Higher-Dose Fluvoxamine and Time to Sustained Recovery in Outpatients With COVID-19
Authors: Stewart Thomas G. , Rebolledo Paulina A. , Mourad Ahmad , Lindsell Christopher J. , Boulware David R. , McCarthy Matthew W. , Thicklin Florence , Garcia del Sol Idania T. , Bramante Carolyn T. , Lenert Leslie A. , Lim Stephen , Williamson John C. , Cardona Orlando Quintero , Scott Jake , Schwasinger-Schmidt Tiffany , Ginde Adit A. , Castro Mario , Jayaweera Dushyantha , Sulkowski Mark , Gentile Nina , McTigue Kathleen , Felker G. Michael , DeLong Allison , Wilder Rhonda , Rothman Russell L. , Collins Sean , Dunsmore Sarah E. , Adam Stacey J. , Hanna George J. , Shenkman Elizabeth , Hernandez Adrian F. , Naggie Susanna ,   Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)-6 Study Group and Investigators, Fraser Ryan , Ward Mark , Gamboa Jackman Jennifer , McAdams M. Patricia , Vail Julia , Korzekwinski Kayla , Oyelakin Martina , Chopp Julie , Randle Desmon , Dockery Samantha , Adkins Rodney , Crow Mathew , Nowell Erin , Wells Kadie , Herbert Alicia , Stone Allegra , Heavlin Heather , Brown Linley , Harding Tina , Harrington Amanda , Beauchaine Meaghan , Lindblom Kelly , Burns Andrea , Aamodt David , Collins Jess , Dixon Sheri , Gao Yue , Graves John , Grindstaff James , Harrell Frank , Lai Jessica , Liao Vicky , Lopez Itzel , Manis Elizabeth , Mankowski Kalley , Marlin Jessica , Merkel Alyssa , Nwosu Sam , Obregon Savannah , Orozco Dirk , Prato Nelson , Rohde Max , Shirey-Rice Jana , Vermillion Krista , Smith Jacob , Tan Hsi-nien , Vance Meghan , Weir Maria , Vincent William (Kelly) , Vincent Raina , Bianchi Ray , Premas Jen , Cordero-Loperena Diana , Rivera Evelyn , Gupta Madhu , Karawan Greg , Arena Joseph , DeAlmeida Sonaly , Ramin Soroush , Nataraj Jaya , Dedier Julien , Ramirez Ana Maria , Waite Katherine , Okulicz Jason , Marcus Joseph , Southwell Alexis , Jacques Genice , Sexton Cedar , Miller David , Brounce Ginger , George-Adebayo Constance , Adebayo Adeolu , Zapatero Jose , Clement Julie , Ronan Theresa , Woods Ashley , Gallegos Christopher , Flys Tamara , Sloan Olivia , Olofintuyi Anthony , Samraj Joshua , Samraj Jackelyn , Vasbinder Alma , Averett Amaya , Slandzicki Alex , Milstone Aaron , Wallan Jessica , Robbs Lindsey , Vogel Claudia , Munoz Sebastian , Kavtaradze David , Watson Casandra , Singleton David , Sevier Marcus , Rivon Maria , Del Pilar Arnold , Spangler Amber , Rao Sohail , Cantu Luis , Krishna Arvind , Daugherty Heidi , Kerr Brandi , Evans Kathy , Spees Robert , Marta Mailyn , Dolor Rowena , Vergara Lorraine , Jordan Jackie , Burruss Valencia , Hurst Terri , Ofotokun Igho , Rebolledo Paulina A. , Zhang Cecilia , Smith Veronica E. , Prabhu Rajesh , Klicka Krystal , Lightfeather Amber , James Vickie , Rogers Marcella , Parihar Pradeep , Torress De'Ambra , Oragwu Chukwuemeka , Oguego Ngozi , Pillai Rajesh , Juma Mustafa , Gabriel Ahab , Ghaly Emad , Michal Marian , Vasquez Michelle , Mamon Angela , Sheets Michelle , Hassanien Gammal , Ismail Samah , Samir Yehia , Meltzer Andrew , Shahamatdar Soroush , Heidish Ryan S. , Brehaut Scott , Roche Angelina , Mehta Manisha , Koppinger Nicole , Baez Jose , Pagan Ivone , Abdelsayed Dallal , Aziz Mina , Robinson Philip , Lozinski Grace , Nguyen Julie , Griffin Alvin , Morris Michael , Love Nicole , Mattox Bonnie , Martin Raykel , Pardue Victoria , Rowland Teddy , Ruiz-Unger Juan , Reyes Lionel , Zamora Yadira , Bacallao Navila , Cienki John , Cohen Jonathan , Yuan Ying , Li Jenny , Szeto Jeremy , Sulkowski Mark , Stelmash Lauren , Garcia del Sol Idania , Morales Castillo Ledular , Gutierrez Anya , Prieto Sabrina , Amon Arch , Barbera Andrew , Bugajski Andrew , Wills Walter , Jacklin Kellcee , Lamb Deryl , Harper Amron , Stout Elmer , Weeks Katherine , Griffin Merischia , Pyram-Bernard Nancy , Quintero Arlen , Adhami Eftim , Carrillo Giovanni , Maria Josette , Paudel Diksha , Raymond Oksana , Summers Jeffrey , Turner Tammy , Panaccione Ebony , Szwast Elizabeth , Abdulghani Ahsan , Vasoya Pravin , Miller Conrad , Wiley Hawa , Chan Austin , Khizer Saadia , Shah Nirav , Adeyemi Oluwadamilola , Chi Wei Ning , Chen July , Morton-Jost Melissa , Castex Julie , Feliciano Phillip , Olivo Jacqueline , Maldonado Maria , Vecchiarelli Anthony , Gaytan-Alvarez Diana , Cherukuri Vijaya , Lima Santia , Alicic Radica , Lambert Allison A. , Urbat Carissa , Baxter Joni , Cooper Ann , Linn Dawn , Fisher Laura , Patel Vijay , Patel Yuti , Talati Roshan , Patel Priti , Ellison Leonard , Roman Angee , Harrison Jeffrey , Moy James , Naquiallah Dina , Shah Binod , Singh Upinder , Jazayeri Yasmin , O’Donnell Andrew , Quintero Orlando , Pathak Divya , Gupta Anita , Chandrasekar N , Curtis Clifford , White Briana , Dockery Martha , Hicks Maya , Fortt Tabitha , Fortt Anisa , Jones-Ince Ingrid , McKee Alix , Wilson Jason , Farlow Brenda , Gentile Nina , Grady Casey , Richwine Randall , Williams Tearani , Pazier Penny , Michelson Edward , Watts Susan , Kariyawasam Diluma , Rodriguez Leann , Luis Garcia Jose , Manresa Ismarys , Achong Angel , Garcia Mari , Khetpal Sangeeta , Posey Faith , Mahadevan Arvind , Gnoni Martin , VandeWeerd Carla , Sappington Erica , Roberts Mitchell , Wang Jennifer , Adams Melissa , Ding Xinyi , D'Andrea Mark , Lim Stephen , Swink Wayne , Bozant Emily , Powers-Fletcher Margaret , Miller Delia , Mukunzi Sylvere , Manning Brittney , Isache Carmen , Bowman Jennifer , Callaghan-Brown Angelique , Martin Debra , Ast Ashley , Duran Brent , Cornejo Ashlie , Archer Allie , Jayaweera Dushyantha , Almanzar Maria , Motel Vanessa , Bhat Neeta , Parra Daniela , Pullen Matthew , Campora Paula , Robinson Matthew , Seithel Michelle , Sekikawa Akira , Klawson Emily , Arnold Jonathan , Ostrosky-Zeichner Luis , Umana Virginia , Nielsen Laura , Grimes Carolyn Z. , Patterson Thomas F. , Tragus Robin , Soileau Bridgette T. , Jackson Patrick E.H. , Hallowell Carolina , Haughey Heather M. , Vaidya-Tank Bhavna , Gould Cameron , Goyal Parul , Sommers Sue , Pangburn Haley , Jones Carly , Williamson John , Abbott Rica , Seagle Hannah , DeComarmond Mathias , Pickell Nicholas , Umana Unwana , Alleyne Candace , Armas Eddie , Perez Landabur Ramon O. , De La Cruz Michelle , Ballmajo Martha 
Published: November 2023

Importance

The effect of higher-dose fluvoxamine in reducing symptom duration among outpatients with mild to moderate COVID-19 remains uncertain.

Objective

To assess the effectiveness of fluvoxamine, 100 mg twice daily, compared with placebo, for treating mild to moderate COVID-19.

Design, Setting, and Participants

The ACTIV-6 platform randomized clinical trial aims to evaluate repurposed medications for mild to moderate COVID-19. Between August 25, 2022, and January 20, 2023, a total of 1175 participants were enrolled at 103 US sites for evaluating fluvoxamine; participants were 30 years or older with confirmed SARS-CoV-2 infection and at least 2 acute COVID-19 symptoms for 7 days or less.

Interventions

Participants were randomized to receive fluvoxamine, 50 mg twice daily on day 1 followed by 100 mg twice daily for 12 additional days (n = 601), or placebo (n = 607).

Main Outcomes and Measures

The primary outcome was time to sustained recovery (defined as at least 3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of hospitalization, urgent care visit, emergency department visit, or death; COVID-19 clinical progression scale score; and difference in mean time unwell. Follow-up occurred through day 28.

Results

Among 1208 participants who were randomized and received the study drug, the median (IQR) age was 50 (40-60) years, 65.8% were women, 45.5% identified as Hispanic/Latino, and 76.8% reported receiving at least 2 doses of a SARS-CoV-2 vaccine. Among 589 participants who received fluvoxamine and 586 who received placebo included in the primary analysis, differences in time to sustained recovery were not observed (adjusted hazard ratio [HR], 0.99 [95% credible interval, 0.89-1.09]; P for efficacy = .40]). Additionally, unadjusted median time to sustained recovery was 10 (95% CI, 10-11) days in both the intervention and placebo groups. No deaths were reported. Thirty-five participants reported health care use events (a priori defined as death, hospitalization, or emergency department/urgent care visit): 14 in the fluvoxamine group compared with 21 in the placebo group (HR, 0.69 [95% credible interval, 0.27-1.21]; P for efficacy = .86) There were 7 serious adverse events in 6 participants (2 with fluvoxamine and 4 with placebo) but no deaths.

Conclusions and Relevance

Among outpatients with mild to moderate COVID-19, treatment with fluvoxamine does not reduce duration of COVID-19 symptoms.

Trial Registration

ClinicalTrials.gov Identifier: NCT04885530