Study of Safety, Tolerability and Pharmacokinetics of Serelaxin in Japanese Acute Heart Failure (AHF) Patients

Phase 2CompletedNCT02002702

Novartis Pharmaceuticals46 enrolled

Overview

This is a multicenter, randomized, double-blind, placebo-controlled study to assess safety, tolerability and pharmacokinetics and to explore efficacy of IV infusion of 10 µg/kg/day and 30 µg/kg/day serelaxin for 48 hours compared to placebo, when added to the standard therapy, in approximately 45 Japanese AHF patients.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Acute Heart Failure

Interventions

SerelaxinDRUG

Intravenous infusion

PlaceboDRUG

Placebo

Eligibility

Sex: ALLMin age: 20 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: * Written informed consent must be obtained before any study-specific assessment is performed. * Male or female ≥20 years of age, with body weight ≥30 kg and ≤160 kg * Hospitalized for AHF; AHF is defined as including all of the followings measured at any time between presentation (including the emergency department) and the end of screening: * Dyspnea at rest or with minimal exertion * Pulmonary congestion on chest radiograph * BNP ≥350 pg/mL or NT-proBNP ≥1,400 pg/mL * SBP ≥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 * Received intravenous (IV) furosemide of at least 40 mg (or equivalent) at any time between presentation (this include outpatient clinic, ambulance, or hospital including emergency department) and the start of screening for the study for the treatment of the current acute heart failure (HF) episode. * Impaired renal function defined as an estimated glomerular filtration rate (eGFR) between presentation and randomization of ≥ 25 and≤ 75 mL/min/1.73 m2, calculated using the Japanese formula Key Exclusion Criteria: * Dyspnea primarily due to non-cardiac causes * Temperature \>38.5°C (oral or equivalent) or sepsis or active infection requiring IV anti-microbial treatment * Clinical evidence of acute coronary syndrome currently or within 30 days prior to enrollment. * 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.

Locations (15)

Novartis Investigative Site

Seto, Aichi-ken, Japan

Novartis Investigative Site

Fukuoka, Fukuoka, Japan

Novartis Investigative Site

Iizuka, Fukuoka, Japan

Outcomes

Primary Outcomes

Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy

AEs were defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. SAEs were defined as any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgement of investigators represent significant hazards. AEs leading to discontinuations, or requiring dose adjustment or interruptions and additional therapy were assessed.

Time frame: From start of study treatment up to Day 5 (for AEs); From start of study treatment up to Day 14 (for SAEs)

Maximum Plasma Concentration (Cmax) of Serelaxin

Maximum plasma concentration (Cmax) was defined as the peak level of serelaxin, derived from plasma concentration-time data, using a non-compartmental model approach.

Time frame: Baseline (pre-dose), 1, 2, 24, 48, 49, 52 and 56 hours (post-dose)

Weight Adjusted Clearance (CL) of Serelaxin

Weight adjusted clearance (CL) was defined as the total body clearance of serelaxin after drug administration. CL was calculated as nominal infusion rate divided by Css, using a non-compartmental model approach.

Time frame: Baseline (pre-dose), 1, 2, 24, 48, 49, 52 and 56 hours (post-dose)

Concentration at Steady-state (Css) of Serelaxin

Concentration at steady-state (Css) was defined as concentration at the state of equilibrium obtained at the end of a certain number of administrations. Css of serelaxin in plasma was calculated by using a non-compartmental model approach.

Time frame: Baseline (pre-dose), 1, 2, 24, 48, 49, 52 and 56 hours (post-dose)

Secondary Outcomes

Data from ClinicalTrials.gov

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Change From Baseline in Area Under the Curve (AUC) for Systolic Blood Pressure (SBP) Through 48 Hours of Infusion at Day 5

The area under the curve (AUC) was defined as area under the plasma concentration-time curve from time zero to time of the last time point with measurable concentration, calculated by a trapezoidal method. Systolic blood pressure was measured using a calibrated standard sphygmomanometer after the subject remained in sitting position for 3 minutes at clinic during the visit. Sample collected at: Baseline; 30 \& 60 minutes and then every hour for the first 6 hours of study drug infusion, and then every 3 hours during 48 hours of study drug infusion; every 3 hours until 12 hours following end of infusion, then every 6 hours for 48 hours and then every 24 hours until the earlier of Day 5 or discharge. AUC for SBP is standardized by dividing by the length of respective time ranges.

Time frame: Baseline, 48 hours, Day 5

Change From Baseline in Aldosterone Levels Through Day 14

Aldosterone biomarker was used to assess the effect of serelaxinin on fluid retention. Geometric means of the ratio of post-Baseline values to baseline values of aldosterone was calculated by treatment for the full analysis set.