Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19

Abstract

Background: Early treatment to prevent severe coronavirus disease 2019 (Covid-19) is an important component of the comprehensive response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic.

Methods: In this phase 3, double-blind, randomized, placebo-controlled trial, we used a 2-by-3 factorial design to test the effectiveness of three repurposed drugs - metformin, ivermectin, and fluvoxamine - in preventing serious SARS-CoV-2 infection in nonhospitalized adults who had been enrolled within 3 days after a confirmed diagnosis of infection and less than 7 days after the onset of symptoms. The patients were between the ages of 30 and 85 years, and all had either overweight or obesity. The primary composite end point was hypoxemia (≤93% oxygen saturation on home oximetry), emergency department visit, hospitalization, or death. All analyses used controls who had undergone concurrent randomization and were adjusted for SARS-CoV-2 vaccination and receipt of other trial medications.

Results: A total of 1431 patients underwent randomization; of these patients, 1323 were included in the primary analysis. The median age of the patients was 46 years; 56% were female (6% of whom were pregnant), and 52% had been vaccinated. The adjusted odds ratio for a primary event was 0.84 (95% confidence interval [CI], 0.66 to 1.09; P = 0.19) with metformin, 1.05 (95% CI, 0.76 to 1.45; P = 0.78) with ivermectin, and 0.94 (95% CI, 0.66 to 1.36; P = 0.75) with fluvoxamine. In prespecified secondary analyses, the adjusted odds ratio for emergency department visit, hospitalization, or death was 0.58 (95% CI, 0.35 to 0.94) with metformin, 1.39 (95% CI, 0.72 to 2.69) with ivermectin, and 1.17 (95% CI, 0.57 to 2.40) with fluvoxamine. The adjusted odds ratio for hospitalization or death was 0.47 (95% CI, 0.20 to 1.11) with metformin, 0.73 (95% CI, 0.19 to 2.77) with ivermectin, and 1.11 (95% CI, 0.33 to 3.76) with fluvoxamine.

Conclusions: None of the three medications that were evaluated prevented the occurrence of hypoxemia, an emergency department visit, hospitalization, or death associated with Covid-19. (Funded by the Parsemus Foundation and others; COVID-OUT ClinicalTrials.gov number, NCT04510194.).

Figure 1.. Enrollment and Factorial Design.

Shown is the 2-by-3 factorial design that was developed to test the effectiveness of three repurposed drugs — metformin, ivermectin, and fluvoxamine — in preventing serious coronavirus disease 2019 (Covid-19) in nonhospitalized adults. Although groups 1 and 2 were the only groups with two active drugs, all the patients received two types of pills to maintain the blind and have a similar pill burden in each group. The primary analysis was performed in the modified intention-to-treat population, which excluded patients who had confirmed that they had not received any trial drug. Details regarding the number of patients who were excluded from the trial are provided in the Supplementary Appendix.

Figure 2.. Total Scores on a Symptom Severity Scale during a 14-Day Period.

The three panels present the composite symptom scores in the active treatment groups and the control groups among the patients who received metformin, ivermectin, or fluvoxamine. Scores were calculated with the use of a generalized estimating equation after adjustment for the baseline score, vaccination status, and receipt of other medications during the trial. Shown on the y axis is the composite score of 14 symptoms, which were graded as none (0), mild (1), moderate (2), or severe (3). Overall, 80% of the patients contributed data on the symptom logs; the frequency of missing data was approximately 25% on each of the 14 days. Additional details regarding specific symptoms are provided in Figures S4 and S5 in the Supplementary Appendix.