The effect of TRV027 on coagulation in COVID‐19: A pilot randomized, placebo‐controlled trial

Robbins, A; Bakri, Nur Amalina Che; Toke‐Bjolgerud, Edward; Edwards, Aaron; Vikraman, Asha; Michalsky, Cathy; Fossler, Michael J.; Lemm, Nana‐Marie; Medhipour, Savviz; Budd, William; Gravani, Athanasia; Hurley, Lisa; Kapil, Vikas; Jackson, Aimee; Lonsdale, Derrick; Latham, Victoria; Laffan, Michael; Chapman, Neil; Cooper, Nichola; Szydlo, Richard; Boyle, Joseph; Pollock, Katrina M; Owen, David R.

doi:10.1111/bcp.15618

Cited by 4 publications

(3 citation statements)

References 27 publications

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“…Therefore, we plan to comprehensively select 20 biomarkers involved in different mechanisms of thrombosis for COVID-19 to fill the gap in this area of research. Randomised control trials (RCTs) are a credible way to test if a risk factor causes a certain outcome, 18 but they are not always practicable because they can be very costly, lengthy, and sometimes unethical. When an RCT is not an option to study the effect of a risk factor on an outcome, using genetic variable methods might be a good substitute.…”

Section: Introductionmentioning

confidence: 99%

Causal Effects of COVID-19 on the Risk of Thrombosis: A Two-Sample Mendel Randomization Study

Li,

Zeng,

et al. 2024

Thromb Haemost

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Background: COVID-19 and thrombosis are linked, but the biomolecular mechanism is unclear. We aimed to investigate the causal relationship between COVID-19 and thrombotic biomarkers. Methods: We used Two-sample Mendelian Randomization (MR) to assess the effect of COVID-19 on 20 thrombotic biomarkers. We estimated causality using Inverse variance weighting with multiplicative random effect, and performed sensitivity analysis using weighted median, MR Egger regression and MR pleiotropy residual sum and outlier (MR-PRESSO) methods. We used R language for the analysis. Results: All COVID-19 classes showed lower levels of tissue factor pathway inhibitor (TFPI) and interleukin-1 receptor type 1 (IL-1R1). COVID-19 significantly reduced TFPI (OR=0.639, 95%CI: 0.435-0.938) and IL-1R1 (OR=0.603, 95%CI=0.417-0.872), nearly doubling the odds. We also found that COVID-19 lowered multiple coagulation factor deficiency protein 2 (MCFD2) and increased C-C motif chemokine 3 (CCL3). Hospitalised COVID-19 cases had less plasminogen activator, tissue type (tPA) and P-selectin glycoprotein ligand 1 (PSGL-1), while severe cases had lower mean platelet volume (MPV) and platelet count. These changes in TFPI, tPA, IL-1R1, MPV and platelet count suggested a higher risk of thrombosis. Decreased PSGL-1 indicated a lower risk of thrombosis. Conclusions: This study demonstrated that COVID-19 causally influences thrombosis at the biomolecular level, mainly by reducing TFPI and IL-1R1. Three other biomarkers also implied that COVID-19 increases thrombosis risk. We confirmed the reduction of platelet count and MPV, providing clues to the pathogenesis of COVID-19 and thrombosis. Our findings may have implications for the prevention and treatment of thrombotic complications in COVID-19 patients.

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Section: Introductionmentioning

confidence: 99%

Causal Effects of COVID-19 on the Risk of Thrombosis: A Two-Sample Mendel Randomization Study

Li,

Zeng,

et al. 2024

Thromb Haemost

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“…[11][12][13][14] Thus, the RAS is an appealing target for COVID-19 drug development (eFigure 1 in Supplement 1). However, early trials evaluating investigational and repurposed RAS drugs for the treatment of COVID-19 have not clearly demonstrated efficacy, [15][16][17][18][19] and whether pharmacological modulation of the RAS can provide benefit for patients with severe COVID-19 remains unclear.…”

mentioning

confidence: 99%

“…In the TXA-127 trial, synthetic angiotensin (1-7) 20 (TXA-127) was compared with placebo. In the TRV-027 trial, an angiotensin II type 1 receptor-biased ligand 19,21 (TRV-027) was compared with placebo.…”

mentioning

confidence: 99%

Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor–Biased Ligand in Adults With COVID-19

Self

Shotwell

Gibbs

et al. 2023

JAMA

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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

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Biomarkers of early SARS-CoV-2 infection before the onset of respiratory symptoms

Teng,

Quek,

Nguyen

et al. 2024

Clinical Microbiology and Infection

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The effect of TRV027 on coagulation in COVID‐19: A pilot randomized, placebo‐controlled trial

Cited by 4 publications

References 27 publications

Causal Effects of COVID-19 on the Risk of Thrombosis: A Two-Sample Mendel Randomization Study

Causal Effects of COVID-19 on the Risk of Thrombosis: A Two-Sample Mendel Randomization Study

Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor–Biased Ligand in Adults With COVID-19

Biomarkers of early SARS-CoV-2 infection before the onset of respiratory symptoms

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