The University of Minnesota recently added important generic study drugs to critically important yet not widely known clinical trial investigating outpatient treatment for SARS-CoV-2 infection, the virus behind COVID-19. Now economical, well-known drugs including Ivermectin and Fluvoxamine as well as Metformin are put to the COVID-19 test in this study called “COVIDOUT.” Led by Carolyn Bramante, MD, MPH, and a study team of sub-investigators, coordinators, and other study staff, the study was made possible by funding from the Parsemus Foundation initially probing the potential benefits of Metformin. Additional funding from the Rainwater Foundation, FastGrants, and UnitedHealth Group made it possible to expand the trial to an efficient factorial trial design. The COVIDOUT clinical trial targets an incredibly important segment of the COVID-19 diseases spectrum, that is the approximately 90% of the total cases that fall in either the asymptomatic or mild-to-moderate symptomatic category. Presently, there are no authorized treatments for this massive population. Put another way, out of the approximately 34 million total COVID-19 cases in the United States, about 30.6 million of these would fall into this category. In addition to vaccination and appropriate public health measures, a holistic and comprehensive strategy to beat COVID-19 includes therapeutic, outpatient options for this class of COVID-19 patients. While a few pharmaceutical companies, such as Merck and Pfizer as well as AstraZeneca, are testing therapies that target this lucrative market, around the world other generic drugs are either under investigation or are actually in use such as Ivermectin, Favipiravir, and others. With a group of impressive partners, including the nation’s largest health payer, UnitedHealth Group, as well as public hospitals such as Hennepin County Medical Center, Northwestern University, University of Colorado and Olive View-UCLA Education & Research Institute, the 1,124 patient, 30+ in age COVID-OUT study “factorial” randomized clinical trial could literally lead to national-level acceptance of both Ivermectin and Fluvoxamine as well as Metformin as low-cost treatments for COVID-19. The study needs support, so those that know of someone that recently tested positive for COVID-19 and that meet inclusion criteria can participate as the study drug can be shipped to the patient’s home location, nation-wide. The COVID-OUT study website has more details. Clinics may participate as co-Investigators with Dr. Bramante as well.
TrialSite briefly caught up with Dr. Carolyn Bramante who has been quite busy throughout the pandemic. The Assistant Professor in the Division of General Internal Medicine has focused on obesity treatment for children and adults. A critically important and timely research area, Bramante dedicated to public health causes and health equity, is an expert in helping patients work to change their daily behavior among other pragmatic weight management approaches.
Dr. Bramante emphasized the importance of this trial and the urgent need for treatments at the early onset, mild to moderate stage of the COVID-19 disease. She emphasized to TrialSite her gratitude for her mentor, the esteemed Dr. David Boulware, and for the team, both internal to the University of Minnesota and external partners all collaborating in this critical endeavor.
The Study Drugs
This University of Minnesota sponsored study looks at three generic, low-cost potential drugs targeting COVID-19. What follows is a brief TrialSite review of these interventions. TrialSite reminds that none of these genetic therapies are authorized for COVID-19 in the United States by the FDA nor recommended by the National Institutes of Health (NIH).
Metformin: Discovered in 1922, this first-line medication is used for treating type 2 diabetes with a focus on patients who are overweight. The drug is also used for polycystic ovary syndrome. The University of Minnesota includes metformin in the study due to a number of data points such as a University of Alabama at Birmingham study indicating that the use of metformin prior to COVID-19 infection may reduce the death rate. The study results were peer reviewed and published in Frontiers in Endocrinology.
Fluvoxamine: Currently FDA approved as an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class, the drug is used for the treatment of depression disorder and obsessive-compulsive disorder (OCD). TrialSite has followed fluvoxamine studies led by Washington University St. Louis School of Medicine and funded by the COVID-19 Early Treatment Fund, which was created by a frequent contributor to TrialSite, tech entrepreneur Steve Kirsch. Fluvoxamine’s potential was showcased on 60 Minutes. See the TrialSite article for a more comprehensive overview.
Ivermectin: TrialSite has monitored ivermectin-based research more than any media platform worldwide. First identified by Australian researchers as a possible candidate for drug repurposing, the developed world showed little interest but research and actual care options took off in numerous low-and middle-income countries (LMICs) from the compelling work of Dr. Tarek Alam of Bangladesh to numerous initiatives in Peru and Bolivia.
In Zimbabwe, a prominent local physician helped pave the way to a form of emergency authorization for clinical research as a care option—this southern African nation experienced a precipitous drop in COVID-19 cases since then. After a dramatic legal conflict leading to a high court case, the South African regulator allowed for use of the drug targeting COVID-19. Some local health authorities in Brazil authorized ivermectin for early-onset usage for COVID-19 while a few Eastern European nations have authorized either under emergency use (Slovakia) or as an off-label option, such as in Macedonia and Bulgaria. Last summer, Broward County, Florida physician-researchers in the ICON observational study demonstrated the drug could reduce COVID-19 death rates. Most recently, India added ivermectin to its national protocol. The world’s fifth most populated country’s largest state, Uttar Pradesh, announced an aggressive population-wide ivermectin treatment regimen in late April. By late May, the COVID-19 cases had plummeted. TrialSite, of course, cannot prove that the two are correlated but there is most definitely an observation. In America, while approved as an antiparasitic drug for humans, it’s not approved for COVID-19 but is used off label even though the National Institutes of Health (NIH) cannot recommend for or against due to what they declare is a lack of sufficient data. This is despite the fact that over 50 studies have been completed (over 20 randomized controlled trials) as well as a few notable meta-analyses.
What is a Factorial Randomized Study?
The University of Minnesota physician and principal investigator explained to TrialSite’s founder Daniel O’Connor that a factorial trial involves two or greater investigational interventional comparisons executed in parallel. A majority of this class of trials includes two factors, and each of them has two levels, hence known as 2X2 factorial trials. However, this class of trial can include 3X2 trials or even such studies that may investigate three, four, or greater interventions all in parallel. In the COVID-OUT trial, 5 active treatment arms are being compared to the same placebo arm. Thus only 17% of participants will receive a placebo.
This class of clinical trial, if designed properly, can offer flexibility and economy as it facilitates a couple of different studies for the price of one. Mostly these studies are designed and executed in such a way that the effects of the investigational interventions are not based on an interaction between two or more study drugs. However, factorial studies can involve a pursuit to assess the benefit of an interaction involving two investigational interventions.
The COVID-19-OUT study (NCT04510194) is scheduled to conclude by the end of 2021.
This particular study has been designed to identify any deltas in continuous laboratory outcomes involving five different sub-investigations. One sub-study investigates the benefit of metformin treatment in non-hospitalized adults with positive COVID-19 tests and whether this treatment can prevent hypoxia and emergency department utilization for COVID-19.
Another aim of this study evaluates metformin versus fluvoxamine versus ivermectin versus metformin plus fluvoxamine versus metformin plus ivermectin treatment also in non-hospitalized adults who have tested positive for COVID-19. Here Dr. Bramante and the study team seek to understand which approach is superior to preventing COVID-19 disease progression.
Yet another sub-study evaluates metformin as a treatment in non-hospitalized adults with a positive COVID-19 test and whether this common generic drug used for diabetes can improve viral load and CRP.
The study also includes the evaluation of active treatment arms against the placebo—are they superior? Do they work far better than not when it comes to improving viral load and serologic markers associated with COVID-19 as well as the gut microbiome in those with mild-to-moderate COVID-19 with no need for hospitalization? The study team also seeks to better understand if any active treatment arms help prevent what’s known as long-covid syndrome or post-acute sequelae of SARS-CoV-2 or PASC.
The study includes 6 arms that involve an experimental treatment arm called 1) “Metformin Only Group.” Here, those participating will receive metformin alone. Another placebo comparator group 2) “Treatment-Arm—Placebo Group” involves COVID-19 non-hospitalized participants that receive only a placebo. In a third Experimental arm called 3)“Ivermectin Only Group” participants, again COVID-19 positive but not requiring hospitalization (representing about 90% of all COVID-19 cases) involves participants receiving ivermectin alone.
Yet another Experimental arm includes 4) “Fluvoxamine Only Group” where participants meeting the inclusion criteria receive fluvoxamine alone. This is followed by another experimental group called the 5) “Metformin and Fluvoxamine Group” where study participants receive metformin and fluvoxamine. A final arm known as the 5) “Metformin and Ivermectin Group” and involves those patients meeting the inclusion criteria receiving both the generic diabetes drug and the common anti-parasitic drug used all over the world now for COVID-19.
Call to Action: Support the COVID-19-OUT study. If you know of someone that recently tested positive for COVID-19, they are potentially eligible regardless of location. Direct them to the study’s website.