Effect of Higher-Dose Ivermectin for 6 Days vs Placebo on Time to Sustained Recovery in Outpatients With COVID-19
Authors: Naggie Susanna , Boulware David R. , Lindsell Christopher J. , Stewart Thomas G. , Slandzicki Alex J. , Lim Stephen C. , Cohen Jonathan , Kavtaradze David , Amon Arch P. , Gabriel Ahab , Gentile Nina , Felker G. Michael , Jayaweera Dushyantha , McCarthy Matthew W. , Sulkowski Mark , Rothman Russell L. , Wilson Sybil , DeLong Allison , Remaly April , Wilder Rhonda , Collins Sean , Dunsmore Sarah E. , Adam Stacey J. , Thicklin Florence , Hanna George J. , Ginde Adit A. , Castro Mario , McTigue Kathleen , Shenkman Elizabeth , Hernandez Adrian F. ,   Accelerating Covid-19 Therapeutic Interventions and Vaccines (ACTIV)-6 Study Group and Investigators, Vincent William (Kelly) , Vincent Raina , Bianchi Ray , Premas Jen , Cordero-Loperena Diana , Rivera Evelyn , Gupta Madhu , Karawan Greg , Ziomek Carey , Arena Joseph , DeAlmeida Sonaly , Ramin Soroush , Nataraj Jaya , Paasche-Orlow Michael , Henault Lori , Waite Katie , Miller David , Brounce Ginger , George-Adebayo Constance , Adebayo Adeolu , Wallan Jessica , Vogel Claudia , Munoz Sebastian , Watson Cassandra , Singleton David , Rivon Maria , Sevier Amanda , Del Pilar Arnold , Spangler Amber , Rao Sohail , Cantu Luis , Krishna Arvind , Evans Kathy , Falkner Tylene , Kerr Brandi , Spees Robert , Marta Mailyn , Harrington Amanda , Dolor Rowena , Frazier Madison , Vergara Lorraine , Wilson Jessica , Burruss Valencia , Hurst Terri , Ofotokun Igho , Rebolledo Pauline , Prabhu Rajesh , Klicka Krystal , Lightfeather Amber , James Vicki , Rogers Marcella , Parihar Pradeep , Torress De'Ambra , Oragwu Chukwuemeka , Oguego Ngozi , Pillai Rajesh , Juma Mustafa , Ghaly Emad , Al-Haddadin Dafer , Ramirez Courtney , Hassanien Gammal , Ismail Samah , Meltzer Andrew , Moran Seamus , Brehaut Scott , Roche Angelina , Mehta Manisha , Koppinger Nicole , Baez Jose , Pagan Ivone , Abdelsayed Dallal , Aziz Mina , Robinson Philip , Nguyen Julie , Pardue Victoria , Hammons Lisa , Ruiz-Unger Juan , Gonzalez Susan , Reyes Lionel , Cienki John , Jimenez Gisselle , Wong Matthew , Yuan Ying , Li Jenny , Szeto Jeremy , Stelmash Lauren , Haight Daniel , Lamb Deryl , Harper Amron , Pyram-Bernard Nancy , Quintero Arlen , Adhami Eftim , Maria Josette , Paudel Diksha , Raymond Oksana , Summers Jeffrey , Turner Tammy , Lenert Leslie , Gallegos Sam , Szwast Elizabeth Ann , Abdulghani Ahsan , Vasoya Pravin , Miller Conrad , Wiley Hawa , Shah Nirav , Klein Tovah , Castex Julie , Feliciano Phillip , Olivo Jacqueline , Ghaly Marian , Javed Zainub , Nawrocki Alexandra , Vecchiarelli Anthony , Vigil Nikki , Cherukuri Vijaya , Burden Erica , Linn Dawn , Fisher Laura , Patel Vijay , Patel Praksha , Patel Yuti , Ellison Leonard , Harrison Jeffrey , Shah Binod , Shah Sugata , Singh Upinder , Donahue Julia , Jazayeri Yasmin , Gupta Anita , Chandrasekar N , Moritz Beth , Fortt Tabitha , Fortt Anisa , Jones-Ince Ingrid , McKee Alix , Schattinger Christy , Wilson Jason , Farlow Brenda , Finlaw Lillian , Richwine Randall , Williams Tearani , Paizer Penny , Carson Lisa , Michelson Edward , Austin Danielle , Khetpal Sangeeta , Cantrell Tiffany , Franklin Drew , Marshall Karissa , Mahadevan Arvind , Rosequist Madelyn , Gnoni Martin , Daffner Crystal , VandeWeerd Carla , Roberts Mitchell , D'Andrea Mark , Swink Wayne , Powers-Fletcher Margaret , Mukunzi Sylvere , Hensley Jamie , Manning Brittney , Isache Carmen , Bowman Jennifer , Callaghan-Brown Angelique , Scott Taylor , Schwasinger-Schmidt Tiffany , Cornejo Ashlie , Almanzar Maria , Ginsburg Letty , Hajaz Americo , Bramante Carolyn , Robinson Matthew , Seithel Michelle , Sekikawa Akira , Klawson Emily , Ostrosky Luis , Umana Virginia , Patterson Thomas , Tragus Robin , Jackson Patrick , Hallowell Caroline , Haughey Heather , Vaidya-Tank Bhavna , Gould Cameron , Goyal Parul , Gatewood Carly , Williamson John , Seagle Hannah , Salsgiver Elizabeth , Armas Eddie , Cheng Jhonsai , Huerta Priscilla , Garcia-Diaz Julia , Aamodt David , Ayers JaMario , Collins Jess , Graves John , Grindstaff James , Lai Jessica , Lopez Itzel , Marlin Jessica , Merkel Alyssa , Nwosu Sam , Obregon Savannah , Orozco Dirk , Perez-Torres Yoli , Prato Nelson , Ratcliff Colleen , Rhode Max , Shirey-Rice Jana , Vermillion Krista , Tan Hsi-Nien , Tregoning Seibert , Vance Meghan , Vongsamphanh Amber , Weir Maria , Zaleski Nicole , Bozzette Samuel , Passamani Gene 
Published: February 2023

ImportanceIt 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.ObjectiveTo 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 ParticipantsThe 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 1432 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.InterventionsParticipants were randomly assigned to receive ivermectin, with a maximum targeted dose of 600 μg/kg (n = 708) daily, or placebo (n = 724) for 6 days.Main Outcomes and MeasuresThe 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.ResultsAmong 1432 randomized participants who received study medication or placebo, the median (IQR) age was 48 (38-58) years, 854 (59.6%) were women, and 1188 (83.1%) 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 12 (11-12) days in the placebo group. The hazard ratio for improvement in time to recovery was 1.02 (95% credible interval, 0.92-1.12; P value for efficacy = .65). Among those receiving ivermectin, 39 (5.5%) were hospitalized, died, or had urgent or emergency care visits compared with 42 (5.8%) receiving placebo (hazard ratio, 0.97 [95% credible interval, 0.60-1.45]; P = .55). In the ivermectin group, 1 participant died and 6 were hospitalized (1.0%); 2 participants (0.3%) were hospitalized in the placebo group and there were no deaths. Adverse events were uncommon in both groups.Conclusions and RelevanceAmong 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 RegistrationClinicalTrials.gov Identifier: NCT04885530