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

Phase 3

Terminated

Conditions: Acute Heart Failure

Interventions: Drug: Placebo
Drug: Serelaxin
Other: Standard of CareTherapy

Registration Number: NCT02007720

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 876

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Serelaxin	Standard of CareTherapy	Patients will receive continuous intravenous infusion of serelaxin(30 µg/kg/day) for 48 hours.
Placebo	Placebo	Patients will receive continuous intravenous infusion of matching placebo serelaxin for 48 hours.
Placebo	Standard of CareTherapy	Patients will receive continuous intravenous infusion of matching placebo serelaxin for 48 hours.
Serelaxin	Serelaxin	Patients will receive continuous intravenous infusion of serelaxin(30 µg/kg/day) for 48 hours.

Primary Outcome Measures

Name	Time	Method
Percentage of Patients With a Clinical Composite Endpoint of Treatment Success, Treatment Failure, or no Change.	through day 5	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.

Secondary Outcome Measures

Name	Time	Method
Time to WHF	Through Day 5	Results are given in terms of number of participants with at least one worsening heart failure (WHF) event through day 5 (pre-defined timeframe).
Time to CV Death	Through Day 180	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).
Time to All-cause Death	Through Day 180	Results are given in terms of number of participants with all cause death event through day 180 (pre-defined timeframe).
Time to Moderate or Marked Improvements in Dyspnea by Likert Scale, Expressed in Days	Through Day 5	Time to event is computed as the number of days from randomization to moderate or marked improvements in dyspnea by Likert scale
Dyspnea by VAS-AUC Changes	Through Day 5	Change from baseline in Dyspena by VAS-AUC through Day 5, expressed in mm-hours
Length of Intensive Care Unit (ICU) and/or Coronary Care Unit (CCU) Stay for the Index AHF Hospitalization	Up to day 30	Length of stay will be defined as the hospitalization discharge date and the time minus the baseline date and time plus 1 day
Renal Dysfunction and Prevention of Worsening of Renal Function	Through Day 5	number of participants with renal dysfunction or in-hospital worsening of renal function through Day 5
Time to Re-hospitalization Due to Heart Failure and Renal Impairment	Through Day 180	Time to event is computed as the number of days from randomization to re-hospitalization due to Heart Failure and renal impairment
Time to CV Death or Re-hospitalization Due to Heart Failure/ Renal Failure	Through Day 180	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).
Time to In-hospital Worsening Heart Failure Through Day 5	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.
Use of Loop Diuretic and Vasoactive Agents	Through Day 5	Number of patients reported with use of loop diuretic and vasoactive agents from randomization 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.	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.	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.