Safety of Repeat Doses of IV Serelaxin in Subjects With Chronic Heart Failure

Study Overview
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Brief Summary
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The purpose of this study was to assess the safety of repeat doses of serelaxin in chronic heart failure.

Official Title
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Prospective, Double-Blind, Multicenter Study Evaluating the Safety of Repeat Doses of IV Serelaxin in Subjects With Chronic Heart Failure

Conditions
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Chronic Heart Failure

Intervention / Treatment
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* Drug: RLX030 (serelaxin)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Body weight of ≤ 160 kg. Subjects with compensated CHF (NYHA Class II - III) at time of screening with a prior documented history of chronic heart failure. NT-proBNP >300 pg/ml (according to central measurement) at visit 1. Subjects treated with appropriate and guideline-indicated CHF standard of care. Ability to comply with all requirements, including ability to receive at least a 48 hour infusion plus follow-up time required for each dosing visit. Key Exclusion Criteria: Current acute decompensated HF Any major solid organ transplant recipient or planned anticipated organ transplant within 1 year. Documented history of untreated ventricular arrhythmia with syncopal episodes, ventricular tachycardia, or ventricular fibrillation without ICD (implantable cardioverter defibrillator) with significant hemodynamic consequences within the 3 months prior to screening. Presence of hemodynamically significant mitral and /or aortic valve disease, except mitral regurgitation secondary to left ventricular dilatation: including significant left ventricular outflow obstruction (e.g., obstructive hypertrophic cardiomyopathy, severe aortic stenosis) Subjects with severe renal impairment defined as pre-randomization eGFR < 30 ml/min/1.73m2 calculated using the sMDRD equation and/or those receiving current or planned dialysis or ultrafiltration

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

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RLX030 (serelaxin)<br>Randomized patients received an IV infusion of 30 μg/kg/day of serelaxin for 48 hours at randomization and at Weeks 4 and 8 | Drug: RLX030 (serelaxin)<br>* RLX030 (serelaxin) was administered according to a weight-range adjusted dosing regimen at a nominal dose of 30 μg/kg/day as a continuous IV infusion for 48 hours.<br>* Other names: RLX030;|
| Placebo Comparator: Placebo<br>Randomized patients received an IV infusion of placebo of serelaxin for 48 hours at randomization and at Weeks 4 and 8 | Drug: Placebo<br>* Matching placebo of serelaxin was administered as a continuous IV infusion for 48 hours.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Chronic Heart Failure (CHF) Who Develop Anti-serelaxin Antibodies at Any Time Following Repeat Administration of IV Continuous Infusions of Serelaxin Administered for up to 48 Hours in 16 Weeks | A patient is considered antibody positive during the study if he/she had at least two infusions and had at least one evaluable measurement to test for anti-serelaxin antibodies after each infusion and all evaluable antibody test results were positive. A patient is considered antibody negative during the study if he/she had at least two infusions and had at least one evaluable measurement to test for anti-serelaxin antibodies after each infusion and all evaluable antibody test results were negative. A patient's antibody status is considered to be undetermined during the study if it is not defined as positive or negative. | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Chronic Heart Failure Who Develop Positive Anti-serelaxin Antibodies After a Single Infusion of Serelaxin Over Time up to Week 16 | A patient is considered antibody positive during the study if he/she had at least two infusions and had at least one evaluable measurement to test for anti-serelaxin antibodies after each infusion and all evaluable antibody test results were positive. Each time period is defined as the time frame from study drug initiation (or the visit if there is no infusion) to prior to study drug initiation of the next period (or the visit if no there is no infusion). n= The total number of subjects with evaluable antibody status during the defined period. | Randomization to Week 4, Week 4 to Week 8, Week 8 to Week 12, week 12 to week 16 | 
| Antibody Titers in Participants With Chronic Heart Failure Who Develop Positive Anti-serelaxin Antibodies (Neutralizing, Non-neutralizing or Both) at Any Time Following 3 Repeated Infusions and at Week 4, Week 8 and Week 12 |  | Week 4, Week 8, Week 12 | 
| Percentage of Participants With Chronic Heart Failure With Positive Antibody Status Who Develop Non-neutralizing Anti-serelaxin Antibodies Following 3 Repeated Infusions (i.e. at Week 4, Week 8, and Week 12) | A patient is considered antibody positive during the study if he/she had at least two infusions and had at least one evaluable measurement to test for anti-serelaxin antibodies after each infusion and all evaluable antibody test results were positive. n = the total number of subjects with evaluable antibody status after specified number of infusions | At Week 4, Week 8, Week 12 | 
| Number of Participants With Adverse Events Such as Adjudicated Potential Hypersensitivity or Infusion Reactions | Incidence rate of special interest, indicative of hypersensitivity reactions which occur during and after administration of repeated infusions of serelaxin relative to placebo in subjects with chronic heart failure is reported. Hypersensitivity reactions or infusion reactions can be headache, nausea, fever, chills, dizziness, flush, pruritus, chest and/or back pain. | 16 weeks | 
| Pharmacokinetics of RLX030: Area Under the Plasma Concentration Time Curve From Time Zero up to 48 Hours Post Dose (AUC 0-48) | Due to sparse PK sampling, AUC 0-48 hours was not analyzed. | pre-infusion and 8, 24 and 48 hours post each infusion. | 
| Pharmacokinetics of RLXL030: Actual Concentrations at Steady State (Css) | Concentration at steady state (Css) was estimated using C48 or C24 for patients who received the intended rate of infusion for at least 24hours. n: Number of patients with valid PK parameters available | pre-infusion and 24, 48 hours post each infusion | 
| Pharmacokinetics of RLX030: Cmax Steady State (Cmaxss) Concentration at 48 Hours | This analysis was not done due to sparse PK sampling. | 48 hours post each infusion | 
| Pharmacokinetics of RLX030: Clearance of Serelaxin (CL) | Clearance (CL) was calculated using concentration at steady state (Css) and the actual delivered dose rate. n: Number of patients with valid PK parameters available within 48 hours post each infusion. | 48 hours post each infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Heart Failure, CHF, Heart Failure, HF, Immunogenicity, Anti-bodies, Hypersensitivity, Serelaxin, RELAX-REPEAT