Clinical trial NCT04510194: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Covid19
SARS-CoV Infection
Lead sponsor: University of Minnesota
Sponsor class: OTHER
Collaborators: name: UnitedHealth Group
name: Northwestern University
name: Hennepin County Medical Center, Minneapolis
name: University of Colorado, Denver
name: Olive View-UCLA Education & Research Institute
First posted: 2020-08-12
Enrollment: 1323
Sex: ALL
Minimum age (years): 30
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Count of Participants With Hypoxia Only
timeFrame: 14 days
measure: Count of Participants With ED Visit, Hospitalization or Death
timeFrame: 14 days
measure: Count of Participants With Hospitalization or Death
timeFrame: 14 days
measure: Count of Participants Who Died
timeFrame: 14 days
Secondary outcomes:
Other outcomes:
Locations:
city: Sylmar
country: United States
facility: Olive View UCLA Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado Denver; Department of Medicine; Anschutz Health and Wellness Center
state: Colorado
city: Golden
country: United States
facility: New West Physicians
state: Colorado
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine
state: Illinois
city: Greenfield
country: United States
facility: American Health Network of Indiana
state: Indiana
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
Study officials:
affiliation: University of Minnesota
name: Carolyn Bramante, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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.
citation: Bramante CT, Huling JD, Tignanelli CJ, Buse JB, Liebovitz DM, Nicklas JM, Cohen K, Puskarich MA, Belani HK, Proper JL, Siegel LK, Klatt NR, Odde DJ, Luke DG, Anderson B, Karger AB, Ingraham NE, Hartman KM, Rao V, Hagen AA, Patel B, Fenno SL, Avula N, Reddy NV, Erickson SM, Lindberg S, Fricton R, Lee S, Zaman A, Saveraid HG, Tordsen WJ, Pullen MF, Biros M, Sherwood NE, Thompson JL, Boulware DR, Murray TA; COVID-OUT Trial Team. Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19. N Engl J Med. 2022 Aug 18;387(7):599-610. doi: 10.1056/NEJMoa2201662.
citation: Dodds MG, Doyle EB, Reiersen AM, Brown F, Rayner CR. Fluvoxamine for the treatment of COVID-19. Lancet Glob Health. 2022 Mar;10(3):e332. doi: 10.1016/S2214-109X(22)00006-7. No abstract available.