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

Primary Purpose

Acute Heart Failure

Status

Completed

Phase

Phase 2

Locations

Japan

Study Type

Interventional

Intervention

Serelaxin

Placebo

About this trial

This is an interventional treatment trial for Acute Heart Failure focused on measuring Acute heart failure (AHF),, Japanese,, Safety and tolerability, Pharmacokinetics,, Renal Impairment

Eligibility Criteria

20 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Placebo Comparator

Arm Label

Serelaxin 10 mcg/kg/Day

Serelaxin 30 mcg/kg/Day

Placebo

Arm Description

Participants received 10 mcg/kg/day serelaxin as continuous i.v. infusion for 48 hours.

Participants received 30 mcg/kg/day serelaxin as continuous i.v. infusion for 48 hours.

Participants received continuous i.v. infusion of placebo matched to serelaxin for 48 hours.

Outcomes

Primary Outcome Measures

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.

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.

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.

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.

Secondary Outcome Measures

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.

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.

Change From Baseline in Cystatin-C Levels Through Day 14

Cystatin-C biomarker was used to assess the effect of serelaxinin on worsening of renal function. Geometric means of the ratio of post-Baseline values to baseline values of Cystatin-C was calculated by treatment for the full analysis set.

Change From Baseline in High Sensitivity Troponin-T Levels Through Day 14

High sensitivity Troponin-T biomarker was used to assess the effect of serelaxin on myocardial damage. Geometric means of the ratio of post-Baseline values to baseline values of high sensitivity troponin-t was calculated by treatment for the full analysis set.

Change From Baseline in NT-proBNP Levels Through Day 14

NT-proBNP biomarker was used to assess the effect of serelaxinin on degree of cardiac wall stress and congestion. Geometric means of the ratio of post-Baseline values to baseline values of NT-proBNP was calculated by treatment for the full analysis set.

Change From Baseline in Neutrophil Gelatinase-asc Lipocalin (NGAL) Levels Through Day 14

Neutrophil gelatinase-asc lipocalin (NGAL) biomarker was used to assess the effect of serelaxin on kidney function. Geometric means of the ratio of post-Baseline values to baseline values of NGAL was calculated by treatment for the full analysis set.

Full Information

NCT ID

NCT02002702

First Posted

December 1, 2013

Last Updated

September 11, 2015

Sponsor

Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT02002702

Brief Title

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

Official Title

A Multicenter, Randomized, Double-blind, Placebo-controlled Phase II Study to Assess the Safety, Tolerability and Pharmacokinetics of Serelaxin When Added to Standard Therapy in Japanese Acute Heart Failure Patients

Study Type

Interventional

2. Study Status

Record Verification Date

September 2015

Overall Recruitment Status

Completed

Study Start Date

January 2014 (undefined)

Primary Completion Date

August 2014 (Actual)

Study Completion Date

August 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acute Heart Failure

Keywords

Acute heart failure (AHF),, Japanese,, Safety and tolerability, Pharmacokinetics,, Renal Impairment

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

46 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Serelaxin 10 mcg/kg/Day

Arm Type

Experimental

Arm Description

Participants received 10 mcg/kg/day serelaxin as continuous i.v. infusion for 48 hours.

Arm Title

Serelaxin 30 mcg/kg/Day

Arm Type

Experimental

Arm Description

Participants received 30 mcg/kg/day serelaxin as continuous i.v. infusion for 48 hours.

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Participants received continuous i.v. infusion of placebo matched to serelaxin for 48 hours.

Intervention Type

Drug

Intervention Name(s)

Serelaxin

Intervention Description

Intravenous infusion

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Placebo

Primary Outcome Measure Information:

Title

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

Description

Time Frame

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

Title

Maximum Plasma Concentration (Cmax) of Serelaxin

Description

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)

Title

Weight Adjusted Clearance (CL) of Serelaxin

Description

Time Frame

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

Title

Concentration at Steady-state (Css) of Serelaxin

Description

Time Frame

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

Secondary Outcome Measure Information:

Title

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

Description

Time Frame

Baseline, 48 hours, Day 5

Title

Change From Baseline in Aldosterone Levels Through Day 14

Description

Time Frame