospital stay in IVM arm compared to SOC arm (9 vs. 15 days; P < 0.001)
  • Lower mortality in IVM arm compared to SOC arm (0.9% vs. 6.8%; P < 0.05)
Key Limitations:
  • Not randomized
  • Disease severity at admission was reported as mild or moderate, but 12% of patients in IVM arm and 9% in SOC arm had SpO2 <94%
  • Even though only 10% of patients developed pneumonia, 60% received antibiotics.
  • Possibility of harm from concomitant medications

Interpretation:

  • Compared to SOC, IVM use was associated with faster rates of viral clearance and better clinical outcomes, including shorter hospital stay and lower mortality.