Efficacy, Safety and Tolerability of Sexelaxin When Added to Standard Therapy in AHF

Study Overview
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Brief Summary
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The purpose of the study was to evaluate the efficacy, safety and tolerability of intravenous infusion of serelaxin, when added to standard therapy, in acute heart failure (AHF) patients.

Official Title
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A Multicenter, Randomized, Double-blind, Placebo Controlled Phase III Study to Evaluate the Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in Acute Heart Failure Patients

Conditions
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Acute Heart Failure

Intervention / Treatment
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* Drug: Serelaxin
* Drug: Placebo
* Other: Standard of CareTherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ≥ 18 years of age, with body weight ≤160 kg Hospitalized for AHF; AHF is defined as including all of the following measured at any time between presentation (including the emergency department and outpatient clinic) and at the end of screening: Persistent dyspnea at rest or with minimal exertion at screening and at the time of randomization Pulmonary congestion on chest radiograph Brain natriuretic peptide (BNP) ≥500 pg/mL or NT-proBNP ≥2,000 pg/mL Systolic BP ≥125 mmHg at the start and at the end of screening Able to be randomized within 16 hours from presentation to the hospital, including the emergency department and outpatient clinic Received intravenous furosemide of at least 40 mg total (or equivalent) at any time between presentation (this includes outpatient clinic, ambulance, or hospital including emergency department) and the start of screening for the study for the treatment of the current acute HF episode Renal impairment defined as an estimate glomerular filtration rate using the between presentation and randomization of ≥ 25 and ≤75mL/min/1.73m2, calculated using the Modification of Diet in Renal Disease formula (or modified sMDRD formula according to specific ethnic groups and local practice guidelines). Exclusion Criteria: Dyspnea primarily due to non-cardiac causes Temperature >38.5°C (oral or equivalent), sepsis, active and clinically significant infection requiring IV anti-microbial treatment or known presence or evidence of Human Immunodeficiency Virus (HIV) infection (based on history and/or clinical findings, including laboratory results obtained during screening period). Clinical evidence of acute coronary syndrome currently or within 30 days prior to enrollment *Patients with systolic blood pressure >180 mmHg at the end of screening AHF due to significant arrhythmias, which include any of the following: sustained ventricular tachycardia, bradycardia with sustained ventricular rate <45 beats per minute, or atrial fibrillation/flutter with sustained ventricular response of >130 beats per minute Hepatic disease unrelated to Heart Failure etiology and as determined by any one of the following: AST and/or ALT values exceeding 3 X ULN and/or bilirubin > 1.5 X ULN at screening or history of hepatic encephalopathy, esophageal varices, or portacaval shunt, or a diagnosis of cirrhosis by any means, or evidence of chronic Hepatitis B (presence of hepatitis B surface antigen production: positive HBsAg), or chronic Hepatitis C infection (presence of Hepatitis C genetic replication: positive Hepatitis C viral RNA, based on history and/or clinical findings, including laboratory results obtained during screening period). *Significant uncorrected left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy or severe aortic stenosis (i.e., aortic valve area <1.0 cm2 or mean gradient >50 mmHg on prior or current echocardiogram), and severe mitral stenosis History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past year with a life expectancy less than 1 year

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Patients will receive continuous intravenous infusion of matching placebo serelaxin for 48 hours. | Drug: Placebo<br>* Intravenous infusion<br>Other: Standard of CareTherapy<br>* This treatment can include but is not limited to intravenous and/or oral diuretics, ACE inhibitors/angiotensin receptor antagonists, β blockers, and aldosterone receptor antagonists, etc.<br>|
| Experimental: Serelaxin<br>Patients will receive continuous intravenous infusion of serelaxin(30 µg/kg/day) for 48 hours. | Drug: Serelaxin<br>* Intravenous infusion<br>Other: Standard of CareTherapy<br>* This treatment can include but is not limited to intravenous and/or oral diuretics, ACE inhibitors/angiotensin receptor antagonists, β blockers, and aldosterone receptor antagonists, etc.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With a Clinical Composite Endpoint of Treatment Success, Treatment Failure, or no Change. | The trichotomous clinical composite endpoint of treatment success, treatment failure, or no change. Treatment success defined as improvement of dyspnea by Likert scale and at least 2 points improvement by at least 2 physician assessed signs and symptoms (orthopnea, rales edema, and jugular venous pulse) at Day 2; treatment failure defined as worsening heart failure, death, or re-hospitalization due to heart failure or renal failure through Day 5; no change defined as neither the criteria for treatment success nor the criteria for treatment failure was met through Day 5. | through day 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to All-cause Death | Results are given in terms of number of participants with all cause death event through day 180 (pre-defined timeframe). | Through Day 180 | 
| Time to Moderate or Marked Improvements in Dyspnea by Likert Scale, Expressed in Days | Time to event is computed as the number of days from randomization to moderate or marked improvements in dyspnea by Likert scale | Through Day 5 | 
| Dyspnea by VAS-AUC Changes | Change from baseline in Dyspena by VAS-AUC through Day 5, expressed in mm-hours | Through Day 5 | 
| Length of Intensive Care Unit (ICU) and/or Coronary Care Unit (CCU) Stay for the Index AHF Hospitalization | Length of stay will be defined as the hospitalization discharge date and the time minus the baseline date and time plus 1 day | Up to day 30 | 
| Renal Dysfunction and Prevention of Worsening of Renal Function | number of participants with renal dysfunction or in-hospital worsening of renal function through Day 5 | Through Day 5 | 
| Time to Re-hospitalization Due to Heart Failure and Renal Impairment | Time to event is computed as the number of days from randomization to re-hospitalization due to Heart Failure and renal impairment | Through Day 180 | 
| Time to CV Death or Re-hospitalization Due to Heart Failure/ Renal Failure | Results are given in terms of number of participants with CV death or at least one re-hospitalization due to Heart Failure through day 180 (pre-defined timeframe). | Through Day 180 | 
| Time to In-hospital Worsening Heart Failure Through Day 5 | Results are given in terms of number of participants with at least one in-hospital worsening heart failure through day 5 (pre-defined timeframe). In-hospital worsening heart failure is defined by symptoms only, signs only, and both symptoms and signs. | Through Day 5 | 
| Use of Loop Diuretic and Vasoactive Agents | Number of patients reported with use of loop diuretic and vasoactive agents from randomization through Day 5 | Through Day 5 | 
| Change From Baseline in Cardio-renal Biomarkers |  | Day 2 and Day 5 | 
| Number of Patients Reported With Total Adverse Events, Serious Adverse Events and Death. | To evaluate the safety and tolerability of intravenous serelaxin in AHF patients, number of patients with total adverse events, serious adverse events and death will be analyzed. | For the safety evaluation, all adverse events will be collected from signing of the informed consent form through Day 5 for non-serious AEs and through Day 14 for serious AEs. | 
| Time to WHF | Results are given in terms of number of participants with at least one worsening heart failure (WHF) event through day 5 (pre-defined timeframe). | Through Day 5 | 
| Time to CV Death | analysis of time to CEC CV death through day 180 : results are given in terms of number of participants with CV death event through day 180 (pre-defined timeframe). | Through Day 180 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Serelaxin,, WHF,, Likert Scale,, RELAX-AHF-ASIA,, RLX030,, AHF,, acute heart failure