Safety of Repeat Doses of IV Serelaxin in Subjects With Chronic Heart Failure (RELAX-REPEAT)

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

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

Study Overview

• Status: Completed
• Conditions: Chronic Heart Failure
• Intervention / Treatment: Drug: RLX030 (serelaxin); Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 321
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Geelong, Australia, 3220
    • Novartis Investigative Site
  • Melbourne, Australia, VIC 3004
    • Novartis Investigative Site
• Czech Republic
  • Brno - Bohunice, Czech Republic, 625 00
    • Novartis Investigative Site
  • JIhlava, Czech Republic, 586 01
    • Novartis Investigative Site
  • Praha 2, Czech Republic, 128 08
    • Novartis Investigative Site
• Finland
  • Turku, Finland, 20521
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 10117
    • Novartis Investigative Site
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Dresden, Germany, 01069
    • Novartis Investigative Site
  • Frankfurt, Germany, 60488
    • Novartis Investigative Site
  • Greifswald, Germany, 17475
    • Novartis Investigative Site
  • Grunstadt, Germany, D-67269
    • Novartis Investigative Site
  • Jena, Germany, 07740
    • Novartis Investigative Site
  • Kiel, Germany, 24105
    • Novartis Investigative Site
  • Luebeck, Germany, 23562
    • Novartis Investigative Site
  • Magdeburg, Germany, 39112
    • Novartis Investigative Site
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30159
      • Novartis Investigative Site
• Italy
  • AR
    • Cortona, AR, Italy, 52044
      • Novartis Investigative Site
  • BS
    • Brescia, BS, Italy, 25123
      • Novartis Investigative Site
  • MB
    • Monza, MB, Italy, 20900
      • Novartis Investigative Site
  • MI
    • Vimercate, MI, Italy, 200059
      • Novartis Investigative Site
• Netherlands
  • Groningen, Netherlands
    • Novartis Investigative Site
  • Rotterdam, Netherlands, 3000 CA
    • Novartis Investigative Site
  • The Netherlands
    • Sneek, The Netherlands, Netherlands, 8601 ZR
      • Novartis Investigative Site
• Norway
  • Oslo, Norway, 0424
    • Novartis Investigative Site
• Romania
  • Bucharest, Romania, 021659
    • Novartis Investigative Site
  • Bucuresti, Romania, 014461
    • Novartis Investigative Site
  • Craiova, Romania, 200642
    • Novartis Investigative Site
  • Sibiu, Romania, 550245
    • Novartis Investigative Site
  • Mures
    • Targu Mures, Mures, Romania, 540136
      • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation, 117198
    • Novartis Investigative Site
  • Moscow, Russian Federation, 109469
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28007
    • Novartis Investigative Site
  • Madrid, Spain, 28040
    • Novartis Investigative Site
  • Andalucia
    • Malaga, Andalucia, Spain, 29010
      • Novartis Investigative Site
    • Sevilla, Andalucia, Spain, 41014
      • Novartis Investigative Site
  • Cadiz
    • Villamartin, Cadiz, Spain, 11650
      • Novartis Investigative Site
• Sweden
  • Stockholm, Sweden, 141 86
    • Novartis Investigative Site
• Turkey
  • Diskapi / Ankara, Turkey, 06110
    • Novartis Investigative Site
  • Haydarpasa/Istanbul, Turkey, 34668
    • Novartis Investigative Site
  • Kocaeli, Turkey, 41380
    • Novartis Investigative Site
  • Meselik / Eskisehir, Turkey, 26480
    • Novartis Investigative Site
  • Sivas, Turkey, 58140
    • Novartis Investigative Site
• United States
  • California
    • Anaheim, California, United States, 92801
      • Novartis Investigative Site
  • Colorado
    • Colorado Springs, Colorado, United States, 80918
      • Novartis Investigative Site
  • Florida
    • Jacksonville, Florida, United States, 32216
      • Novartis Investigative Site
    • South Miami, Florida, United States, 33143
      • Novartis Investigative Site
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Novartis Investigative Site
    • Minneapolis, Minnesota, United States, 55417
      • Novartis Investigative Site
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7075
      • Novartis Investigative Site
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • Novartis Investigative Site
  • Virginia
    • Richmond, Virginia, United States, 23298-0050
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: RLX030 (serelaxin); 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); 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.; Other Names: RLX030
PLACEBO_COMPARATOR: Placebo; Randomized patients received an IV infusion of placebo of serelaxin for 48 hours at randomization and at Weeks 4 and 8	Drug: Placebo; Matching placebo of serelaxin was administered as a continuous IV infusion for 48 hours.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Kumar VA, Wilson SS, Ayaz SI, Levy PD. Targeted biological therapies reach the heart: the case of serelaxin for heart failure. Drugs Today (Barc). 2015 Oct;51(10):591-7. doi: 10.1358/dot.2015.51.10.2386731.

Study record dates

Study Major Dates

• Study Start: May 1, 2014
• Primary Completion (ACTUAL): September 1, 2015
• Study Completion (ACTUAL): September 1, 2015

Study Registration Dates

• First Submitted: November 6, 2013
• First Submitted That Met QC Criteria: November 6, 2013
• First Posted (ESTIMATE): November 13, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): November 9, 2016
• Last Update Submitted That Met QC Criteria: September 21, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: Chronic Heart Failure, CHF, Heart Failure, HF, Immunogenicity, Anti-bodies, Hypersensitivity, Serelaxin, RELAX-REPEAT
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: CRLX030A2209; 2013-002781-39 (EUDRACT_NUMBER)