• ACTIV-3/TICO Study Group, Christina Barkauskas, Eleftherios Mylonakis, Garyfallia Poulakou, Barnaby E Young, David M Vock, Lianne Siegel, Nicole Engen, Greg Grandits, Nilima R Mosaly, Andrew M Vekstein, Ralph Rogers, Fadi Shehadeh, Matthew Kaczynski, Evangelia K Mylona, Konstantinos N Syrigos, Vasiliki Rapti, David C Lye, Diong Shiau Hui, Lindsay Leither, Kirk U Knowlton, Mamta K Jain, Rubria Marines-Price, Alice Osuji, J Scott Overcash, Ioannis Kalomenidis, Zafeiria Barmparessou, Michael Waters, Karla Zepeda, Peter Chen, Sam Torbati, Francis Kiweewa, Nicholus Sebudde, Eyad Almasri, Alyssa Hughes, Sanjay R Bhagani, Alison Rodger, Uriel Sandkovsky, Robert L Gottlieb, Eriobu Nnakelu, Barbara Trautner, Vidya Menon, Joseph Lutaakome, Michael Matthay, Philip Robinson, Konstantinos Protopapas, Nikolaos Koulouris, Ivan Kimuli, Amiran Baduashvili, Dominique L Braun, Huldrych F Günthard, Srikanth Ramachandruni, Robert Kidega, Kami Kim, Timothy J Hatlen, Andrew N Phillips, Daniel D Murray, Tomas O Jensen, Maria L Padilla, Evan X Accardi, Katy Shaw-Saliba, Robin L Dewar, Marc Teitelbaum, Ven Natarajan, Sylvain Laverdure, Helene C Highbarger, M Tauseef Rehman, Susan Vogel, David Vallée, Page Crew, Negin Atri, Adam J Schechner, Sarah Pett, Fleur Hudson, Jonathan Badrock, Giota Touloumi, Samuel M Brown, Wesley H Self, Crystal M North, Adit A Ginde, Christina C Chang, Anthony Kelleher, Stephanie Nagy-Agren, Shikha Vasudeva, David Looney, Hien H Nguyen, Adriana Sánchez, Amy C Weintrob, Birgit Grund, Shweta Sharma, Cavan S Reilly, Roger Paredes, Agnieszka Bednarska, Norman P Gerry, Abdel G Babiker, Victoria J Davey, Annetine C Gelijns, Elizabeth S Higgs, Virginia Kan, Gail Matthews, B Taylor Thompson, Philippe Legenne, Richa Chandra, H Clifford Lane, James D Neaton, and Jens D Lundgren.
• Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Duke Health, Durham, North Carolina.
• Ann. Intern. Med. 2022 Sep 1; 175 (9): 126612741266-1274.

BackgroundEnsovibep (MP0420) is a designed ankyrin repeat protein, a novel class of engineered proteins, under investigation as a treatment of SARS-CoV-2 infection.ObjectiveTo investigate if ensovibep, in addition to remdesivir and other standard care, improves clinical outcomes among patients hospitalized with COVID-19 compared with standard care alone.DesignDouble-blind, randomized, placebo-controlled, clinical trial. (ClinicalTrials.gov: NCT04501978).SettingMultinational, multicenter trial.ParticipantsAdults hospitalized with COVID-19.InterventionIntravenous ensovibep, 600 mg, or placebo.MeasurementsEnsovibep was assessed for early futility on the basis of pulmonary ordinal scores at day 5. The primary outcome was time to sustained recovery through day 90, defined as 14 consecutive days at home or place of usual residence after hospital discharge. A composite safety outcome that included death, serious adverse events, end-organ disease, and serious infections was assessed through day 90.ResultsAn independent data and safety monitoring board recommended that enrollment be halted for early futility after 485 patients were randomly assigned and received an infusion of ensovibep (n = 247) or placebo (n = 238). The odds ratio (OR) for a more favorable pulmonary outcome in the ensovibep (vs. placebo) group at day 5 was 0.93 (95% CI, 0.67 to 1.30; P = 0.68; OR > 1 would favor ensovibep). The 90-day cumulative incidence of sustained recovery was 82% for ensovibep and 80% for placebo (subhazard ratio [sHR], 1.06 [CI, 0.88 to 1.28]; sHR > 1 would favor ensovibep). The primary composite safety outcome at day 90 occurred in 78 ensovibep participants (32%) and 70 placebo participants (29%) (HR, 1.07 [CI, 0.77 to 1.47]; HR < 1 would favor ensovibep).LimitationThe trial was prematurely stopped because of futility, limiting power for the primary outcome.ConclusionCompared with placebo, ensovibep did not improve clinical outcomes for hospitalized participants with COVID-19 receiving standard care, including remdesivir; no safety concerns were identified.Primary Funding SourceNational Institutes of Health.

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