Effect of Ivermectin vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19
Susanna Naggie, David R. Boulware, Christopher J. Lindsell, Thomas G. Stewart, Nina Gentile, Sean P. Collins, Matthew W. McCarthy, Dushyantha Jayaweera, Mario Castro, Mark Sulkowski, Kathleen M. McTigue, Florence Thicklin, G. Michael Felker, Adit A. Ginde, Carolyn T. Bramante, Alex Slandzicki, Ahab Gabriel, Nirav Shah, Leslie Lenert, Sarah E. Dunsmore, Stacey J. Adam, Allison DeLong, George J. Hanna, April Remaly, Rhonda Wilder, Sybil Wilson, Elizabeth Shenkman, Adrian F. Hernandez, Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-6) Study Group and Investigators, William Vincent, Raina Vincent, Ray Bianchi, Jen Premas, Diana Cordero-Loperena, E. M. Rivera, Madhu Gupta, Greg Karawan, Carey Ziomek, Joseph Arena, Sonaly DeAlmeida, Soroush Ramin, Jaya Nataraj, Michael K. Paasche‐Orlow, Lori Henault, Katie Waite, David Miller, Ginger Brounce, Constance George-Adebayo, Adeolu Adebayo, Jessica Wallan, Alex Slandzicki, 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, G. Michael Felker, Amanda Harrington, Rowena J Dolor, 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, Ahab Gabriel, Emad Ghaly, Dafer Al-Haddadin, Courtney Ramirez, Gammal Hassanien, Samah Ismail, Andrew Meltzer, Seamus Moran, Scott Brehaut, Angelina Roche, Manisha Mehta
Abstract
Importance: The effectiveness of ivermectin to shorten symptom duration or prevent hospitalization among outpatients in the US with mild to moderate symptomatic COVID-19 is unknown. Objective: To evaluate the efficacy of ivermectin, 400 μg/kg, daily for 3 days compared with placebo for the treatment of early mild to moderate COVID-19. Design, Setting, and Participants: ACTIV-6, an ongoing, decentralized, double-blind, randomized, placebo-controlled platform trial, was designed to evaluate repurposed therapies in outpatients with mild to moderate COVID-19. A total of 1591 participants aged 30 years and older with confirmed COVID-19, experiencing 2 or more symptoms of acute infection for 7 days or less, were enrolled from June 23, 2021, through February 4, 2022, with follow-up data through May 31, 2022, at 93 sites in the US. Interventions: Participants were randomized to receive ivermectin, 400 μg/kg (n = 817), daily for 3 days or placebo (n = 774). Main Outcomes and Measures: Time to sustained recovery, defined as at least 3 consecutive days without symptoms. There were 7 secondary outcomes, including a composite of hospitalization or death by day 28. Results: Among 1800 participants who were randomized (mean [SD] age, 48 [12] years; 932 women [58.6%]; 753 [47.3%] reported receiving at least 2 doses of a SARS-CoV-2 vaccine), 1591 completed the trial. The hazard ratio (HR) for improvement in time to recovery was 1.07 (95% credible interval [CrI], 0.96-1.17; posterior P value [HR >1] = .91). The median time to recovery was 12 days (IQR, 11-13) in the ivermectin group and 13 days (IQR, 12-14) in the placebo group. There were 10 hospitalizations or deaths in the ivermectin group and 9 in the placebo group (1.2% vs 1.2%; HR, 1.1 [95% CrI, 0.4-2.6]). The most common serious adverse events were COVID-19 pneumonia (ivermectin [n = 5]; placebo [n = 7]) and venous thromboembolism (ivermectin [n = 1]; placebo [n = 5]). Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with ivermectin, compared with placebo, did not significantly improve time to recovery. These findings do not support the use of ivermectin in patients with mild to moderate COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.