Efficacy of Three Repurposed Drugs in Preventing Serious SARS-CoV-2 Infection in Non-Hospitalized Adults

In a recent study published in NEJMresearchers conducted a phase III clinical trial to test the efficacy of three repurposing drugs, metformin, ivermectin and fluvoxamine, to prevent progression to severe coronavirus disease (COVID-19) in 2019 .

Background

Current vaccines and inpatient treatment for COVID-19, including monoclonal antibodies (mAbs), have limitations. Drug-drug interactions and the continued evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) limit their use or render them ineffective. Biophysical modeling predicted that protein translation could be a target for antiviral therapy and identified three agents: metformin, ivermectin and fluvoxamine.

In addition, metformin in vitro Activity against SARS-CoV-2 and other ribonucleic acid (RNA) viruses.Similarly, ivermectin is in vitro Activities against SARS-CoV-2. The drug’s assessed dose was too low in clinical trials, and more data are urgently needed. In a non-randomized prospective cohort study, a 50 mg dose of fluvoxamine was proven to be effective, with a better side effect profile than the 100 mg dose. Therefore, studies should evaluate efficacy at lower doses.

About research

In this study, researchers used a 2 x 3 factorial design to test three oral generic medicines for early outpatient treatment of SARS-CoV-2 infection. They remotely recruited all study patients who received study drug at home until January 28, 2022. The study cohort consisted of overweight or obese adults aged 30 to 85 who were enrolled in the study within 3 days of a confirmed COVID-19 diagnosis.

Researchers administered study drug within 7 days after onset of symptoms COVID-19 symptomsAll study analyzes used controls adjusted for SARS-CoV-2 vaccination and other investigational agents. Each patient had an equal chance of being assigned to one of her six study groups, who received a combination of drugs, as follows:

1. Group 1, metformin and fluvoxamine.
2. Group 2, metformin and ivermectin.
3. Group 3, metformin and placebo.
4. Group 4, placebo and fluvoxamine.
5. Group 5, placebo and ivermectin.When
6. Group 6, placebo vs placebo.

Only groups 1 and 2 received two active drugs. Even patients in other groups received two tablets to maintain blinding. These groups received study drug at the following doses:

1. fast-acting metformin administered in escalating doses up to 1500 mg per day for 6 days for 14 days;
2. 390–470 μg ivermectation per kilogram per day for 3 days, and
3. Fluvoxamine 50 mg twice daily for 14 days.

The study had an independent data and safety monitoring committee that monitored the safety, efficacy, and futility of all three study drugs and reviewed three interim reports. They used the Kim-DeMets alpha consumption function to calculate efficacy monitoring boundaries for each investigational drug.

The team employed prespecified analyzes in a modified intentional treatment population. They estimated the effect of each study drug on the composite primary endpoint using logistic regression after adjusting for other study drug assignments and SARS-CoV-2 vaccination status.

The primary endpoint of this study was severe COVID-19, defined as a composite of hypoxemia, emergency department (ED) visit, hospitalization, or death. The primary endpoint follow-up ended on 14 February 2022. Secondary endpoints were daily symptom severity, change in cumulative symptom score, and drug discontinuation. After adjusting for baseline symptom severity, other study drugs, and SARS-CoV-2 vaccination status, the team assessed symptom severity using a generalized estimating formula. They did not impute about 25% of missing data in daily symptom logs.

Survey results

There were 1323 patients in the primary study analysis, with a median age of 46 years. Of these, 56% were female (6% pregnant) and 52% were vaccinated. The adjusted odds ratios (OR) for metformin, ivermectin, and fluvoxamine for primary events were 0.84, 1.05, and 0.94, respectively, all with 95% confidence intervals (CI). Additionally, the adjusted OR for emergency department visit, hospitalization, or death for secondary analysis was 0.58 for metformin, 1.39 for ivermectin, and 1.17 for fluvoxamine. The adjusted OR for hospitalization or death was 0.47 for metformin, 0.73 for ivermectin, and 1.11 for fluvoxamine.

The patient was started on metformin at a dose of 1500 mg daily without dose adjustment, which may have caused side effects. In the metformin group he was hospitalized in 8 of 168 patients, whereas in the control group he was hospitalized in her 14 of 179 patients. Another trial showed that higher doses of metformin may not improve anti-inflammatory effects. May have high peak systemic exposure.

The authors found no evidence that low-dose fluvoxamine, 50 mg twice daily, prevented major events in this population. Sigma-1 receptor agonism is a key mechanism of fluvoxamine against SARS-CoV-2. Perhaps obese patients may require higher doses to be effective.Interestingly, in his third interim review, the research panel recommended discontinuation of fluvoxamine due to futility.

Similarly, the authors found no evidence that ivermectin prevented major events in the study population. did.In several other studies testing ivermectin, the drug showed better results in patients with chronic diseases. strongyloidiasisa parasitic infection seen during the course of COVID-19, prevented life-threatening overinfection.

Conclusion

A current phase III, randomized, double-blind, placebo-controlled trial, called COVID-OUT, tested three agents, none of which were associated with progression to hypoxemia, emergency department visits, hospitalization, or hospitalization. did not prevent adult deaths from COVID-19. However, other trials should evaluate these findings before making definitive conclusions. efficacy of metformin, ivermectin, fluvoxamine.

Studies suggest that metformin combats COVID-19 via anti-inflammatory and antiviral activity and prevents hyperglycemia during acute illness. Similarly, in obese patients, topiramate and bupropion are used together with repurposed generic drugs. Therefore, future studies should investigate whether these proposed mechanisms are clinically effective in treating her COVID-19.