Biased ligand of the angiotensin II type 1 receptor in patients with acute heart failure: A randomized, double-blind, placebo-controlled, phase IIB, dose ranging trial (BLAST-AHF)

Peter Pang, Javed Butler, Sean P. Collins, Gad Cotter, Beth A. Davison, Justin A. Ezekowitz, Gerasimos Filippatos, Phillip D. Levy, Marco Metra, Piotr Ponikowski, John R. Teerlink, Adriaan A. Voors, David Bharucha, Kathleen Goin, David G. Soergel, G. Michael Felker

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Aims Currently, no acute heart failure (AHF) therapy definitively improves outcomes. Reducing morbidity and mortality from acute heart failure (AHF) remains an unmet need. TRV027 is a novel 'biased' ligand of the angiotensin II type 1 receptor (AT1R), selectively antagonizing the negative effects of angiotensin II, while preserving the potential pro-contractility effects of AT1R stimulation. BLAST-AHF was designed to determine the safety, efficacy, and optimal dose of TRV027 to advance into future studies. Methods and results BLAST-AHF was a multi-centre, international, randomized, double-blind, placebo-controlled, parallel group, phase IIb dose-ranging study, enrolling patients with AHF into 4 groups: Placebo, 1, 5, or 25mg/h of TRV027. Treatment was by IV infusion for 48-96 h. The primary composite endpoint was comprised of the following: (i) time from baseline to death through day 30, (ii) time from baseline to heart failure re-hospitalization through day 30, (iii) the first assessment time point following worsening heart failure through day 5, (iv) change in dyspnea visual analogue scale (VAS) score calculated as the area under the curve (AUC) representing the change from baseline over time from baseline through day 5, and (v) length of initial hospital stay (in days) from baseline. Analyses were by modified intention-to-treat. Overall, 621 patients were enrolled. After 254 patients, a pre-specified interim analysis resulted in several protocol changes, including a lower blood pressure inclusion criterion as well as a new allocation scheme of 2:1:2:1, overweighting both placebo, and the 5mg/h dose. TRV027 did not confer any benefit over placebo at any dose with regards to the primary composite endpoint or any of the individual components. There were no significant safety issues with TRV027. Conclusion In this phase IIb dose-ranging AHF study, TRV027 did not improve clinical status through 30-day follow-up compared with placebo.

Original languageEnglish (US)
Pages (from-to)2364-2373
Number of pages10
JournalEuropean Heart Journal
Volume38
Issue number30
DOIs
StatePublished - Aug 7 2017

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Angiotensin Type 1 Receptor
Heart Failure
Placebos
Ligands
Safety
Visual Analog Scale
Angiotensin II
Dyspnea
Area Under Curve
sarcosine-arginyl-valyl-tyrosyl-isoleucyl-histidyl-prolyl-alanine
Length of Stay
Hospitalization
Blood Pressure
Morbidity
Mortality
Therapeutics

Keywords

  • Acute heart failure
  • Angiotensin-II
  • Biased ligand
  • Clinical trials

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Biased ligand of the angiotensin II type 1 receptor in patients with acute heart failure : A randomized, double-blind, placebo-controlled, phase IIB, dose ranging trial (BLAST-AHF). / Pang, Peter; Butler, Javed; Collins, Sean P.; Cotter, Gad; Davison, Beth A.; Ezekowitz, Justin A.; Filippatos, Gerasimos; Levy, Phillip D.; Metra, Marco; Ponikowski, Piotr; Teerlink, John R.; Voors, Adriaan A.; Bharucha, David; Goin, Kathleen; Soergel, David G.; Felker, G. Michael.

In: European Heart Journal, Vol. 38, No. 30, 07.08.2017, p. 2364-2373.

Research output: Contribution to journalArticle

Pang, P, Butler, J, Collins, SP, Cotter, G, Davison, BA, Ezekowitz, JA, Filippatos, G, Levy, PD, Metra, M, Ponikowski, P, Teerlink, JR, Voors, AA, Bharucha, D, Goin, K, Soergel, DG & Felker, GM 2017, 'Biased ligand of the angiotensin II type 1 receptor in patients with acute heart failure: A randomized, double-blind, placebo-controlled, phase IIB, dose ranging trial (BLAST-AHF)', European Heart Journal, vol. 38, no. 30, pp. 2364-2373. https://doi.org/10.1093/eurheartj/ehx196
Pang, Peter ; Butler, Javed ; Collins, Sean P. ; Cotter, Gad ; Davison, Beth A. ; Ezekowitz, Justin A. ; Filippatos, Gerasimos ; Levy, Phillip D. ; Metra, Marco ; Ponikowski, Piotr ; Teerlink, John R. ; Voors, Adriaan A. ; Bharucha, David ; Goin, Kathleen ; Soergel, David G. ; Felker, G. Michael. / Biased ligand of the angiotensin II type 1 receptor in patients with acute heart failure : A randomized, double-blind, placebo-controlled, phase IIB, dose ranging trial (BLAST-AHF). In: European Heart Journal. 2017 ; Vol. 38, No. 30. pp. 2364-2373.
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abstract = "Aims Currently, no acute heart failure (AHF) therapy definitively improves outcomes. Reducing morbidity and mortality from acute heart failure (AHF) remains an unmet need. TRV027 is a novel 'biased' ligand of the angiotensin II type 1 receptor (AT1R), selectively antagonizing the negative effects of angiotensin II, while preserving the potential pro-contractility effects of AT1R stimulation. BLAST-AHF was designed to determine the safety, efficacy, and optimal dose of TRV027 to advance into future studies. Methods and results BLAST-AHF was a multi-centre, international, randomized, double-blind, placebo-controlled, parallel group, phase IIb dose-ranging study, enrolling patients with AHF into 4 groups: Placebo, 1, 5, or 25mg/h of TRV027. Treatment was by IV infusion for 48-96 h. The primary composite endpoint was comprised of the following: (i) time from baseline to death through day 30, (ii) time from baseline to heart failure re-hospitalization through day 30, (iii) the first assessment time point following worsening heart failure through day 5, (iv) change in dyspnea visual analogue scale (VAS) score calculated as the area under the curve (AUC) representing the change from baseline over time from baseline through day 5, and (v) length of initial hospital stay (in days) from baseline. Analyses were by modified intention-to-treat. Overall, 621 patients were enrolled. After 254 patients, a pre-specified interim analysis resulted in several protocol changes, including a lower blood pressure inclusion criterion as well as a new allocation scheme of 2:1:2:1, overweighting both placebo, and the 5mg/h dose. TRV027 did not confer any benefit over placebo at any dose with regards to the primary composite endpoint or any of the individual components. There were no significant safety issues with TRV027. Conclusion In this phase IIb dose-ranging AHF study, TRV027 did not improve clinical status through 30-day follow-up compared with placebo.",
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T2 - A randomized, double-blind, placebo-controlled, phase IIB, dose ranging trial (BLAST-AHF)

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AU - Butler, Javed

AU - Collins, Sean P.

AU - Cotter, Gad

AU - Davison, Beth A.

AU - Ezekowitz, Justin A.

AU - Filippatos, Gerasimos

AU - Levy, Phillip D.

AU - Metra, Marco

AU - Ponikowski, Piotr

AU - Teerlink, John R.

AU - Voors, Adriaan A.

AU - Bharucha, David

AU - Goin, Kathleen

AU - Soergel, David G.

AU - Felker, G. Michael

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N2 - Aims Currently, no acute heart failure (AHF) therapy definitively improves outcomes. Reducing morbidity and mortality from acute heart failure (AHF) remains an unmet need. TRV027 is a novel 'biased' ligand of the angiotensin II type 1 receptor (AT1R), selectively antagonizing the negative effects of angiotensin II, while preserving the potential pro-contractility effects of AT1R stimulation. BLAST-AHF was designed to determine the safety, efficacy, and optimal dose of TRV027 to advance into future studies. Methods and results BLAST-AHF was a multi-centre, international, randomized, double-blind, placebo-controlled, parallel group, phase IIb dose-ranging study, enrolling patients with AHF into 4 groups: Placebo, 1, 5, or 25mg/h of TRV027. Treatment was by IV infusion for 48-96 h. The primary composite endpoint was comprised of the following: (i) time from baseline to death through day 30, (ii) time from baseline to heart failure re-hospitalization through day 30, (iii) the first assessment time point following worsening heart failure through day 5, (iv) change in dyspnea visual analogue scale (VAS) score calculated as the area under the curve (AUC) representing the change from baseline over time from baseline through day 5, and (v) length of initial hospital stay (in days) from baseline. Analyses were by modified intention-to-treat. Overall, 621 patients were enrolled. After 254 patients, a pre-specified interim analysis resulted in several protocol changes, including a lower blood pressure inclusion criterion as well as a new allocation scheme of 2:1:2:1, overweighting both placebo, and the 5mg/h dose. TRV027 did not confer any benefit over placebo at any dose with regards to the primary composite endpoint or any of the individual components. There were no significant safety issues with TRV027. Conclusion In this phase IIb dose-ranging AHF study, TRV027 did not improve clinical status through 30-day follow-up compared with placebo.

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KW - Acute heart failure

KW - Angiotensin-II

KW - Biased ligand

KW - Clinical trials

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