In a recent study published in NEJM, researchers conducted a phase III clinical trial to test the effectiveness of three repurposed drugs – metformin, ivermectin, and fluvoxamine, in preventing progression to severe coronavirus disease 2019 (COVID-19).

Background

Current vaccines and inpatient treatments for COVID-19, including monoclonal antibodies (mAbs), have limitations. Drug-drug interactions and continuous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution either restrict their use or turn them ineffective. Biophysical modeling predicted that protein translation might be an antiviral therapy target and identified three medications – metformin, ivermectin, and fluvoxamine.

Moreover, metformin has shown in vitro activity against SARS-CoV-2 and other ribonucleic acid (RNA) viruses. Likewise, ivermectin showed in vitro activity against SARS-CoV-2. Since the evaluated dose of this drug was too low in a clinical trial, there is an urgent need for more data. Fluvoxamine at a 50 mg dose proved effective and had a better side-effect profile than the 100-mg dose in a non-randomized prospective cohort study; therefore, studies should evaluate its efficacy at a lower dose.

About the study

In the present study, researchers used a two-by-three factorial design to test three oral, generic medications for early outpatient treatment of SARS-CoV-2 infection. They recruited all the trial patients remotely till January 28, 2022, who received trial drugs at home. The study cohort comprised 30 to 85-year-old adults, either overweight or obese, enrolled for the study within three days after a confirmed COVID-19 diagnosis.

The researchers administered the test drug(s) within seven days after the onset of COVID-19 symptoms. All study analyses used controls, adjusted for SARS-CoV-2 vaccination and other trial medications. Each patient had an equal probability of assignment to any of the six trial groups, receiving drugs in combinations, 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; and
6. Group 6, placebo and placebo.

Only Groups 1 and 2 received two active medications; even patients in other groups received two types of pills to maintain the blinding. These groups received the trial drugs in dosages as follows:

1. instant-release metformin administered with an increase in dose over six days to 1500 mg per day for 14 days,
2. 390 to 470 μg of ivermection per kilogram per day for three days, and
3. 50 mg fluvoxamine twice daily for 14 days.

The study had an independent data and safety monitoring board to monitor the safety, efficacy, and futility of all three trial drugs for which they reviewed three interim reports. They used a Kim–DeMets alpha-spending function to compute the efficacy-monitoring boundaries for each trial drug.

The team employed the pre-specified analysis in the modified intention-to-treat population, which helped exclude patients who provided consent but withdrew before receiving trial drugs. They used logistic regression after adjustment for other trial-drug assignments and SARS-CoV-2 vaccination status to estimate the effect of each trial drug on the composite primary endpoint.

The study's primary endpoint was severe COVID-19, defined as a complex of hypoxemia, emergency department (ED) visit, hospitalization, or death. The follow-up for the primary endpoint ended on February 14, 2022. The secondary endpoints were daily symptom severity, an altered cumulative symptom score, and drug discontinuations. The team assessed symptom severity using generalized estimating equations after adjustment for baseline symptom severity, other trial medications, and SARS-CoV-2 vaccination status. They did not impute approximately 25% of missing data in daily symptom logs.

Study findings

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

Patients started metformin at a dose of 1500 mg per day without dose adjustment, which might have caused side effects. While hospitalization occurred in eight of 168 patients in the metformin group, it occurred in 14 of 179 patients in the control group. Another trial showed that a higher dose of metformin might not improve anti-inflammatory actions. Also,  instant-release metformin might have higher peak systemic exposure, which might be relevant in SARS-CoV-2 infection.

The authors found no evidence that fluvoxamine at a low dose of 50 mg twice daily prevented a primary event in this population. Agonism of the sigma-1 receptor is an important mechanism of fluvoxamine against SARS-CoV-2; perhaps, obese patients might require its higher dose to produce an effect. Intriguingly, the study board recommended discontinuing fluvoxamine because of futility at the third interim review.

Likewise, the authors found no evidence that ivermectin prevented a primary event in the study population. They tested a higher dose, a median of 430 μg per kilogram per day. In some other studies testing ivermectin, this drug showed a better outcome in patients with chronic Strongyloides stercoralis, a parasitic infection seen during COVID-19 progression and prevented life-threatening hyperinfection.

Conclusions

The current phase III, randomized, double-blind, placebo-controlled trial termed COVID-OUT tested three drugs, all of which could not prevent progression to hypoxemia, ED visit, hospitalization, or death in non-hospitalized adults with COVID-19. However, other trials should evaluate these findings before making definitive conclusions concerning the efficacy of metformin, ivermectin, and fluvoxamine.

Studies have proposed that metformin combat COVID-19 via anti-inflammatory and antiviral activity and prevent hyperglycemia during acute illness. Similarly, for obese patients, topiramate and bupropion are used alongside repurposed generic medications. Therefore, future studies should investigate whether these proposed mechanisms are clinically effective in COVID-19 treatment.

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.

In a recent study published in NEJM, researchers conducted a phase III clinical trial to test the effectiveness of three repurposed drugs – metformin, ivermectin, and fluvoxamine, in preventing progression to severe coronavirus disease 2019 (COVID-19).

Background

Current vaccines and inpatient treatments for COVID-19, including monoclonal antibodies (mAbs), have limitations. Drug-drug interactions and continuous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution either restrict their use or turn them ineffective. Biophysical modeling predicted that protein translation might be an antiviral therapy target and identified three medications – metformin, ivermectin, and fluvoxamine.

Moreover, metformin has shown in vitro activity against SARS-CoV-2 and other ribonucleic acid (RNA) viruses. Likewise, ivermectin showed in vitro activity against SARS-CoV-2. Since the evaluated dose of this drug was too low in a clinical trial, there is an urgent need for more data. Fluvoxamine at a 50 mg dose proved effective and had a better side-effect profile than the 100-mg dose in a non-randomized prospective cohort study; therefore, studies should evaluate its efficacy at a lower dose.

About the study

In the present study, researchers used a two-by-three factorial design to test three oral, generic medications for early outpatient treatment of SARS-CoV-2 infection. They recruited all the trial patients remotely till January 28, 2022, who received trial drugs at home. The study cohort comprised 30 to 85-year-old adults, either overweight or obese, enrolled for the study within three days after a confirmed COVID-19 diagnosis.

The researchers administered the test drug(s) within seven days after the onset of COVID-19 symptoms. All study analyses used controls, adjusted for SARS-CoV-2 vaccination and other trial medications. Each patient had an equal probability of assignment to any of the six trial groups, receiving drugs in combinations, 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; and
6. Group 6, placebo and placebo.

Only Groups 1 and 2 received two active medications; even patients in other groups received two types of pills to maintain the blinding. These groups received the trial drugs in dosages as follows:

1. instant-release metformin administered with an increase in dose over six days to 1500 mg per day for 14 days,
2. 390 to 470 μg of ivermection per kilogram per day for three days, and
3. 50 mg fluvoxamine twice daily for 14 days.

The study had an independent data and safety monitoring board to monitor the safety, efficacy, and futility of all three trial drugs for which they reviewed three interim reports. They used a Kim–DeMets alpha-spending function to compute the efficacy-monitoring boundaries for each trial drug.

The team employed the pre-specified analysis in the modified intention-to-treat population, which helped exclude patients who provided consent but withdrew before receiving trial drugs. They used logistic regression after adjustment for other trial-drug assignments and SARS-CoV-2 vaccination status to estimate the effect of each trial drug on the composite primary endpoint.

The study's primary endpoint was severe COVID-19, defined as a complex of hypoxemia, emergency department (ED) visit, hospitalization, or death. The follow-up for the primary endpoint ended on February 14, 2022. The secondary endpoints were daily symptom severity, an altered cumulative symptom score, and drug discontinuations. The team assessed symptom severity using generalized estimating equations after adjustment for baseline symptom severity, other trial medications, and SARS-CoV-2 vaccination status. They did not impute approximately 25% of missing data in daily symptom logs.

Study findings

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

Patients started metformin at a dose of 1500 mg per day without dose adjustment, which might have caused side effects. While hospitalization occurred in eight of 168 patients in the metformin group, it occurred in 14 of 179 patients in the control group. Another trial showed that a higher dose of metformin might not improve anti-inflammatory actions. Also,  instant-release metformin might have higher peak systemic exposure, which might be relevant in SARS-CoV-2 infection.

The authors found no evidence that fluvoxamine at a low dose of 50 mg twice daily prevented a primary event in this population. Agonism of the sigma-1 receptor is an important mechanism of fluvoxamine against SARS-CoV-2; perhaps, obese patients might require its higher dose to produce an effect. Intriguingly, the study board recommended discontinuing fluvoxamine because of futility at the third interim review.

Likewise, the authors found no evidence that ivermectin prevented a primary event in the study population. They tested a higher dose, a median of 430 μg per kilogram per day. In some other studies testing ivermectin, this drug showed a better outcome in patients with chronic Strongyloides stercoralis, a parasitic infection seen during COVID-19 progression and prevented life-threatening hyperinfection.

Conclusions

The current phase III, randomized, double-blind, placebo-controlled trial termed COVID-OUT tested three drugs, all of which could not prevent progression to hypoxemia, ED visit, hospitalization, or death in non-hospitalized adults with COVID-19. However, other trials should evaluate these findings before making definitive conclusions concerning the efficacy of metformin, ivermectin, and fluvoxamine.

Studies have proposed that metformin combat COVID-19 via anti-inflammatory and antiviral activity and prevent hyperglycemia during acute illness. Similarly, for obese patients, topiramate and bupropion are used alongside repurposed generic medications. Therefore, future studies should investigate whether these proposed mechanisms are clinically effective in COVID-19 treatment.

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.