Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor–Biased Ligand in Adults With COVID-19
Authors: Self Wesley H. , Shotwell Matthew S. , Gibbs Kevin W. , de Wit Marjolein , Files D. Clark , Harkins Michelle , Hudock Kristin M. , Merck Lisa H. , Moskowitz Ari , Apodaca Krystle D. , Barksdale Aaron , Safdar Basmah , Javaheri Ali , Sturek Jeffrey M. , Schrager Harry , Iovine Nicole , Tiffany Brian , Douglas Ivor S. , Levitt Joseph , Busse Laurence W. , Ginde Adit A. , Brown Samuel M. , Hager David N. , Boyle Katherine , Duggal Abhijit , Khan Akram , Lanspa Michael , Chen Peter , Puskarich Michael , Vonderhaar Derek , Venkateshaiah Lokesh , Gentile Nina , Rosenberg Yves , Troendle James , Bistran-Hall Amanda J. , DeClercq Josh , Lavieri Robert , Joly Meghan Morrison , Orr Michael , Pulley Jill , Rice Todd W. , Schildcrout Jonathan S. , Semler Matthew W. , Wang Li , Bernard Gordon R. , Collins Sean P. ,   ACTIV-4 Host Tissue Investigators, Becker Richard C. , del Zoppo Gregory , Henke Peter , Holubkov Richard , Johnson Maryl , Kerr Kim , Lipman Hannah I. , Lurie Fedor , Pitt Bertram , Vesely Sara K. , Fleg Jerome L. , Aamodt Dave , Ayers J'Mario , Clark Debra , Collins Jessica , Cook Maya , Dixon Sheri , Graves John , Jordan Courtney , Lindsell Christopher J. , Lopez Itzel , McKeel David , Orozco Dirk , Prato Nelson , Qi Ally , Qutab Madiha , Stoughton Christa , Vermillion Krista , Walsh Kelly , Winchell Stephanie , Young Taylor , Franklin Richard , Wagner Elizabeth , Walther Thomas , Demitrack Mark , Johnson Jakea , Walsh Ryan , Bales Brian , Miller Karen , Torr Donna , Barot Harsh , Landreth Leigha , LaRose Mary , Parks Lisa , Teixeira J. Pedro , Cardenas Sandra , Ceniceros Juan A. , Cunningham Amy G. , Kunkel Susan , Lovato Debbie M. , Zimmerman Brooklin , Nguyen Thanh , Zeger Wesley , Nichols Heather , Wiedel Noah , Javaheri Ali , Stilinovic Stephanie , Brokowski Carolyn , Lu Jing , Solberg Muriel , Lee Dana , Roach Kristopher , Tiffany Brian , Tanner Charlotte , Taylor Annette , Zumbahl Jennine , Syed Aamer , Mason Jessica , Jackson Patrick E. H. , Coleman Rachael W. , Haughey Heather M. , Cherabuddi Kartik , James Nastasia , Wakeman Rebecca , Duncan Christopher , Montero Cynthia , Rogers Angela J. , Wilson Jennifer G. , Vojnik Rosemary , Perez Cynthia , Wyles David , Hiller Terra D. , Oakes Judy L. , Garcia Ana Z. , Gong Michelle , Mohamed Amira , Andrea Luke , Nair Rahul , Nkemdirim William , Lopez Brenda , Boujid Sabah , Torres Martha , Garcia Ofelia , Martinez Flora , Baduashvili Amiran , Bastman Jill , Chauhan Lakshmi , Douin David J. , Finck Lani , Licursi Ashley , ten Lohuis Caitlin , Zhang Sophia , Bender William , Tovar Santiago , Hayes Sharon , Kurtzman Nicholas , Rosseto Elinita , Scaffidi Douglas , Shapiro Nathan , Pak Jonathan , Allada Gopal , Briceno Genesis , Peña Jose , Oh Minn , Ali Harith , Beselman Sasha , Eby Yolanda , Klimov Vitaliy , Hite R. Duncan , Tanzeem Hammad , Droege Chris , Winter Jessica , Jackman Susan , Caudill Antonina , Bayoumi Emad , Pascual Ethan , Chen Po-En , Mucha Simon , Thiruchelvam Nirosshan , Siuba Matthew , Mehkri Omar , Driver Brian E. , Hendrickson Audrey F. , Kaus Olivia R. , Ontiveros Christina , Riehm Amy , Laudun Sylvia , Hudock Debra , Ensley Christopher , Shaner Valerie , Gentile Nina , Isenberg Derek , Reimer Hannah , Cincola Paul , Harris Estelle S. , Callahan Sean J. , Yamane Misty B. , Barrios Macy AG , Desai Neeraj , Bharara Amit , Keller Michael , Majumder Prat , Dohe Carrie , D’Armiento Jeanine , Goldklang Monica , Wagener Gebhard , Fonseca Laura , Valezquez-Sanchez Itzel , Johnson Nicholas J. , Petersen Emily , Fuentes Megan , Newton Maranda , Gundel Stephanie , Srinivasan Vasisht , Steel Tessa , Robinson Bryce 
Published: April 2023

ImportancePreclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II compared with angiotensin (1-7) and may be an important contributor to COVID-19 pathophysiology.ObjectiveTo evaluate the efficacy and safety of RAS modulation using 2 investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor–biased ligand), that are hypothesized to potentiate the action of angiotensin (1-7) and mitigate the action of the angiotensin II.Design, Setting, and ParticipantsTwo randomized clinical trials including adults hospitalized with acute COVID-19 and new-onset hypoxemia were conducted at 35 sites in the US between July 22, 2021, and April 20, 2022; last follow-up visit: July 26, 2022.InterventionsA 0.5-mg/kg intravenous infusion of TXA-127 once daily for 5 days or placebo. A 12-mg/h continuous intravenous infusion of TRV-027 for 5 days or placebo.Main Outcomes and MeasuresThe primary outcome was oxygen-free days, an ordinal outcome that classifies a patient’s status at day 28 based on mortality and duration of supplemental oxygen use; an adjusted odds ratio (OR) greater than 1.0 indicated superiority of the RAS agent vs placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included allergic reaction, new kidney replacement therapy, and hypotension.ResultsBoth trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, and 274 [79.9%] not Hispanic), 170 received TXA-127 and 173 received placebo. Of 290 patients in the TRV-027 trial (199 [68.6%] aged 31-64 years, 168 [57.9%] men, 195 [67.2%] White, and 225 [77.6%] not Hispanic), 145 received TRV-027 and 145 received placebo. Compared with placebo, both TXA-127 (unadjusted mean difference, −2.3 [95% CrI, −4.8 to 0.2]; adjusted OR, 0.88 [95% CrI, 0.59 to 1.30]) and TRV-027 (unadjusted mean difference, −2.4 [95% CrI, −5.1 to 0.3]; adjusted OR, 0.74 [95% CrI, 0.48 to 1.13]) resulted in no difference in oxygen-free days. In the TXA-127 trial, 28-day all-cause mortality occurred in 22 of 163 patients (13.5%) in the TXA-127 group vs 22 of 166 patients (13.3%) in the placebo group (adjusted OR, 0.83 [95% CrI, 0.41 to 1.66]). In the TRV-027 trial, 28-day all-cause mortality occurred in 29 of 141 patients (20.6%) in the TRV-027 group vs 18 of 140 patients (12.9%) in the placebo group (adjusted OR, 1.52 [95% CrI, 0.75 to 3.08]). The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo.Conclusions and RelevanceIn adults with severe COVID-19, RAS modulation (TXA-127 or TRV-027) did not improve oxygen-free days vs placebo. These results do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for patients with severe COVID-19.Trial RegistrationClinicalTrials.gov Identifier: NCT04924660