Study of the Vascular Effects of Serelaxin

A Multicenter, Double Blind, Randomized, Parallel Group, Placebo-controlled Study to Evaluate the Effects of Intravenous Serelaxin Infusion on Micro- and Macrovascular Function in Patients With Coronary Artery Disease

This was a mechanistic study in patients with coronary artery disease on the effects of Serelaxin on micro- and macrovascular function.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease
• Intervention / Treatment: Drug: Serelaxin; Other: Placebo

Detailed Description

double blind, randomized, parallel group, placebo controlled study

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Edinburgh, United Kingdom, EHN 2XU
    • Novartis Investigative Site
  • Leicester, United Kingdom, LE3 9QP
    • Novartis Investigative Site
  • West Dumbartonshire
    • Clydebank, West Dumbartonshire, United Kingdom, G81 4HX
      • 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

Inclusion Criteria:

• Male and female patients ≥18 years of age, with body weight <160 kg.
• Patients with proven obstructive coronary artery disease, determined either by functional (e.g. treadmill testing) or non-invasive clinical imaging assessments (e.g. stress-echo, PET or SPECT myocardial perfusion), or invasive coronary angiography or by CT coronary angiography at any point in time in patients with or without mild left ventricular systolic dysfunction (LVSD)

Exclusion Criteria:

• Previous treatment with serelaxin (also known as: RLX030, relaxin)
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of study treatment.
• Current or planned dialysis.
• Impaired renal function during screening defined as an estimated glomerular filtration rate (eGFR) at screening and prior to treatment of <30 mL/min/1.73 m2, calculated using the simplified Modification of Diet in Renal Disease (sMDRD) equation due to potential issue with administration of GdDTPA used as the MRI contrast agent.
• Sick-Sinus-Syndrome
• Current or history of pulmonary edema, including suspected sepsis.
• restrictive, or constrictive cardiomyopathy (does not include restrictive mitral filling patterns seen on Doppler echocardiographic assessments of diastolic function)
• Known significant valvular disease (including any of the following: severe aortic stenosis [AVA < 1.0 or peak gradient > 50 on prior or current echocardiogram], severe aortic regurgitation, or severe mitral stenosis).
• Clinical diagnosis of acute coronary syndrome (ACS) including unstable angina within 30 days prior to screening as determined by both clinical and enzymatic criteria
• Troponin elevation and dynamics indicative of ACS at any time between screening and randomization.
• Previous myocardial infarction within 3 months of screening
• History of Coronary Artery Bypass Graft (CABG) surgery
• Heart failure due to significant arrhythmias (including any of the following: ventricular tachycardia, bradyarrhythmias with ventricular rate < 45 beats per minute or any second or third degree AV block or atrial fibrillation/flutter with ventricular response of > 120 beats per minute)
• Any surgical or medical condition which in the opinion of the investigator may place the patient at higher risk from his/her participation in the study (e.g., history of poor tolerance of adenosine or 3 vessel coronary disease)
• Acute myocarditis or hypertrophic obstructive, restrictive, or constrictive cardiomyopathy (does not include restrictive mitral filling patterns seen on Doppler echocardiographic assessments of diastolic function).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Serelaxin; Serelaxin was administered at a dose of 30 μg/kg/24h by intravenous infusion for 48 hours	Drug: Serelaxin; Serelaxin solution diluted in 5% glucose volume/volume (v/v) solution; Other Names: RLX030, relaxin
Placebo Comparator: Placebo; Placebo was administered by intravenous infusion for 48 hours	Other: Placebo; 5% v/v glucose solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Statistical Analysis of Change From Baseline to Day 3 in Myocardial Perfusion Endpoints Compared With Mid Perfusion Reserve Index Using ANCOVA End Points	Global MPRI (Myocardial Perfusion Reserve Index) is defined as ratio between mean global myocardial blood flow values at rest and during adenosine stress with Mid Perfusion Reserve Index or Midl PRI (Mid Perfusion Reserve Index) which is defined as ratio between mid myocardial blood flow values at rest and during adenosine stress	baseline to Day 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Aortic Distensibility Measured by MRI	Measurements of arterial stiffness from cardiac MRI - Mean (SD) [n] Aortic distensibility was assessed by MRI and pulse wave velocity using the SphygmoCor device. (mmHg-1)	At pre-dose on Day 1 (baseline) until Day 180 after the start of drug infusion
Change From Baseline in Aortic Velocity	Summary table for measurements of arterial velocity from cardiac MRI - Mean (SD) [n] Aortic distensibility was assessed by MRI and pulse wave velocity using the SphygmoCor device	At pre-dose on Day 1 (baseline) until Day 180 after the start of drug infusion
Change From Baseline in Augmentation Index Measured From Sphygmocor Device	Summary of values and change from baseline in augmentation index by time and treatment The change from baseline in Augmentation Index was analyzed using a repeated measures analysis of covariance including treatment, time, treatment by time, baseline by time interactions and baseline as fixed factors with an unstructured variance-covariance matrixStatistical analysis of change from baseline in augmentation index using repeated measures Analysis of Covariance	Day1, Day 2, Day 3, Day 30 and Day 180 after the start of infusion
Statistical Analysis of Change From Baseline in Augmentation Index Using Repeated Measures Analysis of Covariance	The change from baseline in Augmentation Index was analyzed using a repeated measures analysis of covariance including treatment, time, treatment by time, baseline by time interactions and baseline as fixed factors with an unstructured variance-covariance matrixStatistical analysis of change from baseline in augmentation index using repeated measures Analysis of Covariance For analysis of change from baseline, only subjects with results at both baseline and post-baseline could be included The augmentation index is a ratio calculated from the blood pressure waveform, it is a measure of wave reflection and arterial stiffness. Augmentation index is commonly accepted as a measure of the enhancement (augmentation) of central aortic pressure by a reflected pulse wave	Day1, Day 2, Day 3, Day 30 and Day 180 after the start of infusion
Change From Baseline in Pulse Wave Velocity Measured From Carotid-femoral Pulse Wave Analysis	Pulse wave velocity was assessed by the SphygmoCor device	Day1, Day 2, Day 3, Day 30 and Day 180 after the start of infusion
Serum Concentration of Serelaxin	Summary statistics of serelaxin serum PK concentrations Blood samples were taken to measure serelaxin concentration	Day1, Day 2, Day 3 and Day 30 after the start of infusion
Serum Concentration of Antibodies to Serelaxin	Frequency and percentage of anti-Serelaxin antibodies Blood samples were taken to measure antibodies to serelaxin concentration at Pre-dose on Day 1, and at Day 30 after the start of the 48h drug infusion	From pre-dose on Day 1 until Day 30 after the start of drug infusion
Systemic Clearance of Serelaxin	Systemic clearance was estimated using the rate of serelaxin infusion and the steady state concentration	From pre-dose on Day 1 until 48h after the start of drug infusion

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): February 3, 2014
• Primary Completion (Actual): August 17, 2016
• Study Completion (Actual): August 17, 2016

Study Registration Dates

• First Submitted: November 4, 2013
• First Submitted That Met QC Criteria: November 4, 2013
• First Posted (Estimate): November 8, 2013

Study Record Updates

• Last Update Posted (Actual): July 1, 2019
• Last Update Submitted That Met QC Criteria: April 5, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: coronary artery disease
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease
• Other Study ID Numbers: CRLX030A2203; 2012-001945-42 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No