Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor–Biased Ligand in Adults With COVID-19: Two Randomized Clinical Trials
Open accessAbstract
Importance: Preclinical 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. Objective: To 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 Participants: Two 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. Interventions: A 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 Measures: The 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. Results: Both 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 Relevance: In 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 Registration: ClinicalTrials.gov Identifier: NCT04924660.
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The phase 2 improvement with C21 was not confirmed in phase 3, and recent clinical trials testing TRV-027 and TXA-127 did not show clinical improvement in this patient population.
“but these observations were not confirmed in phase 3, and recently clinical trials testing this therapeutic approach using a biased agonist of AT1R (TRV-027) and a synthetic Angiotensin-1-7 (TXA-127) did not show clinical improvement in this patient population.23”
All these elements could explain the differences in efficacy of BIO101 and TXA-127 on COVID-19 respiratory symptoms and mortality.
“All these elements could explain the differences in efficacy of BIO101 and TXA-127 on COVID-19 respiratory symptoms and mortality.23”
Self and colleagues did not evaluate mortality beyond 28 days.
“Moreover, they didn't evaluate mortality further than 28 days.”
The study by Self and colleagues had limited drug exposure (5 days maximum of treatment) compared to the longer treatment period with BIO101 (mean 8.9 days).
“In addition, the limited drug exposure (5 days maximum of treatment) in their study compared to the longer treatment period with BIO101 (mean number of days on treatment of 8.9 days in the BIO101 group) spanning from 1 to 28 days maximum, appear as a further plausible cause for the different clinical results reported.”
The primary outcomes evaluated by Self and colleagues (oxygen-free days) differed from the proportion of patients with respiratory failure or death evaluated in the present study.
“For instance, the primary outcomes evaluated by Self and colleagues: oxygen-free days differed from the proportion of patients with respiratory failure or death which was evaluated in the present study.”
Two clinical trials testing TRV-027 (an AT1R blocker) and TXA-127 (an analogue of Ang-1-7) did not show clinical improvement in the same patient population.
“More recently, two clinical trials testing TRV-027 (an AT1R blocker), and TXA-127 (an analogue of Ang-1-7), did not show clinical improvement in the same patient population.23”
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Targeting the Renin-Angiotensin-Aldosterone System: Preclinical and Clinical Developments
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The statistical design and analysis of pandemic platform trials: Implications for the future
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Renin-Angiotensin System Modulation in Adults With COVID-19—Reply
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- Authors
- Self, W. H., Shotwell, M. S., Gibbs, K. W., de Wit, M., Files, D. C., Harkins, M., Hudock, K. M., Merck, L. H., Moskowitz, A., Apodaca, K. D., Barksdale, A., Safdar, B., Javaheri, A., Sturek, J. M., Schrager, H., Iovine, N., Tiffany, B., Douglas, I. S., Levitt, J., Busse, L. W., Ginde, A. A., Brown, S. M., Hager, D. N., Boyle, K., Duggal, A., Khan, A., Lanspa, M., Chen, P., Puskarich, M., Vonderhaar, D., Venkateshaiah, L., Gentile, N., Rosenberg, Y., Troendle, J., Bistran-Hall, A. J., DeClercq, J., Lavieri, R., Joly, M. M., Orr, M., Pulley, J., Rice, T. W., Schildcrout, J. S., Semler, M. W., Wang, L., Bernard, G. R., Collins, S. P., ACTIV-4 Host Tissue Investigators, Becker, R. C., del Zoppo, G., Henke, P., Holubkov, R., Johnson, M., Kerr, K., Lipman, H. I., Lurie, F., Pitt, B., Vesely, S. K., Fleg, J. L., Aamodt, D., Ayers, J., Clark, D., Collins, J., Cook, M., Dixon, S., Graves, J., Jordan, C., Lindsell, C. J., Lopez, I., McKeel, D., Orozco, D., Prato, N., Qi, A., Qutab, M., Stoughton, C., Vermillion, K., Walsh, K., Winchell, S., Young, T., Franklin, R., Wagner, E., Walther, T., Demitrack, M., Johnson, J., Walsh, R., Bales, B., Miller, K., Torr, D., Barot, H., Landreth, L., LaRose, M., Parks, L., Teixeira, J. P., Cardenas, S., Ceniceros, J. A., Cunningham, A. G., Kunkel, S., Lovato, D. M., Zimmerman, B., Nguyen, T., Zeger, W., Nichols, H., Wiedel, N., Javaheri, A., Stilinovic, S., Brokowski, C., Lu, J., Solberg, M., Lee, D., Roach, K., Tiffany, B., Tanner, C., Taylor, A., Zumbahl, J., Syed, A., Mason, J., Jackson, P. E. H., Coleman, R. W., Haughey, H. M., Cherabuddi, K., James, N., Wakeman, R., Duncan, C., Montero, C., Rogers, A. J., Wilson, J. G., Vojnik, R., Perez, C., Wyles, D., Hiller, T. D., Oakes, J. L., Garcia, A. Z., Gong, M., Mohamed, A., Andrea, L., Nair, R., Nkemdirim, W., Lopez, B., Boujid, S., Torres, M., Garcia, O., Martinez, F., Baduashvili, A., Bastman, J., Chauhan, L., Douin, D. J., Finck, L., Licursi, A., ten Lohuis, C., Zhang, S., Bender, W., Tovar, S., Hayes, S., Kurtzman, N., Rosseto, E., Scaffidi, D., Shapiro, N., Pak, J., Allada, G., Briceno, G., Peña, J., Oh, M., Ali, H., Beselman, S., Eby, Y., Klimov, V., Hite, R. D., Tanzeem, H., Droege, C., Winter, J., Jackman, S., Caudill, A., Bayoumi, E., Pascual, E., Chen, P.-E., Mucha, S., Thiruchelvam, N., Siuba, M., Mehkri, O., Driver, B. E., Hendrickson, A. F., Kaus, O. R., Ontiveros, C., Riehm, A., Laudun, S., Hudock, D., Ensley, C., Shaner, V., Gentile, N., Isenberg, D., Reimer, H., Cincola, P., Harris, E. S., Callahan, S. J., Yamane, M. B., Barrios, M. A., Desai, N., Bharara, A., Keller, M., Majumder, P., Dohe, C., D’Armiento, J., Goldklang, M., Wagener, G., Fonseca, L., Valezquez-Sanchez, I., Johnson, N. J., Petersen, E., Fuentes, M., Newton, M., Gundel, S., Srinivasan, V., Steel, T., & Robinson, B.
- Affiliations
- Vanderbilt University (US)
- Vanderbilt University Medical Center (US)
- Wake Forest University Health Sciences (US)
- Department of Medicine, Virginia Commonwealth University, Richmond
- University of New Mexico (US)
- University of Cincinnati (US)
- Virginia Commonwealth University (US)
- Montefiore Medical Center (US)
- University of Nebraska Medical Center (US)
- Yale University (US)
- University of Virginia (US)
- Newton Wellesley Hospital (US)
- University of Florida (US)
- Denver Health Medical Center (US)
- Stanford Medicine (US)
- Emory University (US)
- University of Colorado Anschutz (US)
- Intermountain Medical Center (US)
- Johns Hopkins University (US)
- Beth Israel Deaconess Medical Center (US)
- Cleveland Clinic (US)
- Oregon Health & Science University (US)
- Cedars-Sinai Medical Center (US)
- University of Minnesota (US)
- Ochsner Medical Center (US)
- Cleveland Clinic Akron General (US)
- National Heart, Lung, and Blood Institute (US)
- Association Clinique et Thérapeutique Infantile du Val de Marne (FR)
- for the ACTIV-4 Host Tissue Investigators
- Corresponding author
- Self, Wesley H.
- ORCID
- Self, Wesley H.
- Shotwell, Matthew S.
- Gibbs, Kevin W.
- Files, D. Clark
- Harkins, Michelle
- Hudock, Kristin M.
- Merck, Lisa H.
- Moskowitz, Ari
- Barksdale, Aaron
- Safdar, Basmah
- Sturek, Jeffrey M.
- Iovine, Nicole
- 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
- Rosenberg, Yves
- Troendle, James
- 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.
- Becker, Richard C.
- Henke, Peter
- Holubkov, Richard
- Lurie, Fedor
- Pitt, Bertram
- Vesely, Sara K.
- Fleg, Jerome L.
- Lindsell, Christopher J.
- Walther, Thomas
- Demitrack, Mark
- Walsh, Ryan
- Miller, Karen
- Teixeira, J. Pedro
- Ceniceros, Juan A.
- Zeger, Wesley
- Wiedel, Noah
- Solberg, Muriel
- Roach, Kristopher
- Syed, Aamer
- Mason, Jessica
- Jackson, Patrick E. H.
- Duncan, Christopher
- Rogers, Angela J.
- Wilson, Jennifer G.
- Wyles, David
- Hiller, Terra D.
- Oakes, Judy L.
- Gong, Michelle
- Mohamed, Amira
- Andrea, Luke
- Nair, Rahul
- Baduashvili, Amiran
- Chauhan, Lakshmi
- Douin, David J.
- Finck, Lani
- Tovar, Santiago
- Kurtzman, Nicholas
- Shapiro, Nathan
- Oh, Minn
- Eby, Yolanda
- Hite, R. Duncan
- Caudill, Antonina
- Thiruchelvam, Nirosshan
- Siuba, Matthew
- Mehkri, Omar
- Driver, Brian E.
- Shaner, Valerie
- Isenberg, Derek
- Harris, Estelle S.
- Callahan, Sean J.
- Goldklang, Monica
- Wagener, Gebhard
- Fonseca, Laura
- Johnson, Nicholas J.
- Srinivasan, Vasisht
- Steel, Tessa
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2023-04-11
- Volume
- 329
- Issue
- 14
- Pages
- 1170
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC10091180
- OpenAlex
- W4364352018
- Cited by
- 52
- References
- 39
- Citations by year
- 2026: 11 · 2025: 14 · 2024: 16 · 2023: 11
- FWCI
- 10.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (COVID-19, UL1TR002243, UL1TR001863)
- National Heart, Lung, and Blood Institute (OT2HL156812)
- National Institute of Neurological Disorders and Stroke (R01NS113393)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Keywords
- renin-angiotensin system, angiotensin-(1-7), angiotensin II type 1 receptor, biased ligands, COVID-19 pandemic, SARS-CoV-2, 28-day mortality, hospitalized adults, drug safety
- MeSH terms
- COVID-19, SARS-CoV-2, Adult, Angiotensin I, Angiotensin II, Angiotensins, Hypoxia, Female, Humans, Infusions, Intravenous, Ligands, Male, Middle Aged, Oligopeptides, Peptide Fragments, Renin-Angiotensin System, Vasodilator Agents, Randomized Controlled Trials as Topic, Receptor, Angiotensin, Type 1
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