Abstract: Fluvoxamine for early treatment of COVID-19: the STOP COVID trials Eric Lenze, M.D. Wallace & Lucille Renard Professor of Psychiatry & Anesthesiology Washington University School of Medicine, St Louis, MO Lenze disclosures (past 36 months) • Grant support (non-federal): COVID Early Treatment Fund, Mercatus Center Emergent Ventures (Fast Grants), the Skoll Foundation, the Taylor Family Institute for Innovative Psychiatric Research, the Center for Brain Research in Mood Disorders, the Patient-Centered Outcomes Research Institute, Janssen, and the Barnes Jewish Foundation. • Consulting fees: Janssen, Jazz Pharmaceuticals. • Patent: Lenze & Reiersen have applied for a patent for the use of fluvoxamine in the treatment of COVID-19. Anatomy of innovations Pearl Kendrick & Grace Eldering • • • • • Unexpected people/places Serendipity + trial & error A collective enterprise Need freedom Need champions Rewind…March 25, 2020 To: Eric Lenze From: Angela Reiersen “…regarding the possibility of using SSRIs as potential treatment for COVID-19 cytokine storm…especially fluvoxamine” Angela Reiersen, M.D. (Washington University, St Louis) Observation of patients with Wolfram Syndrome (Rare genetic disorder with dysregulated Endoplasmic Reticulum (ER) Stress Response) Poor outcomes with sertraline; better with other SSRIs (including fluvoxamine) Review of pharmacology: Many SSRIs also affect another receptor, the Sigma-1 receptor (S1R) : Many are S1R agonists (activators); sertraline is S1R antagonist. Review of S1R literature: What do we know about the S1R and ER stress response? Dorian Rosen and Alban Gaultier (at University of Virginia) Fluvoxamine prevents death in mice exposed to inflammatory triggers (such as Fecal Induced Peritonitis [FIP])… …and reduces cytokine production in human blood exposed to Lipopolysaccharide (LPS, another inflammatory trigger) Rosen…& Gaultier, “Modification of the sigma-1 receptor-IRE1 pathway is beneficial in preclinical models of inflammation and sepsis.” Science Translational Medicine, 2019 Hypothesis: Fluvoxamine activates S1R and reduces IRE1-mediated inflammation • The S1R modulates the ER stress response, involved with virus-host interactions and cytokine production. • S1R agonist dampens inflammation and interferes with viral functions through inhibition of IRE1. From Sukhatme, Reiersen, et al, “Fluvoxamine: A review of its mechanism of action and its role in COVID-19”, Front Pharmacol 2021 S1R=sigma-1 receptor; ER=endoplasmic reticulum; IRE1=inositol-requiring 1 enzyme STOP COVID trial hypothesis: fluvoxamine, given early in COVID-19, prevents clinical deterioration Caline Mattar. M.D. Participants: n=152 age 18+ SARS CoV-2+ Community-dwelling Symptomatic (<7d) Intervention: Fluvoxamine x 15d Control: Placebo x 15d Outcomes: Primary: clinical deterioration (=SOB and/or hospitalization + O2 <92%) Secondary: -symptom change Participants surveyed twice daily x 15 days O2 saturation Vital signs Symptoms Reminder to take study medication 1st decision: start fast and be pragmatic Use EHR to screen for SARS-CoV-2 PCR+ persons, then e-consent Provide study supples (pills, pulse ox, BP cuff) and instructions 2nd decision: take the study to the patient 3rd decision: non-contact but high-touch Patients self-monitor and enter their data. We call them to check on their status. Many COVID trials failed. How we succeeded… 1st patient randomized July: finish recruitment May: recruitment,..