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

Abstract

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.

Figure 1.. Patient Screening, Randomization, and Participation in the TXA-127 Trial and in the TRV-027 Trial

^aThe criteria were not mutually exclusive; some potential participants met multiple criteria for ineligibility. ^bThe patient, clinical team, or both, was not pursuing full medical management (eg, a do not intubate order). ^cIncluded (1) the patient was to be discharged from the hospital before the study procedures could be initiated, (2) the patient was enrolled in another trial, and (3) the patient’s situation presented logistical challenges for trial enrollment. ^dPatients eligible for more than 1 trial were randomized with equal probability to a specific trial. Patients were randomized to active vs placebo in an m:1 ratio, with m representing the number of trials for which the patient was eligible. Patients randomized to placebo were included in the placebo groups of each trial for which they were eligible. Patients randomized to receive an active drug contributed only to the trial they were randomized. Thus, patients randomized to receive active fostamatinib did not contribute to either the TXA-127 trial or the TRV-027 trial, whereas patients assigned to placebo fostamatinib were included in the placebo groups for the TXA-127 and TRV-027 trials if they were eligible for those trials. This design with a shared placebo group reduces the total number of patients who received placebo while retaining a statistically efficient 1:1 active vs placebo allocation for each trial. ^eDid not receive the randomized study drug or were randomized but did not meet the enrollment criteria.

Figure 2.. Primary Outcome of Oxygen-Free Days Between Randomization and Day 28 in the TXA-127 Trial and in the TRV-027 Trial

The day of randomization was study day 0. The total sample size was 343 patients in the TXA-127 trial. The total sample size was 290 patients in the TRV-027 trial. Patients were followed up until the earlier of death or day 28. The numbers at risk shown in panels A and B are the numbers of patients who were not deceased, withdrawn, or lost to follow-up. The plots in panels C and D display the proportion of patients in each of the 30 levels (range, −1 to 28 days) of the oxygen-free days ordinal scale at day 28. The oxygen-free days outcome demonstrated null results for TXA-127 vs placebo and TRV-027 vs placebo with point estimates in the direction of inferiority for the TXA-127 trial (adjusted OR, 0.88 [95% credible interval, 0.59 to 1.30]) and for the TRV-027 trial (adjusted OR, 0.74 [95% credible interval, 0.48 to 1.13]).

Figure 3.. Primary Outcome of Oxygen-Free Days by Baseline Characteristics in the TXA-127 Trial and in the TRV-027 Trial

ACE indicates angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CrI, credible interval; HFNC, high-flow nasal cannula; OR, odds ratio; and WHO, World Health Organization. The ORs were adjusted for sex, age group, and baseline WHO ordinal scale level. An oxygen-free day was calculated as 28 minus the number of days between randomization (day 0) and liberation from new supplemental oxygen use during the 28 days. Patients who died before day 28 were coded as having −1 oxygen-free days (worst possible outcome). The subgroup analyses of oxygen-free days included patients with partially observed data (only known to be within a certain range). Additional information appears in eTables 11 and 12 in Supplement 1, including the number of patients with partially observed oxygen-free days. ^aNot prespecified as a subgrouping variable; thus, heterogeneity of treatment effect by sex is a post hoc analysis. ^bThe WHO COVID-19 clinical progression scale is an 8-level ordinal scale representing the worst patient clinical status on a given day. The descriptions for levels 1-8 appear in footnote ^d in Table 1. ^cPatients with unknown vaccination status were excluded (17 patients in the TXA-127 trial and 10 patients in the TRV-027 trial).