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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Acute Heart Failure

Intervention / Treatment
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* Drug: Serelaxin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 20 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 |
| --- | --- |
| Experimental: Serelaxin 10 mcg/kg/Day<br>Participants received 10 mcg/kg/day serelaxin as continuous i.v. infusion for 48 hours. | Drug: Serelaxin<br>* Intravenous infusion<br>|
| Experimental: Serelaxin 30 mcg/kg/Day<br>Participants received 30 mcg/kg/day serelaxin as continuous i.v. infusion for 48 hours. | Drug: Serelaxin<br>* Intravenous infusion<br>|
| Placebo Comparator: Placebo<br>Participants received continuous i.v. infusion of placebo matched to serelaxin for 48 hours. | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | Baseline (pre-dose), 1, 2, 24, 48, 49, 52 and 56 hours (post-dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | Baseline, Day 1, Day 2, Day 5, Day 14 | 
| 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. | Baseline, Day 1, Day 2, Day 5, Day 14 | 
| 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. | Baseline, Day 1, Day 2, Day 5, Day 14 | 
| 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. | Baseline, Day 1, Day 2, Day 5, Day 14 | 
| 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. | Baseline, Day 1, Day 2, Day 5, Day 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute heart failure (AHF),, Japanese,, Safety and tolerability, Pharmacokinetics,, Renal Impairment