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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 : May 6, 2021
Sponsor:
Collaborators:
UnitedHealth Group
Northwestern University
Hennepin County Medical Center, Minneapolis
University of Colorado, Denver
Olive View-UCLA Education & Research Institute
Information provided by (Responsible Party):
University of Minnesota

Tracking Information
First Submitted Date  ICMJE August 7, 2020
First Posted Date  ICMJE August 12, 2020
Last Update Posted Date May 6, 2021
Actual Study Start Date  ICMJE January 1, 2021
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 17, 2021)
  • 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).
Original Primary Outcome Measures  ICMJE
 (submitted: August 10, 2020)
  • Rate of Death due to COVID-19 [ Time Frame: 14 days ]
    Outcome reported as the percent of participants in each arm who expire due to COVID-19 within 14 days of the initiation of treatment.
  • Rate of Hospitalization due to COVID-19 [ Time Frame: 14 days ]
    Outcome reported as the percent of participants in each arm who are admitted to hospital due to COVID-19 within 14 days of the initiation of treatment.
  • Rate of Emergency Department Utilization [ Time Frame: 14 days ]
    Outcome reported as the percent of participants in each arm who utilize emergency department services due to COVID-19 within 14 days of the initiation of treatment.
  • Rate of Urgent Care Utilization [ Time Frame: 14 days ]
    Outcome reported as the percent of participants in each arm who utilize urgent care services due to COVID-19 within 14 days of the initiation of treatment.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 17, 2021)
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 10, 2020)
  • Incidence of Possible COVID-19 Symptoms [ Time Frame: 14 days, 28 days ]
    Outcome measured using a visual analog Scale of COVID-19 symptom maximum severity at days 14 and 28 among those who develop PCR or antibody positivity. Scale ranges from 1-10 with higher scores indicating great symptom severity.
  • Incidence of all-cause study medicine discontinuation [ Time Frame: 28 days ]
    Outcome reported as the percent of participants in each arm who discontinue use of the study drug due to any reason.
  • Disease Severity Rating [ Time Frame: 7, 14, and 28 days ]
    Outcome reported as the percent of participants who fall into each of 8 ordinal categories on days 7, 14, and 28 of study treatment.
    1. Death;
    2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO);
    3. Hospitalized, on non-invasive ventilation or high flow oxygen devices;
    4. Hospitalized, requiring supplemental oxygen;
    5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise);
    6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care;
    7. Not hospitalized, limitation on activities and/or requiring home oxygen;
    8. Not hospitalized, no limitations on activities.
  • Dyspnea Assessment (PROMIS survey) [ Time Frame: 28 days ]
    The PROMIS Dyspnea (shortness of breath) item banks and pools assess self-reported Functional Limitations, Severity, Activity Motivation, Activity Requirements, Airborne Exposure, Assistant Devices Resources, Characteristics, Emotional Response, Task Avoidance and Time Extension as they related to dyspnea. The 33-item Severity bank assesses the severity of difficulty breathing during various specific activities. Each activity is rated in terms of degree of dyspnea (0 = no shortness of breath, 1 = mildly short of breath, 2 = moderately short of breath, 3 = severely short of breath) while engaging in the activity over the past 7 days. Total scores range from 0 to 99 with higher scores reflecting greater levels of dyspnea during daily activity.
  • Global Health Survey (PROMIS survey) [ Time Frame: 28 days ]
    The PROMIS Gobal-10 is a 10-item short-form survey measuring symptoms, functioning, and healthcare-related quality of life for a wide variety of chronic diseases and conditions. Nine items are rated on a 5-point scale. Item 7 is rated on an 11-point scale and then transformed to a 5-point scale. Items 3, 6, 7, and 8 are scored in reverse. Item scores are summed to calculate a total raw score. Raw scores are then matched with a t-score using a scoring table. Outcome will be reported as t-score. T-scores range from 16.2 to 67.7 with higher scores indicating greater global health.
  • Seroconversion of SARS-Cov2 Antibodies OR SARS-Cov2 PCR Positivity (Prevention Cohort Only) [ Time Frame: up to 3 months ]
    Outcome reported as the percent of participants in the treatment and placebo groups who contract SARS-CoV-2 during participation in the prevention arm of the study.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Outpatient Treatment of COVID-19 With Metformin
Official Title  ICMJE COVIDOUT: Outpatient Treatment of COVID-19 With Metformin (Former Title: MET-COVID)
Brief Summary

The purpose of this trial is to conduct a Stage 1 Substudy powered to detect a difference in continuous laboratory outcomes:

  1. Test if metformin treatment in non-hospitalized adults with SARS-CoV-2 infection can prevent hypoxia and emergency department utilization for Covid-19.
  2. Test if metformin vs fluvoxamine vs ivermectin vs metformin+fluvoxxamine vs metformin+ivermectin treatment in non-hospitalized adults with SARS-CoV-2 disease can prevent Covid-19 disease progression.
  3. Test if metformin treatment in non-hospitalized adults with SARS-CoV-2 can improve viral load and CRP(self-collected, laboratory subsidy)
  4. To understand if the active treatment arms are superior to placebo in improving viral load, serologic markers associated with Covid-19, and gut microbiome in non-hospitalized adults with SARS-CoV-2 infection.
  5. To understand if any of the active treatment arms prevent long-covid syndrome, PASC (post-acute sequelae of SARS-CoV-2 infection).
Detailed Description

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:

  1. Cariou et al, Diabetologia, adults with diabetes (DM) in France: OR mortality 0.59 (0.42, 0.84)
  2. Crouse et al, medrxiv.org adults with DM at Univ of Alabama Birmingham: OR mortality 0.33 (0.13-0.84)
  3. 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.
  4. Lou et al, Am J Trop Med, adults with diabetes in China, OR for survival: 4.36 (1.22-15.59)
  5. 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).
  6. 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.

In addition to metformin, fluvoxamine appears to have important anti-viral and anti-inflammatory effects in SARS-CoV-2 infection. There is evidence that SARS-CoV-2 infection causes ER stress and activates pathways of unfolded protein response. Sigma-1 receptor (S1R) is an ER chaperone protein that regulates cytokine production through interaction with IRE1. S1R modulation has demonstrated significant changes to coronavirus replication, and atypical antipsychotics with S1R activity have displayed protective effects against clinical deterioration. Fluvoxamine is a selective serotonin reuptake inhibitor that is a powerful S1R agonist. Fluvoxamine has previously been shown to protect mice from septic shock and reduce the inflammatory response. There is potential for fluvoxamine as an immunomodulatory treatment for SARS-Cov-2. Fluvoxamine in CACO2 cells infected with SARS-Cov-2 had a reduction in production of a subset of cytokines including IL-6, IL-8, CXCL1, and CXCL10.53 A randomized controlled clinical trial of 152 patients showed that patients who received fluvoxamine were less likely to experience clinical deterioration, or serious adverse events due to SARS-Cov-2 when compared to placebo (0% vs. 8%). A follow-up real-world observational cohort had similar findings of 0% (0/65) hospitalization with fluvoxamine vs. 12% (6/48) with observation.

Ivermectin has also shown anti-inflammatory effects that would reduce the harmful cytokine cascade noted in severe Covid-19 disease. A recent trial assessing a multi-therapy including 12mg one-time dose of ivermectin found a 75% reduction in hospitalizations. Another small double-blinded RCT showed significant increased chance of viral clearance after a 5-day course of ivermectin. Another March 2021 RCT reported no effect on diminishing symptoms, but was under-powered for assessing reductions in hospitalization. An RCT with ivermectin must be done in the US, as endemic strongyloidiasis in other countries may confound results.

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. The intervention is metformin, a biguanide, administered in its immediate release formation, 1,500mg daily.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
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.
Primary Purpose: Treatment
Condition  ICMJE
  • Covid19
  • SARS-CoV Infection
Intervention  ICMJE
  • Drug: Metformin
    Metformin; immediate release formation; 1,500mg daily
    Other Name: glucophage
  • Drug: Placebo
    placebo; appearance and size-matched to study drug
  • Drug: Fluvoxamine
    An antidepressant, administered in twice-daily dosing, 50 mg twice per day for 14 days
    Other Name: Luvox
  • Drug: Ivermectin
    An antiparasitic medication administered as 28 mg for weight category <104 mg, and 42 mg for weight category >104 kg.
    Other Name: Stromectol
Study Arms  ICMJE
  • Experimental: Treatment Arm - Metformin Only 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 alone.
    Intervention: Drug: Metformin
  • 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.
    Intervention: Drug: Placebo
  • Experimental: Treatment Arm - Ivermectin Only 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 ivermectin alone.
    Intervention: Drug: Ivermectin
  • Experimental: Treatment Arm - Fluvoxamine Only 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 fluvoxamine alone.
    Intervention: Drug: Fluvoxamine
  • Experimental: Treatment Arm - Metformin and Fluvoxamine 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 metformin and fluvoxamine.
    Interventions:
    • Drug: Metformin
    • Drug: Fluvoxamine
  • Experimental: Treatment Arm - Metformin and Ivermectin 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 metformin and ivermectin.
    Interventions:
    • Drug: Metformin
    • Drug: Ivermectin
Publications * Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, O'Meara MJ, Rezelj VV, Guo JZ, Swaney DL, Tummino TA, Hüttenhain R, Kaake RM, Richards AL, Tutuncuoglu B, Foussard H, Batra J, Haas K, Modak M, Kim M, Haas P, Polacco BJ, Braberg H, Fabius JM, Eckhardt M, Soucheray M, Bennett MJ, Cakir M, McGregor MJ, Li Q, Meyer B, Roesch F, Vallet T, Mac Kain A, Miorin L, Moreno E, Naing ZZC, Zhou Y, Peng S, Shi Y, Zhang Z, Shen W, Kirby IT, Melnyk JE, Chorba JS, Lou K, Dai SA, Barrio-Hernandez I, Memon D, Hernandez-Armenta C, Lyu J, Mathy CJP, Perica T, Pilla KB, Ganesan SJ, Saltzberg DJ, Rakesh R, Liu X, Rosenthal SB, Calviello L, Venkataramanan S, Liboy-Lugo J, Lin Y, Huang XP, Liu Y, Wankowicz SA, Bohn M, Safari M, Ugur FS, Koh C, Savar NS, Tran QD, Shengjuler D, Fletcher SJ, O'Neal MC, Cai Y, Chang JCJ, Broadhurst DJ, Klippsten S, Sharp PP, Wenzell NA, Kuzuoglu-Ozturk D, Wang HY, Trenker R, Young JM, Cavero DA, Hiatt J, Roth TL, Rathore U, Subramanian A, Noack J, Hubert M, Stroud RM, Frankel AD, Rosenberg OS, Verba KA, Agard DA, Ott M, Emerman M, Jura N, von Zastrow M, Verdin E, Ashworth A, Schwartz O, d'Enfert C, Mukherjee S, Jacobson M, Malik HS, Fujimori DG, Ideker T, Craik CS, Floor SN, Fraser JS, Gross JD, Sali A, Roth BL, Ruggero D, Taunton J, Kortemme T, Beltrao P, Vignuzzi M, García-Sastre A, Shokat KM, Shoichet BK, Krogan NJ. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020 Jul;583(7816):459-468. doi: 10.1038/s41586-020-2286-9. Epub 2020 Apr 30.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 3, 2021)
1160
Original Estimated Enrollment  ICMJE
 (submitted: August 10, 2020)
1522
Estimated Study Completion Date  ICMJE August 2021
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria, Stage 1 Treatment Trial:

  • Positive laboratory test for active SARS-CoV-2 viral infection based on local laboratory standard (i.e. +PCR) within 3 days of randomization; negative antibody test not required.
  • Age >=30 years and < 85 years
  • GFR>45ml/min within 2 weeks of enrollment or after enrollment
  • Patient has medical record visible within the EHR of participating sites
  • BMI >= 25kg/m2 by self-report height/weight or >= 23kg/m2 in patients who self-identify in S. Asian or Latinx background.59-61
  • Willing and able to comply with study procedures
  • Has an address and electronic device for communication

Exclusion Criteria, Stage 1 Treatment Trial:

  • Symptom onset greater than 7 days before randomization (symptoms not required for inclusion).
  • Currently taking metformin
  • Estimated Glomerular Filtration Rate (eGFR) of < 45ml/min/1.73 m2
  • Electronic medical record history of severe liver disease
  • Other liver disease that in the opinion of the investigator, would affect metformin clearance
  • Documented AST or ALT > 3 times the upper limit of normal within 3 months of randomization (if available in electronic medical record)
  • EHR of NYHA Stage 3 or 4 heart failure
  • Inability to obtain informed consent
  • Enrollment in another blinded RCT for COVID
  • Alcohol use disorder
  • Hospitalized, for COVID-19 or other reasons.
  • Metformin: Electronic history of severe kidney disease, other kidney disease that in the opinion of the investigator would affect clearance, unstable heart failure (Stage 3 or 4), allergic reaction to metformin in the past
  • Metformin participants taking these medications: cimetidine, hydroxychloroquine, insulin, sulfonylurea, dolutegravir, patiromer, ranolazine, tafenoquine
  • Fluvoxamine: Bipolar disease, allergic reaction to fluvoxamine in the past
  • Fluvoxamine participants taking these medications: rasagiline, selegiline, monoamine oxidase inhibitors, linezolid, duloxetine, methylene blue, tizanidine, ramelteon, alosetron, agomelatine, bromopride, dapoxetine, tasimelteon, thioridazine, urokinase, pimozide
  • Ivermectin: Allergic reaction to ivermectin in the past, current loa loa or onchocerciasis infection, typhoid, BCG, or cholera vaccination within the past 14-days or 3 days after
  • Ivermectin participants taking sodium picosulfate
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 30 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Carolyn Bramante, MD 612-624-5624 metstudy@umn.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04510194
Other Study ID Numbers  ICMJE GIM-2020-29324
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party University of Minnesota
Study Sponsor  ICMJE University of Minnesota
Collaborators  ICMJE
  • UnitedHealth Group
  • Northwestern University
  • Hennepin County Medical Center, Minneapolis
  • University of Colorado, Denver
  • Olive View-UCLA Education & Research Institute
Investigators  ICMJE
Principal Investigator: Carolyn Bramante, MD University of Minnesota
PRS Account University of Minnesota
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP