On December 17, 2020, Lenze and colleagues began a new nationwide, fully remote (internet-based) Phase III randomized controlled trial named STOP COVID 2 (StopCovidTrial.com; ClinicalTrials.gov: NCT04668950) to confirm the initial results from their preliminary trial. This trial is taking place in the USA and Canada, with nation-wide internet-based enrollment and telemedicine appointments for all study interactions. The preliminary trial (STOP COVID) resulted in few cases of clinical deterioration overall due to limited sample size and relatively young and healthy participants, resulting in low precision of the effect size estimate . STOP COVID 2 aimed to recruit 1100 participants with eligibility criteria similar to the first trial (SARS-CoV-2 positive and symptomatic within 7 days of symptoms onset, residing in the community rather than in a hospital or other institutional setting); however, in this trial the sample was enriched, with participants needing to have one or more of the following risk factors for more severe COVID-19: aged ≥ 40 years, obesity, diabetes, hypertension, heart disease, lung disease, an immune condition, and/or being African American, Latinx, or Native American.
On May 19, 2021, STOP COVID 2 stopped enrolling new participants on the advice of the Data and Safety Monitoring Board, based on an overall lower rate of clinical deterioration than anticipated (leading to a much larger sample size necessary to observe the a priori minimum detectable effect), the decreasing number of volunteers enrolling in the trial, and their review of the unblinded interim results to date. There were no adverse safety signals, but due to successful vaccination roll-out in the USA and Canada, the trial was no longer expected to accrue the needed number of participants. Participants already enrolled in the trial finished their assigned doses of therapy and will complete the planned follow-up questionnaires at 15 and ~90 days to assess short- and long-term secondary outcomes. This trial has the same duration and primary outcome as the initial trial (clinical deterioration within 15 days of enrollment, defined by dyspnea and hypoxia), but has lower dosing: 100 mg twice/day, instead of three times daily for 15 days, of either fluvoxamine or placebo. With enrollment halted, the trial will not have the required sample size and statistical power to detect an effect of fluvoxamine on the primary outcome. However, this trial also includes a secondary outcome of health functioning and symptoms assessed at 15 days and again at 3 months, measured by the Global Health Scale , and an exploratory symptom questionnaire to assess any effect of fluvoxamine on long-term COVID-19 morbidity.
In January 2021, Drs Bramante, Boulware, and colleagues at the University of Minnesota; Northwestern University; University of Colorado, Denver; UCLA Olive View; and OptumLabs began stage 1 of a Phase III, factorial randomized clinical trial known as COVID-19-OUT (covidout.com; ClinicalTrials.gov: NCT04510194). The initial stage of the quadruple-blinded trial enrolled 70 patients, with the fully enrolled trial having a planned 1160 participants. This factorial trial has five experimental arms (fluvoxamine only, metformin only, ivermectin only, metformin plus fluvoxamine, or metformin plus ivermectin), with one placebo arm. Adults aged 30 to 85 years are eligible for inclusion within ≤ 3 days of a positive PCR test for SARS-CoV-2 infection if they are asymptomatic or have had symptoms for < 7 days before randomization, enroll within 3 days of testing, have a body mass index ≥ 25 kg/m2 by self-report height/weight or ≥ 23 kg/m2 for patients who self-identify as South Asian or Latinx. A glomerular filtration rate (GFR) will be obtained in persons older than age 75 years or who have a history of heart, kidney, or liver failure if a GFR is not visible within the electronic health record within 2 weeks, to ensure these high-risk individuals have a GFR > 45 mL/min. The primary outcome measures are (1) decreased oxygenation at 14 days (defined as pulse oxygen saturation ≤ 93 % on home monitoring), (2) emergency department utilization for COVID-19 symptoms at 14 days (and/or hospitalization/death), and (3) post-acute sequelae of SARS-CoV-2 infection (PASC) assessment at 6 and 12 months. This trial is currently enrolling.
Another trail also enrolling is ACTIV-6 (ClinicalTrials.gov: NCT04885530), which is a Phase III, placebo-controlled, randomized trial, run by Dr. Naggie at Duke Clinical Research Institute. This trial has three experimental arms (ivermectin, fluvoxamine, and fluticasone), with a placebo comparator arm matched to each experimental arm. Both participants and the study teams know which study drug they have been allocated but are blinded to whether they are in the experimental or placebo comparator arms for that study drug. Adults aged ≥ 30 years with SARS-CoV-2 infection confirmed within 10 days of study screening with two or more current symptoms of acute SARS-CoV-2 infection (fatigue, dyspnea, fever, cough, nausea, vomiting, diarrhea, body aches, chills, headache, sore throat, nasal symptoms, or new loss of sense of taste or smell) began enrolling in this study on June 8, 2021, with a goal of enrolling 15,000 participants before a primary completion date of December 2022. The primary outcome measures of this trial are the number of hospitalizations, number of deaths, and number of symptoms within 14 days, as measured by patient reports.
Finally, another randomized controlled trial of fluvoxamine and COVID-19 is underway in Hungary: SigmaDrugs Research Ltd. is currently recruiting for a Phase II trial (ClinicalTrials.gov: NCT04718480), studying the time to clinical recovery after treatment with 74 days of fluvoxamine 100 mg taken twice daily, compared to placebo. Up to 100 adults who have moderately severe cases of COVID-19 (having each of the following: dyspnea without respiratory distress, a respiration rate 22–29 times per minute, resting pulse oxygen saturation ≥ 93%, and pneumonia with pulmonary infiltrates occupying ≤ 50% of the lung-fields) will be enrolled. The primary endpoint of clinical recovery includes resolving to normal any three of the following four clinical indicators: fever, respiratory rate, pulse oxygen saturation, and cough burden. This study has an estimated completion date of December 2021.
Multiple studies of the mechanisms of fluvoxamine's effect on SARS-CoV-2 are also currently underway, including in vitro and animal studies at multiple institutions. Publication of findings from these pending studies is eagerly awaited, as they will offer meaningful contributions to our understanding of how and why early treatment with fluvoxamine may have a beneficial effect on COVID-19–related morbidity and mortality.