ClinicalTrials.gov

History of Changes for Study: NCT04510194
COVID-OUT: Early Outpatient Treatment for SARS-CoV-2 Infection (COVID-19)
Latest version (submitted August 5, 2022) on ClinicalTrials.gov
  • A study version is represented by a row in the table.
  • Select two study versions to compare. One each from columns A and B.
  • Choose either the "Merged" or "Side-by-Side" comparison format to specify how the two study versions are to be displayed. The Side-by-Side format only applies to the Protocol section of the study.
  • Click "Compare" to do the comparison and show the differences.
  • Select a version's Submitted Date link to see a rendering of the study for that version.
  • The yellow A/B choices in the table indicate the study versions currently compared below. A yellow table row indicates the study version currently being viewed.
  • Hover over the "Recruitment Status" to see how the study's recruitment status changed.
  • Study edits or deletions are displayed in red.
  • Study additions are displayed in green.
Study Record Versions
Version A B Submitted Date Changes
1 August 10, 2020 None (earliest Version on record)
2 August 24, 2020 Eligibility and Study Status
3 October 30, 2020 Outcome Measures, Study Status, Eligibility, Arms and Interventions, Study Design and Study Description
4 November 23, 2020 Outcome Measures, Arms and Interventions, Study Description, Study Status, Study Identification, References, Eligibility and Study Design
5 January 12, 2021 Recruitment Status, Study Status, Study Identification, Contacts/Locations and Oversight
6 January 15, 2021 Contacts/Locations and Study Status
7 February 17, 2021 Outcome Measures, Study Status, Arms and Interventions, Study Design, Study Description, Study Identification, Contacts/Locations, Eligibility and Sponsor/Collaborators
8 May 3, 2021 Arms and Interventions, Study Description, Study Status, Eligibility and Study Design
9 May 17, 2021 Contacts/Locations, Study Status, Eligibility, Study Identification, Outcome Measures and Arms and Interventions
10 May 21, 2021 References and Study Status
11 June 1, 2021 Study Status and Arms and Interventions
12 July 30, 2021 Contacts/Locations and Study Status
13 September 13, 2021 Study Status and Study Identification
14 September 30, 2021 Outcome Measures, Study Design, Study Identification, Study Description and Study Status
15 November 16, 2021 Study Status
16 January 20, 2022 Outcome Measures, Study Status, Study Design, Document Section, Eligibility, Arms and Interventions and Study Description
17 March 2, 2022 Recruitment Status, Study Status, Contacts/Locations and Outcome Measures
18 August 5, 2022 Study Status
Comparison Format:

Scroll up to access the controls

Changes (Merged) for Study: NCT04510194
January 20, 2022 (v16) -- March 2, 2022 (v17)

Changes in: Study Status, Outcome Measures and Contacts/Locations

Open or close this module Study Identification
Unique Protocol ID: GIM-2020-29324
Brief Title: COVID-OUT: Early Outpatient Treatment for SARS-CoV-2 Infection (COVID-19)
Official Title: COVID-OUT: Early Outpatient Treatment for SARS-CoV-2 Infection (COVID-19)
Secondary IDs:
Open or close this module Study Status
Record Verification: January 2022 March 2022
Overall Status: Recruiting Active, not recruiting
Study Start: January 1, 2021
Primary Completion: February 2022 2023 [Anticipated]
Study Completion: February 2023 [Anticipated]
First Submitted: August 7, 2020
First Submitted that
Met QC Criteria:
August 10, 2020
First Posted: August 12, 2020 [Actual]
Last Update Submitted that
Met QC Criteria:
January 20, 2022 March 2, 2022
Last Update Posted: January 26 March 7, 2022 [Actual]
Open or close this module Sponsor/Collaborators
Sponsor: University of Minnesota
Responsible Party: Sponsor
Collaborators: UnitedHealth Group
Northwestern University
Hennepin County Medical Center, Minneapolis
University of Colorado, Denver
Olive View-UCLA Education & Research Institute
Open or close this module Oversight
U.S. FDA-regulated Drug: Yes
U.S. FDA-regulated Device: No
Data Monitoring: Yes
Open or close this module Study Description
Brief Summary:

The purpose of this trial is to understand whether:

  1. Metformin vs fluvoxamine vs ivermectin vs metformin+fluvoxamine vs metformin+ivermectin is superior to placebo in non-hospitalized adults with SARS-CoV-2 disease for preventing Covid-19 disease progression.
  2. 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.
  3. 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. Study study assess 3 existing generic medications: metformin, fluvoxamine, and ivermectin.

Metformin: in-silico, in-vitro, ex-vivo tissue assays suggest that metformin inhibits viral replication of SARS-CoV-2 virus (Castle et al; Gordon et al; and Schaller et al). Several retrospective cohort analyses have suggested an association between taking metformin prior to SARS-CoV-2 infection and less severe outcomes. 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 (Lou et al, Diabetes Care 2020).

Fluvoxamine: appears to have 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. 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.

Statistical Considerations:

An independent data safety monitoring board will assess safety approximately twice per month; and will assess futility and efficacy at least twice throughout the study. If one of the arms reaches pre-specified boundaries for futility or efficacy, the DSMB will recommend closing of that arm(s). The detailed statistical analysis plan will be developed by the blinded statistician and co-investigators and per the protocol will be submitted to the DSMB.

Open or close this module Conditions
Conditions: Covid19
SARS-CoV Infection
Keywords:
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 3
Interventional Study Model: Factorial Assignment
Number of Arms: 6
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Allocation: Randomized
Enrollment: 1350 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
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.
Drug: Metformin
Metformin; immediate release formation; 500mg on Day 1; 500mg BID on Day 2 through Day 5; 500mg in AM and 1,000mg in PM on Day 6 through Day 14.
Other Names:
  • 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.
Drug: Placebo
placebo; appearance and size are exact matching to the three study drugs.
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.
Drug: Ivermectin
An anti-parasitic medication administered as 390mcg/kg to 470mcg/kg per day for 3 days
Other Names:
  • Stromectol
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.
Drug: Fluvoxamine
An antidepressant, administered 50mg per day on Day 1; then 50mg twice-daily for Day 2 through Day 14
Other Names:
  • Luvox
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.
Drug: Metformin
Metformin; immediate release formation; 500mg on Day 1; 500mg BID on Day 2 through Day 5; 500mg in AM and 1,000mg in PM on Day 6 through Day 14.
Other Names:
  • glucophage
Drug: Fluvoxamine
An antidepressant, administered 50mg per day on Day 1; then 50mg twice-daily for Day 2 through Day 14
Other Names:
  • Luvox
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.
Drug: Metformin
Metformin; immediate release formation; 500mg on Day 1; 500mg BID on Day 2 through Day 5; 500mg in AM and 1,000mg in PM on Day 6 through Day 14.
Other Names:
  • glucophage
Drug: Ivermectin
An anti-parasitic medication administered as 390mcg/kg to 470mcg/kg per day for 3 days
Other Names:
  • Stromectol
Open or close this module Outcome Measures
Primary Outcome Measures:
1. Clinical Progression
[ Time Frame: 14 days ]

1) Clinical progression, defined as: Emergency department visit for any COVID-19 related symptom (including hospitalization or death) or decrease in O2 saturation (≤93% on room air, or need for supplemental oxygen to maintain an O2 saturation >93%).
Secondary Outcome Measures:
1. Maximum symptom severity
[ Time Frame: 14 days and day 28 14 days ]

Maximum numeric score (defined by adding the symptom score for each individual symptom) on the "Daily Symptom Scale Recommended by FDA for Industry."
2. Clinical Progression Scale
[ Time Frame: 14 days and day 28. ]

Maximum Clinical Support Needed on the Following Scale: 0) No COVID-19 symptoms 1) Outpatient symptomatic but without hypoxia (>93% O2 saturation) 2) Outpatient with O2 saturation > <93% with on room air (or receiving supplemental oxygen requirement; 2 to maintain >93%) ED 3) Emergency Department visit for any COVID symptom; 3 4) Hospitalization for any COVID symptom; 4 5) Hospitalized ICU requiring ventilator support; 5 6) The above + ICU requiring ventilator support for at least 3 days; 6) Requiring extracorporeal membrane oxygenation ( days or ECMO ) ; 7) Death.
3. 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 Symptom improvement or Clinical progression improved.
4. Laboratory Outcome Subsidy - Viral Load
[ Time Frame: Day 1, 5, 10 ]

Self-collection of anterior nasal swab samples is optional for participants. Change in Viral Load between Baseline and Follow-up with be compared between treatment arms.
5. Laboratory Outcome Subsidy
[ Time Frame: Day 1, 5, 10 ]

Collection of blood samples by mobile phlebotomy is optional for participants and determined by availability of mobile phlebotomy. Change in inflammatory and coagulopathic markers will be compared from baseline to follow-up between treatment arms.
6. Laboratory Outcome Subsidy - Microbiome
[ Time Frame: Days 1, 5, 10 ]

Self-collection of stool samples is optional for participants.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.
7. Portion of participants with Post-Acute Sequelae of SARS-CoV-2 infection (PASC)
[ Time Frame: 6 and 12 months ]

PASC assessment will be conducted monthly after enrollment for approximately 9 months with the Questionnaire to characterize long COVID.
Open or close this module Eligibility
Minimum Age: 30 Years
Maximum Age: 85 Years
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
Criteria:

Inclusion Criteria:

  • Positive laboratory test for active SARS-CoV-2 viral infection based on local laboratory standard (i.e. +PCR) within 3 days of randomization.
  • No known history of confirmed SARS-CoV-2 infection
  • BMI >= 25kg/m2 by self-report height/weight or >= 23kg/m2 in patients who self-identify in South Asian or Latinx background.
  • Willing and able to comply with study procedures (i.e. swallow pills)
  • Has an address and electronic device for communication
  • GFR>45ml/min within 2 weeks for patients >75 years old, or with history of heart, kidney, or liver failure.

Exclusion Criteria:

  • Hospitalized, for COVID-19 or other reasons.
  • Symptom onset greater than 7 days before randomization (symptoms not required for inclusion).
  • Immune compromised state (solid organ transplant, bone marrow transplant, AIDS, on high dose steroids)
  • Hepatic impairment (Child-Pugh B and C) or other condition that, in the opinion of the investigator, would affect safety
  • Inability to obtain informed consent
  • Enrollment in another blinded Randomized Controlled Trial for COVID-19
  • Already received an effective (FDA approved/EUA*) therapy for COVID-19 (currently monoclonal antibody treatment)
  • Alcohol use disorder
  • Other unstable medical condition or combination of home medications that in the view of the PI make it unsafe for the individual to participate
  • History of severe kidney disease i.e.:
    1. Stage 4 or 5 CKD, or Estimated Glomerular Filtration Rate (eGFR) of < 45ml/min/1.73 m2
    2. Other kidney disease that in the opinion of the investigator would affect clearance
  • Unstable heart failure (Stage 3 or 4 heart failure)
  • Allergic reaction to metformin, fluvoxamine, or ivermectin in the past
  • Bipolar disease: individuals who report they have bipolar disorder or are taking medication for bipolar disorder (lithium, valproate, high-dose antipsychotic), unless the investigator concludes that the risk for mania is unlikely
  • Current loa loa or onchocerciasis infection
  • Typhoid, BCG, or cholera vaccination within the 14-days or 3 days after

Medication Exclusions:

  • Cimetidine, hydroxychloroquine, insulin, sulfonylurea, dolutegravir, patiromer, ranolazine, tafenoquine.
  • Rasagiline, selegiline, or monoamine oxidase inhibitors, linezolid, methadone
  • Duloxetine, methylene blue
  • Tizanidine, ramelteon, sodium picosulfate
  • Alosetron, agomelatine, bromopride, dapoxetine, tamsimelteon, thioridazine, urokinase, pimozide

The following medications may not need to be excluded when dose for that individual is considered alongside the low dose of fluvoxamine being used and other medications being used. The PI or site PI may review and decide if the patient should be excluded from the fluvoxamine arms:

  1. Taking SSRIs, SNRIs, or tricyclic antidepressants, unless these are at a low dose such that a study investigator concludes that a clinically significant interaction with fluvoxamine (ie either serotonin syndrome or TCA overdose) is unlikely (examples: participant takes escitalopram but only at 10mg daily; that dose plus 100mg fluvoxamine would be insufficient to cause serotonin syndrome; or, participant takes amitriptyline but only at 25mg nightly; even if fluvoxamine inhibits its metabolism, it would be an insufficient dose to cause QTc prolongation or problematic side effects). Risk Class C, monitor therapy.
  2. Individuals who take alprazolam or diazepam and are unwilling to cut the medication by 20% (rationale: fluvoxamine modestly inhibits the metabolism of these drugs). Risk Class C, monitor therapy
  3. Participants taking theophylline, clozapine, or olanzapine (drugs with a narrow therapeutic index that are primarily metabolized by CYP 1A2, which is inhibited by fluvoxamine) will be reviewed with a study investigator and excluded unless the investigator concludes that the risk to the participant is low (this would be unlikely; example: participant takes clozapine only as needed and is willing to avoid it for the 14 days of the study).
  4. Patients will be advised that there is a small risk that the following substances will be affected by fluvoxamine, but that significant effects are not likely at the low dose being used: caffeine, nicotine, melatonin. Risk Class C, monitor therapy
  5. Taking warfarin-also known as Coumadin, NSAIDs, and Aspirin (rationale: increased risk of bleeding), phenytoin (rationale: fluvoxamine inhibits its metabolism), clopidogrel (rationale: fluvoxamine inhibits its metabolism from pro-drug to active drug which raises risk of cardiovascular events), and St John's wort (rationale: fluvoxamine + St John's wort are considered contraindicated because of the risk of serotonin syndrome) Risk C, monitor therapy.
    • Additional COVID-19 treatments to exclude will be decided by a panel of at least 3 Co-Investigators on this study. The additional treatments to exclude will be documented and submitted to the IRB but may be implemented before formal IRB approval is complete. We take this approach because of the rapidly changing treatment landscape of COVID-19. Participation in the study does not prevent them from receiving such treatments after enrollment.
Open or close this module Contacts/Locations
Central Contact Person: Website covidout.com
Telephone: 651-661-9560
Email: covidout@umn.edu
Study Officials: Carolyn Bramante, MD
Principal Investigator
University of Minnesota
Locations: United States, California
Olive View UCLA Medical Center
[Recruiting]
Sylmar, California, United States, 91342
Contact:Contact: Hrishi Belani, MD
Contact:Principal Investigator: Hrishi Belani, MD
Olive View UCLA Medical Center
Sylmar, California, United States, 91342
United States, Colorado
Anschutz Health and Wellness Center
[Recruiting]
Aurora, Colorado, United States, 80045
Contact:Contact: Jacinda Nicklas, MD
Contact:Principal Investigator: Jacinda Nicklas, MD
University of Colorado Denver; Department of Medicine; Anschutz Health and Wellness Center
Aurora, Colorado, United States, 80045
New West Physicians
[Recruiting]
Golden, Colorado, United States, 80401
Contact:Contact: Ken Cohen, MD
Contact:Principal Investigator: Ken Cohen, MD
New West Physicians
Golden, Colorado, United States, 80401
United States, Illinois
Northwestern University Feinberg School of Medicine
[Recruiting]
Chicago, Illinois, United States, 60611
Contact:Contact: David Liebovitz, MD
Contact:Principal Investigator: David Liebovitz, MD
Northwestern University Feinberg School of Medicine
Chicago, Illinois, United States, 60611
United States, Indiana
American Health Network of Indiana
[Recruiting]
Greenfield, Indiana, United States, 46140
Contact:Contact: Andrew Daluga, MD
Contact:Principal Investigator: Andrew Daluga, MD
American Health Network of Indiana
Greenfield, Indiana, United States, 46140
United States, Minnesota
Hennepin County Medical Center
[Recruiting]
Minneapolis, Minnesota, United States, 55415
Contact:Contact: Mike Puskarich, MD
Contact:Principal Investigator: Mike Puskarich, MD
Hennepin County Medical Center
Minneapolis, Minnesota, United States, 55415
University of Minnesota
[Recruiting]
Minneapolis, Minnesota, United States, 55455
Contact:Contact: Carolyn Bramante, MD, MPH covidout@umn.edu
Contact:Sub-Investigator: David Boulware, MD
Contact:Sub-Investigator: Christopher Tignanelli, MD
Contact:Sub-Investigator: David Odde, MD
Contact:Sub-Investigator: Nick Ingraham, MD
Contact:Sub-Investigator: Michelle Biros, MD
University of Minnesota
Minneapolis, Minnesota, United States, 55455
Open or close this module IPDSharing
Plan to Share IPD: Undecided
Open or close this module References
Citations: 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. PubMed 32353859
Castle, B.T., C. Dock, M. Hemmat, S. Kline, C. Tignanelli, R. Rajasingham, D. Masopust, P. Provenzano, R. Langlois, T. Schacker, A. Haase, and D.J. Odde, Biophysical modeling of the SARS-CoV-2 viral cycle reveals ideal antiviral targets. bioRxiv, 2020. https://www.biorxiv.org/content/10.1101/2020.05.22.111237v2.
Links:
Available IPD/Information:
Open or close this module Document Section
Study Protocol
Document Date: December 8, 2021
Uploaded: 01/20/2022 14:24
File Name: Prot_000.pdf

Scroll up to access the controls Scroll to the Study top

U.S. National Library of Medicine | U.S. National Institutes of Health | U.S. Department of Health & Human Services