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Effect of Fluvoxamine vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19

McCarthy et al., JAMA, doi:10.1001/jama.2022.24100 (date from preprint), ACTIV-6, NCT04885530

Oct 2022

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Fluvoxamine

26th treatment shown to reduce risk in November 2021

^*, now known with p = 0.00014 from 21 studies, recognized in 3 countries.

Lower risk for mortality, hospitalization, progression, recovery, and cases.

No treatment is 100% effective. Protocols combine complementary and synergistic treatments. ^* >10% efficacy in meta analysis with ≥3 clinical studies.

4,100+ studies for 60+ treatments. c19early.org

RCT low-risk outpatients with very late treatment (median 5 days, 20% ≥8 days) in the USA, showing no significant differences with low-dose fluvoxamine treatment.

Many of the issues noted for the ivermectin arm Naggie also apply to this arm, for example none of the pre-specified outcomes have been reported fnih.org. In the ivermectin paper the abstract refers to the main post-hoc outcome as the "main outcome", this wording has been updated to "primary outcome" for fluvoxamine.

eFigure 4 shows efficacy continuously declining over time, which may be due to lower severity as the virus evolves. Treatment delay was up to 13 days (eFigure 1). Severe dyspnea at baseline was more common for fluvoxamine (6/586 vs. 3/533, eTable 1).

Authors state that the median treatment delay (5 days) is at the upper limit of the "recommend (sic) start of antiviral medicines (≤5 days)". There is no reference and it's unclear who recommends such late treatment.

Fluvoxamine 50mg twice daily.

1. fnih.org, www.fnih.org/sites/default/files/2021-07/ACTIV-6%20Protocol%20V1.0_01APR2021.pdf.www.fnih.org/sites/default/files/2021-07/ACTIV-6%20Protocol%20V1.0_01APR2021.pdf.

2. Naggie et al., Effect of Ivermectin vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19: A Randomized Clinical Trial, JAMA, doi:10.1001/jama.2022.18590.jamanetwork.com, doi.org.

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risk of hospitalization, 55.0% lower, RR 0.45, p = 0.51, treatment 1 of 670 (0.1%), control 2 of 607 (0.3%), NNT 555, day 28.

C19 pneumonia, 67.6% lower, RR 0.32, p = 0.48, treatment 0 of 615 (0.0%), control 1 of 565 (0.2%), NNT 565, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), C19 pneumonia, eTable 2.

risk of progression, 10.0% higher, RR 1.10, p = 0.78, treatment 26 of 670 (3.9%), control 23 of 607 (3.8%), adjusted per study, urgent or emergency care visits, hospitalizations, or death.

risk of no recovery, 4.2% higher, HR 1.04, p = 0.45, treatment 674, control 614, inverted to make HR<1 favor treatment, post-hoc primary outcome.

clinical progression, 28.0% higher, OR 1.28, p = 0.33, treatment 670, control 607, mid-recovery, day 7, RR approximated with OR.

clinical progression, 17.0% higher, OR 1.17, p = 0.68, treatment 670, control 607, day 14, RR approximated with OR.

clinical progression, 47.0% higher, OR 1.47, p = 0.16, treatment 670, control 607, day 28, RR approximated with OR.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

McCarthy et al., 18 Oct 2022, Double Blind Randomized Controlled Trial, placebo-controlled, USA, peer-reviewed, mean age 48.5, 243 authors, study period 6 August, 2021 - 27 May, 2022, average treatment delay 5.0 days, trial NCT04885530 (history) (ACTIV-6). Contact: naggie@duke.edu.

This Paper Fluvoxamine All

Effect of Fluvoxamine vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19

MD Matthew W Mccarthy, MD, MHS Susanna Naggie, MD, MPH David R Boulware, PhD Christopher J Lindsell, PhD Thomas G Stewart, G Michael Felker, MD Dushyantha Jayaweera, MD Mark Sulkowski, MD Nina Gentile, MD, MPH Carolyn Bramante, MD Upinder Singh, MD, MHS Rowena J Dolor, MD Juan Ruiz-Unger, RN Sybil Wilson, Allison Delong, April Remaly, Rhonda Wilder, MD, MSci Sean Collins, PhD; Sarah E Dunsmore, PhD; Stacey J Adam, Florence Thicklin, MD George Hanna, MD, MPH Adit A Ginde, MD, MPH Mario Castro, MD, MPH, MS Kathleen Mctigue, PhD Elizabeth Shenkman, MD, MHS Adrian F Hernandez, William (kelly) Vincent, Raina Vincent, Ray Bianchi, Jen Premas, Diana Cordero-Loperena Evelyn Rivera, Madhu Gupta, Greg Karawan, Carey Ziomek, Joseph Arena, Sonaly Dealmeida, Soroush Ramin, Jaya Nataraj, Michael Paasche-Orlow, Lori Henault, Katie Waite, David Miller, Ginger Brounce, Constance George-Adebayo, Adeolu Adebayo, Jessica Wallan, Claudia Vogel, Sebastian Munoz, David Kavtaradze, Cassandra Watson, David Singleton, Maria Rivon, Amanda Sevier, Arnold Del Pilar, Amber Spangler, Sohail Rao, Luis Cantu, Arvind Krishna, Kathy Evans, Tylene Falkner, Brandi Kerr, Robert Spees, Mailyn Marta, Amanda Harrington, Madison Frazier, Lorraine Vergara, Jessica Wilson, Valencia Burruss, Terri Hurst, Igho Ofotokun, Laurel Bristow, Rajesh Prabhu, Krystal Klicka, Amber Lightfeather, Vicki James, Marcella Rogers, Pradeep Parihar, De'ambra Torress, Chukwuemeka Oragwu, Ngozi Oguego, Rajesh Pillai, Mustafa Juma, Emad Ghaly, Dafer Al-Haddadin, Courtney Ramirez, Gammal Hassanien, Samah Ismail, Andrew Meltzer, Seamus Moran, Scott Brehaut, Angelina Roche, Manisha Mehta, Nicole Koppinger, Jose Baez, Ivone Pagan, Dallal Abdelsayed, Mina Aziz, Philip Robinson, Julie Nguyen, Victoria Pardue, Llisa Hammons, Susan Gonzalez, Lionel Reyes, John Cienki, Gisselle Jimenez, Jonathan Cohen, Matthew Wong, Ying Yuan, Jeremy Szeto, Lauren Stelmash, Arch Amon, Daniel Haight, Deryl Lamb, Amron Harper, Nancy Pyram-Bernard, Arlen Quintero, Eftim Adhami, Josette Maria, Diksha Paudel, Oksana Raymond, Jeffrey Summers, Tammy Turner, Sam Gallegos, Elizabeth Ann Szwast, Ahsan Abdulghani, Pravin Vasoya, Conrad Miller, Hawa Wiley, Tovah Klein, Julie Castex, Phillip Feliciano, Jacqueline Olivo, Marian Ghaly, Zainub Javed, Alexandra Nawrocki, Anthony Vecchiarelli, Nikki Vigil, Vijaya Cherukuri, Erica Burden, Dawn Linn, Laura Fisher, Vijay Patel, Praksha Patel, Yuti Patel, Leonard Ellison, Jeffrey Harrison, Binod Shah, Sugata Shah, Upinder Shah, Julia Donahue, Yasmin Jazayeri, Anita Gupta, N Chandrasekar, Beth Moritz, Tabitha Fortt, Anisa Fortt, Ingrid Jones-Ince, Alix Mckee, Christy Schattinger, Jason Wilson, Brenda Farlow, Lillian Finlaw, Randall Richwine, Tearani Williams, Penny Paizer, Lisa Carson, Edward Michelson, Danielle Austin, Sangeeta Khetpal, Tiffany Cantrell, Drew Franklin, Karissa Marshall, Arvind Mahadevan, Madelyn Rosequist, Martin Gnoni, Crystal Daffner, Carla Vandeweerd, Mitchell Roberts, Mark D'andrea, Stephen Lim, Wayne Swink, Margaret Powers-Fletcher, Sylvere Mukunzi, Jamie Hensley, Brittney Manning, Carmen Isache, Jennifer Bowman, Angelique Callaghan-Brown, Taylor Scott, Tiffany Schwasinger-Schmidt, Ashlie Cornejo, Maria Almanzar, Letty Ginsburg, Americo Hajaz, Matthew Robinson, Michelle Seithel, Akira Sekikawa, Emily Klawson, Luis Ostrosky, Virginia Umana, Thomas Patterson, Robin Tragus, Patrick Jackson, Caroline Hallowell, Heather Haughey, Bhavna Vaidya-Tank, Cameron Gould, Parul Goyal, Carly Gatewood, John Williamson, Hannah Seagle, Elizabeth Salsgiver, Eddie Armas, Jhonsai Cheng, Priscilla Huerta, Julia Garcia-Diaz, David Aamodt, Jamario Ayers, Jess Collins, John Graves, James Grindstaff, Jessica Lai, Itzel Lopez, Jessica Marlin, Alyssa Merkel, Sam Nwosu, Savannah Obregon, Dirk Orozco, Yoli Perez-Torres, Nelson Prato, Colleen Ratcliff, Max Rhode, Russell Rothman, Jana Shirey-Rice, Krista Vermillion, Hsi-Nien Tan, Seibert Tregoning, Meghan Vance, Amber Vongsamphanh, Maria Weir, Nicole Zaleski

JAMA, doi:10.1001/jama.2022.24100

for the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)-6 Study Group and Investigators IMPORTANCE The effectiveness of fluvoxamine to shorten symptom duration or prevent hospitalization among outpatients with mild to moderate symptomatic COVID-19 is unclear. OBJECTIVE To evaluate the efficacy of low-dose fluvoxamine (50 mg twice daily) for 10 days compared with placebo for the treatment of mild to moderate COVID-19 in the US. DESIGN, SETTING, AND PARTICIPANTS The ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-6) platform randomized clinical trial was designed to test repurposed medications in outpatients with mild to moderate COVID-19. A total of 1288 participants aged 30 years or older with test-confirmed SARS-CoV-2 infection and experiencing 2 or more symptoms of acute COVID-19 for 7 days or less were enrolled between August 6, 2021, and May 27, 2022, at 91 sites in the US. INTERVENTIONS Participants were randomized to receive 50 mg of fluvoxamine twice daily for 10 days or placebo. MAIN OUTCOMES AND MEASURES The primary outcome was time to sustained recovery (defined as the third day of 3 consecutive days without symptoms). There were 7 secondary outcomes, including a composite outcome of hospitalization, urgent care visit, emergency department visit, or death through day 28. RESULTS Among 1331 participants who were randomized (median age, 47 years [IQR, 38-57 years]; 57% were women; and 67% reported receiving Ն2 doses of a SARS-CoV-2 vaccine), 1288 completed the trial (674 in the fluvoxamine group and 614 in the placebo group). The median time to sustained recovery was 12 days (IQR, 11-14 days) in the fluvoxamine group and 13 days (IQR, 12-13 days) in the placebo group (hazard ratio [HR], 0.96 [95% credible interval, 0.86-1.06], posterior P = .21 for the probability of benefit [determined by an HR >1]). For the composite outcome, 26 participants (3.9%) in the fluvoxamine group were hospitalized, had an urgent care visit, had an emergency department visit, or died compared with 23 participants (3.8%) in the placebo group (HR, 1.1 [95% credible interval, 0.5-1.8], posterior P = .35 for the probability of benefit [determined by an HR <1]). One participant in the fluvoxamine group and 2 participants in the placebo group were hospitalized; no deaths occurred in either group. Adverse events were uncommon in both groups. CONCLUSIONS AND RELEVANCE Among outpatients with mild to moderate COVID-19, treatment with 50 mg of fluvoxamine twice daily for 10 days, compared with placebo, did not improve time to sustained recovery. These findings do not support the use of fluvoxamine at this dose and duration in patients with mild to moderate COVID-19.

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Late treatment
is less effective

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