Effect of Higher-Dose Ivermectin for 6 Days vs Placebo on Time to Sustained Recovery in Outpatients With COVID-19
Susanna Naggie, David R. Boulware, Christopher J. Lindsell, Thomas G. Stewart, Alex Slandzicki, Stephen C. Lim, Jonathan B. Cohen, David Kavtaradze, Arch Amon, Ahab Gabriel, Nina Gentile, G. Michael Felker, Dushyantha Jayaweera, Matthew W. McCarthy, Mark Sulkowski, Russell L. Rothman, Sybil Wilson, Allison DeLong, April Remaly, Rhonda Wilder, Sean P. Collins, Sarah E. Dunsmore, Stacey J. Adam, Florence Thicklin, George J. Hanna, Adit A. Ginde, Mario Castro, Kathleen M. McTigue, 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, Claudia Vogel, Sebastian Munoz, 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, Rowena J Dolor, Madison Frazier, Lorraine Vergara, Jessica Wilson, Valencia Burruss, Terri Hurst, Igho Ofotokun, Pauline Rebolledo, 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
Abstract
Importance: It is unknown whether ivermectin, with a maximum targeted dose of 600 μg/kg, shortens symptom duration or prevents hospitalization among outpatients with mild to moderate COVID-19. Objective: To evaluate the effectiveness of ivermectin at a maximum targeted dose of 600 μg/kg daily for 6 days, compared with placebo, for the treatment of early mild to moderate COVID-19. Design, Setting, and Participants: The ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines 6 (ACTIV-6) platform randomized clinical trial was designed to evaluate repurposed therapies among outpatients with mild to moderate COVID-19. A total of 1206 participants older than 30 years with confirmed COVID-19 experiencing at least 2 symptoms of acute infection for less than or equal to 7 days were enrolled at 93 sites in the US from February 16, 2022, through July 22, 2022, with follow-up data through November 10, 2022. Interventions: Participants were randomly assigned to receive ivermectin, with a maximum targeted dose of 600 μg/kg (n = 602) daily, or placebo (n = 604) for 6 days. Main Outcomes and Measures: The primary outcome was time to sustained recovery, defined as at least 3 consecutive days without symptoms. The 7 secondary outcomes included a composite of hospitalization, death, or urgent/emergent care utilization by day 28. Results: Among 1206 randomized participants who received study medication or placebo, the median (IQR) age was 48 (38-58) years, 713 (59.1%) were women, and 1008 (83.5%) reported receiving at least 2 SARS-CoV-2 vaccine doses. The median (IQR) time to sustained recovery was 11 (11-12) days in the ivermectin group and 11 (11-12) days in the placebo group. The hazard ratio (posterior probability of benefit) for improvement in time to recovery was 1.02 (95% credible interval, 0.92-1.13; P = .68). Among those receiving ivermectin, 34 (5.7%) were hospitalized, died, or had urgent or emergency care visits compared with 36 (6.0%) receiving placebo (hazard ratio, 1.0 [95% credible interval, 0.6-1.5]; P = .53). In the ivermectin group, 1 participant died and 4 were hospitalized (0.8%); 2 participants (0.3%) were hospitalized in the placebo group and there were no deaths. Adverse events were uncommon in both groups. Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with ivermectin, with a maximum targeted dose of 600 μg/kg daily for 6 days, compared with placebo did not improve time to sustained recovery. These findings do not support the use of ivermectin in patients with mild to moderate COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.