A Study of CLR325 in Chronic Stable Heart Failure Patients.

Study Overview
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Brief Summary
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The purpose of this study was to determine the safety and tolerability of CLR325 intravenous (i.v.) infusion in patients with stable heart failure to determine if further clinical development of the drug in this indication was warranted.

Official Title
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A Randomized, Subject and Investigator-blind, Placebo-controlled Study of CLR325 in Chronic Stable Heart Failure Patients

Conditions
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Chronic Stable Heart Failure

Intervention / Treatment
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* Drug: CLR325
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male and female patients >18 years of age Body weight between 50 kg and 140 kg Cardiac ejection fraction of ≤ 45% assessed within the last 6 months For PA catheter cohorts, patients who are planned to have a clinically indicated pulmonary artery catheter in place prior to randomization In the opinion of the investigator, heart failure patients who do not require a change in their dose of acetylcholinesterase (ACE), angiotensin receptor blocker (ARB), β-blocker, mineralocorticoid receptor antagonist, or diuretic for 24 h after randomization. At Baseline, vital signs (systolic and diastolic blood pressure and pulse rate) assessment in the supine position after the subject has rested for at least five minutes. Key Exclusion Criteria: Impaired renal function as indicated by clinically significant abnormal creatinine values (Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 calculated using the Modification of Diet in Renal Disease Study (MDRD) equation) History of chronic hepatitis of any non-cardiac etiology History of any active or clinically significant cardiac tachyarrhythmia (such as recurrent atrial fibrillation with rapid ventricular response within the last year) and patients with chronic atrial fibrillation with a pulse rate ≤ 100 bpm Patients who received an i.v. infusion of a cardiac inotrope (e.g., dobutamine or milrinone) in the last 24 h prior to randomization Patients with any significant change in their dose of their ACE, ARB, mineralocorticoid receptor antagonist, diuretic, or β-blocker within the last 12 h Patients with known significant valvular heart diseases indicated by the following: severe aortic stenosis (aortic valve area < 1.0 cm2 or peak gradient > 50 mm Hg as determined by echocardiography) severe mitral stenosis History of acute coronary syndrome within the last 60 days as determined by both clinical and enzymatic criteria For echocardiography-based cohorts only, patients admitted to an inpatient setting for acute decompensated heart failure within the last 30 days For PA catheter cohorts, patients with a pulmonary capillary wedge pressure of <10 mm Hg at Baseline. For echocardiographic cohorts, patients with a lateral E/E' ratio of < 7 on their baseline echocardiogram. For patients in whom a lateral E/E' ratio cannot be determined (e.g., patients in atrial fibrillation), a central venous pressure of < 5 mm Hg on baseline echocardiogram as determined by inferior vena cava criteria.

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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CLR325<br>Patients were assigned to one of the 2 treatment arms in fixed randomization ratio. Patients randomized to this arm received single dose of CLR325 (i.v.) in double blind manner. | Drug: CLR325<br>* CLR325 Concentrate for solution for infusion<br>|
| Placebo Comparator: Placebo<br>Patients were assigned to one of the 2 treatment arms in fixed randomization ratio. Patients randomized to this arm received single dose of placebo (i.v.) in double blind manner. | Other: Placebo<br>* Normal saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Adverse Events, Serious Adverse Events and Death | Analysis of absolute and relative frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths by primary System Organ Class (SOC) in each treatment arm to demonstrate that CLR325 is safe for the treatment of chronic stable heart-failure patients through the monitoring of relevant clinical and laboratory safety parameters. | Day 1 to 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From Time Zero to 18 Hours (AUC0-18hr) | AUC0-18hr is the area under the plasma concentration-time curve from time zero to 18 hours after the start of CLR325 infusion. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Only descriptive analysis performed. | 0, 0.5, 3, 5, 8, 10, 12, and 18 hours post start of CLR325 infusion on Day 1 | 
| Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From From Time Zero to 28 Hours (AUC0-28hrs) | AUC0-28hr is the area under the plasma concentration-time curve from time zero to 28 hours after the start of CLR325 infusion. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Only descriptive analysis performed. | 0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1 | 
| Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) | AUCinf is the area under the plasma concentration-time curve from time zero to infinity. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Only descriptive analysis performed. | 0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1 | 
| Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) | AUClast is the area under the plasma concentration-time curve from time zero to the last measurable concentration sampling time. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Only descriptive analysis performed. | 0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1 | 
| Pharmacokinetic of CLR325: Clearance From Plasma (CL) Following Drug Administration | CL is the systemic (or total body) clearance from plasma following CLR325 infusion. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Only descriptive analysis performed. | 0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1 | 
| Pharmacokinetic of CLR325 and CQJ295: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax,ss) | Cmax,ss is the observed maximum plasma concentration following drug administration at steady state. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Only descriptive analysis performed. | 0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1 | 
| Pharmacokinetic of CLR325 and CQJ295: Terminal Elimination Half-life (T1/2) | T^1/2 is the elimination half-life associated with the terminal slope of a semi logarithmic concentration-time curve. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Only descriptive analysis performed. | 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1 | 
| Pharmacokinetic of CLR325 and CQJ295: Time to Reach the Maximum Concentration After Drug Administration (TMax) | Tmax is the time to reach maximum plasma concentration after single dose administration. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Only descriptive analysis performed. | 0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1 | 
| Pharmacokinetic of CLR325: Volume of Distribution at Steady State Following Intravenous Administration (Vss) | Vss is the volume of distribution at steady state following intravenous administration. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Only descriptive analysis performed. | 0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1 | 
| Pharmacokinetic of CLR325 and CQJ295: Amount of Drug (or Defined Metabolite) Excreted Into the Urine From Time (Ae 0-28 Hours) | Ae 0-28 hours is the amount of drug (or defined metabolite) excreted into the urine from time zero to 28 hours after the start of CLR325 infusion. The urine PK parameters were measured using an non-compartmental methods. Only descriptive analysis performed. | 0-28 hours on Day 1 | 
| Pharmacokinetic of CLR325 and CQJ295: Renal Clearance From Plasma (CLr) Following Drug Administration | CLr is the renal clearance from urine following CLR325 infusion. The urine PK parameters were measured using an non-compartmental methods. Only descriptive analysis performed. | 0-28 hours on Day 1 | 
| Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | Anti-CLR325 anti-apelin antibodies in serum were analyzed predose, Day 10 and Day 28 to determine the immunogenicity of an 18-hour i.v. infusion of CLR325 in heart failure patients. | Baseline (BL), Day 10 (D10) and Day 28 (D28) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Apelin, CLR325, Chronic heart failure