METHODS: Five electronic databases were searched for studies involving tocilizumab, dexamethasone, and methylprednisolone in treating COVID-19. We included case-control and randomized or partially randomized trials. Meta-regression for patient baseline characteristics, co-medications, and tocilizumab dose regimens was performed to identify contributing factors to drug efficacy.

RESULTS: Thirteen randomized controlled trials (RCTs) and twenty-four case-control studies were included in our meta-analysis involving 18,702 patients. Meta-analysis among the RCTs showed that a summary estimate favoring mortality reduction (OR 0.71, 95%CI 0.55 - 0.92) contributed mainly by tocilizumab and dexamethasone. Among case-control studies, meta-analysis showed mortality reduction (OR 0.52, 95%CI 0.36 - 0.75) contributed by tocilizumab and tocilizumab-methylprednisolone combination. Methylprednisolone alone did not reduce mortality except for one study involving high dose pulse therapy. Meta-analysis also found that all three drugs did not significantly reduce mechanical ventilation (OR 0.72, 95%CI 0.32 - 1.60).

STUDY DESIGN: This was an open-label, randomized clinical trial conducted at 14 public hospitals across Malaysia from February to June 2021 among 500 symptomatic, RT-PCR confirmed COVID-19 patients, aged ≥50 years with ≥1 co-morbidity, and hospitalized within first 7 days of illness. Patients were randomized on 1:1 ratio to favipiravir plus standard care or standard care alone. Favipiravir was administered at 1800mg twice-daily on day 1 followed by 800mg twice-daily until day 5. The primary endpoint was rate of clinical progression from non-hypoxia to hypoxia. Secondary outcomes included rates of mechanical ventilation, intensive care unit (ICU) admission, and in-hospital mortality.

RESULTS: Among 500 patients were randomized (mean age, 62.5 [SD 8.0] years; 258 women [51.6%]; and 251 [50.2%] had COVID-19 pneumonia), 487 (97.4%) patients completed the trial. Clinical progression to hypoxia occurred in 46 (18.4%) patients on favipiravir plus standard care and 37 (14.8%) on standard care alone (OR 1.30; 95%CI, 0.81-2.09; P=.28). All three pre-specified secondary end points were similar between both groups. Mechanical ventilation occurred in 6 (2.4%) vs 5 (2.0%) (OR 1.20; 95%CI, 0.36-4.23; P=.76), ICU admission in 13 (5.2%) vs 12 (4.8%) (OR 1.09; 95%CI, 0.48-2.47; P=.84), and in-hospital mortality in 5 (2.0%) vs 0 (OR 12.54; 95%CI, 0.76- 207.84; P=.08).

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.

METHODS: We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry.

RESULTS: At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration.