Outpatient Treatment of COVID-19 With Metformin
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|ClinicalTrials.gov Identifier: NCT04510194|
Recruitment Status : Recruiting
First Posted : August 12, 2020
Last Update Posted : February 21, 2021
The purpose of this trial is to conduct a Stage 1 Substudy powered to detect a difference in continuous laboratory outcomes:
- Test if metformin treatment in non-hospitalized adults with SARS-CoV-2 infection can prevent hypoxia and emergency department utilization for Covid-19.
- Test if metformin treatment in non-hospitalized adults with SARS-CoV-2 disease can prevent Covid-19 disease progression.
- Test if metformin treatment in non-hospitalized adults with SARS-CoV-2 can improve viral load and CRP(self-collected, laboratory subsidy)
|Condition or disease||Intervention/treatment||Phase|
|Covid19 SARS-CoV Infection||Drug: Metformin Drug: Placebo||Phase 2 Phase 3|
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly spreading viral infection causing COVID-19 disease. There currently is no definitive preventive or early outpatient treatment therapy for Covid-19. Six observational studies have found decreased severity of Covid-19 disease among persons with metformin use before diagnosis with Covid-19:
- Cariou et al, Diabetologia, adults with diabetes (DM) in France: OR mortality 0.59 (0.42, 0.84)
- Crouse et al, medrxiv.org adults with DM at Univ of Alabama Birmingham: OR mortality 0.33 (0.13-0.84)
- Bramante et al, Lancet Healthy Longevity, females with DM or obesity, claims data from 50 US5 states: OR mortality 0.759 (0.601, 0.960) by propensity matching; OR 0.785 (0.650, 0.951) by Cox model.
- Lou et al, Am J Trop Med, adults with diabetes in China, OR for survival: 4.36 (1.22-15.59)
- Bramante et al. Under review, in adults with non-alcoholic fatty liver disease and +SARS-CoV-2, OR for admission: 0.42 (0.18-1.01, p=0.05).
- Bramante et al. Under review, in adults with Covid-19, OR for admission 0.46 (0.27-0.80), p<0.01; mortality, OR 0.49 (0.26-0.94); and metformin was associated with lower IL-6 (non-significant) lower neutrophil/lymphocyte ratio and CPR, and equivalent lactate and bicarbonate as non-metformin.
Kow, J Med Virol conducted a meta analysis, with an overall odds ratio for mortality of 0.62 (0.43-0.89).
Gordon et al found decreased SARS-CoV-2 and increased cell viability with metformin in vitro. (Gordon et al, Nature). While anti-viral activity may be contributing to the observational associations of reduced severity of Covid-19, metformin has a proven history of beneficial immune-modulatory effects, including on CRP, IL-6 and TNF-alpha, neutrophil extracellular traps, and improved T cell immunity. Outpatient metformin use has now been associated with lower IL-6, CRP, and neutrophil-lymphocyte ratio in persons with Covid-19.
While vaccine development for SARS-CoV-2 has been promising, there may be reduced willingness among the public to receive a vaccine developed so quickly. This is a substudy with laboratory outcomes (70 patients will be enrolled). The intervention is metformin, a biguanide, administered in its immediate release formation, 1,500mg daily.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||750 participants|
|Intervention Model:||Parallel Assignment|
|Intervention Model Description:||Funding has been obtained for Stage 1 (70 patients) of this fully-powered Phase 3 trial (750 patients total).|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Masking Description:||Only the investigational pharmacy and one statistician have access to patient treatment allocation.|
|Official Title:||COVIDOUT: Outpatient Treatment of COVID-19 With Metformin (Former Title: MET-COVID)|
|Actual Study Start Date :||January 1, 2021|
|Estimated Primary Completion Date :||June 2021|
|Estimated Study Completion Date :||August 2021|
Experimental: Treatment Arm - Treatment Group
Participants in the treatment arm of the trial are those who test positive for SARS-COV-2 infection at the time of screening. Participants in this arm and group will receive the metformin.
Metformin; immediate release formation; 1,500mg daily
Other Name: glucophage
Placebo Comparator: Treatment Arm - Placebo Group
Participants in the treatment arm of the trial are those who test positive for SARS-COV-2 infection at the time of screening. Participants in this arm and group will receive the placebo.
placebo; appearance and size-matched to study drug
- Decreased oxygenation [ Time Frame: 14 days ]SpO2 =< 93% on home monitoring.
- Emergency Department Utilization [ Time Frame: 14 days ]Emergency department utilization for Covid-19 Symptoms (as defined by current CDC definition of Covid-19 symptoms or by treating clinical team).
- Maximum symptom severity [ Time Frame: 14 days and day 28 ]Maximum numeric score (defined by adding the symptom score for each individual symptom) on the "Daily Symptom Scale Recommended by FDA for Industry."
- Clinical Progression Scale [ Time Frame: 14 days and day 28. ]Maximum Clinical Support Needed on the Following Scale: 1) O2 saturation >93% with supplemental oxygen requirement; 2) ED visit for any COVID symptom; 3) Hospitalization for any COVID symptom; 4) Hospitalized requiring ventilator support; 5) The above + ventilator support for at least 3 days; 6) Requiring extracorporeal membrane oxygenation (ECMO); 7) Death.
- Time to meaningful recovery [ Time Frame: 14 days and day 28 ]Symptom improvement of > 2 points or Clinical progression improved by one category and sustained for at least 36 hours
- Laboratory Outcome Subsidy [ Time Frame: Day 1, 5, 10 ]Self-collect anterior nasal swab will be done on the first 70 patients (viral load). Change in Viral Load between Baseline and Follow-up with be compared between treatment arms.
- Laboratory Outcome Subsidy [ Time Frame: Day 1, 5, 10 ]Self-collect finger stick blood will be done on the first 70 patients (CRP). Change in CRP between Baseline and Follow-up with be compared between treatment arms.
- Laboratory Outcome Subsidy [ Time Frame: Day 1, 5, 10 ]Self-collect finger stick blood will be done on the first 70 patients (Albumin). Change in Albumin between Baseline and Follow-up with be compared between treatment arms.
- Laboratory Outcome Subsidy [ Time Frame: Days 1, 5, 10 ]Optional self-collect stool samples.16S rRNA sequencing and shotgun sequencing will be used to assess the impact of metformin-based treatment options for Covid on improving the ratio of beneficial to inflammatory bacteria in the gastrointestinal tract, and the role of the microbiome in health and disease outcomes.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04510194
|Contact: Carolyn Bramante, MDemail@example.com|
|United States, Minnesota|
|University of Minnesota||Recruiting|
|Minneapolis, Minnesota, United States, 55455|
|Contact: Carolyn Bramante, MD, MPH firstname.lastname@example.org|
|Principal Investigator:||Carolyn Bramante, MD||University of Minnesota|