Study of the Vascular Effects of Serelaxin

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

Detailed Description
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double blind, randomized, parallel group, placebo controlled study

Official Title
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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

Conditions
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Coronary Artery Disease

Intervention / Treatment
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* Drug: Serelaxin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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).

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

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: double blind, randomized, parallel group, placebo controlled study
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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coronary artery disease