Elsevier

American Heart Journal

Volume 163, Issue 2, February 2012, Pages 149-155.e1
American Heart Journal

Trial Design
Design of the RELAXin in Acute Heart Failure Study

https://doi.org/10.1016/j.ahj.2011.10.009Get rights and content

Background

Acute heart failure (AHF) remains a major public health burden with a high prevalence and poor prognosis. Relaxin is a naturally occurring peptide hormone that increases cardiac output, arterial compliance, and renal blood flow during pregnancy. The RELAX-AHF-1 study will evaluate the effect of RLX030 (recombinant form of human relaxin 2) on symptom relief and clinical outcomes in patients with AHF.

Methods

The protocol includes a completed phase 2 234-patient dose-finding study (Pre-RELAX-AHF) and an ongoing phase 3 1,160-patient trial (RELAX-AHF-1). Patients with AHF and systolic blood pressure >125 mm Hg are randomized within 16 hours of presentation to a 48-hour IV infusion of RLX030 or placebo. The 30 μg/kg per day dose of RLX030 was chosen for RELAX-AHF-1 based on effects on dyspnea, clinical outcomes, and safety observed in Pre-RELAX-AHF. Primary efficacy end points in RELAX-AHF-1 are (1) the area under the curve of change of the dyspnea Visual Analog Scale from baseline through day 5 and (2) whether the patient reports moderately to markedly better dyspnea at 6, 12, and 24 hours. Secondary efficacy end points include days alive and out of the hospital through day 60 and cardiovascular death or rehospitalization for heart failure or renal failure through day 60. Patients will be followed up through day 180 for mortality. As of September 19, 2011, 978 patients have been enrolled.

Conclusions

Pre-RELAX-AHF results suggested that infusion of RLX030 may accelerate dyspnea relief and improve prognosis in patients hospitalized with AHF. RELAX-AHF-1 will further evaluate these effects.

Section snippets

Background

Acute heart failure (AHF) remains a major public health burden with a high prevalence and a poor prognosis. More than 80% of patients who present to the hospital with AHF complain of dyspnea.1 Despite the importance of symptom relief to patients,2 dyspnea is not relieved substantially in about 50% of patients after 24 hours of therapy and in 25% of patients at discharge.3, 4, 5 Thus, faster and more complete symptom resolution is an important goal in the development of new AHF therapies.6, 7

Pre-RELAX-AHF: the phase 2 study

Pre-RELAX-AHF and RELAX-AHF-1 are described in a single phase 2/3 protocol. The Pre-RELAX-AHF26 was a phase 2, placebo-controlled, double-blind, parallel-group, dose-finding study conducted in 234 patients with AHF, dyspnea, congestion on chest radiograph, elevated natriuretic peptides, mild-to-moderate renal dysfunction, and SBP >125 mm Hg. Patients were randomized within 16 hours of presentation to up to 48 hours of continuous IV infusion of placebo or 10, 30, 100, or 250 μg/kg per day RLX030

Discussion

In Pre-RELAX-AHF, 30 μg/kg per day RLX030 was associated with an increased proportion of patients with dyspnea relief in the first 24 hours, using the Likert scale, and with decreased severity of dyspnea through day 5, using the VAS AUC, compared with placebo.26 Patients treated with RLX030 also tended to have a shorter average hospital stay, more days alive and out of the hospital, lower 60-day risks of CV death or rehospitalization and all-cause death or rehospitalization, and lower 180-day

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