Effect of Ivermectin vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19
Authors: Naggie Susanna , Boulware David R. , Lindsell Christopher J. , Stewart Thomas G. , Gentile Nina , Collins Sean , McCarthy Matthew William , Jayaweera Dushyantha , Castro Mario , Sulkowski Mark , McTigue Kathleen , Thicklin Florence , Felker G. Michael , Ginde Adit A. , Bramante Carolyn T. , Slandzicki Alex J. , Gabriel Ahab , Shah Nirav S. , Lenert Leslie A. , Dunsmore Sarah E. , Adam Stacey J. , DeLong Allison , Hanna George , Remaly April , Wilder Rhonda , Wilson Sybil , 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 , Slandzicki Alex , Vogel Claudia , Munoz Sebastian , Kavtaradze David , 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 , Felker G. Michael , Harrington Amanda , Dolor Rowena , Frazier Madison , Vergara Lorraine , Wilson Jessica , Burruss Valencia , Hurst Terri , Ofotokun Igho , Bristow Laurel , Prabhu Rajesh , Klicka Krystal , Lightfeather Amber , James Vicki , Rogers Marcella , Parihar Pradeep , Torress De'Ambra , Oragwu Chukwuemeka , Oguego Ngozi , Pillai Rajesh , Juma Mustafa , Gabriel Ahab , 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 Llisa , Ruiz-Unger Juan , Gonzalez Susan , Reyes Lionel , Cienki John , Jimenez Gisselle , Cohen Jonathan , Wong Matthew , Yuan Ying , Szeto Jeremy , Sulkowski Mark , Stelmash Lauren , Amon Arch , 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 , Gentile Nina , 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 , Lim Stephen , Swink Wayne , Powers-Fletcher Margaret , Mukunzi Sylvere , Shenkman Elizabeth , Hensley Jamie , Manning Brittney , Isache Carmen , Bowman Jennifer , Callaghan-Brown Angelique , Scott Taylor , Schwasinger-Schmidt Tiffany , Cornejo Ashlie , Jayaweera Dushyantha , 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 , McCarthy Matthew , Salsgiver Elizabeth , Armas Eddie , Cheng Jhonsai , Huerta Priscilla , Garcia-Diaz Julia , Aamodt David , Ayers JaMario , Collins Jess , Graves John , Grindstaff James , Harrell Frank , Lai Jessica , Lopez Itzel , Marlin Jessica , Merkel Alyssa , Nwosu Sam , Obregon Savannah , Orozco Dirk , Perez-Torres Yoli , Prato Nelson , Ratcliff Colleen , Rhode Max , Rothman Russell , Shirey-Rice Jana , Vermillion Krista , Tan Hsi-Nien , Tregoning Seibert , Vance Meghan , Vongsamphanh Amber , Weir Maria , Zaleski Nicole 
Published: October 2022

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 91 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 &amp;gt;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