A Study of CLR325 in Chronic Stable Heart Failure Patients.

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

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.

Study Overview

• Status: Completed
• Conditions: Chronic Stable Heart Failure
• Intervention / Treatment: Other: Placebo; Drug: CLR325

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Aalst, Belgium, 9300
    • Novartis Investigative Site
• Germany
  • Greifswald, Germany, 17475
    • Novartis Investigative Site
  • Bavaria
    • Regensburg, Bavaria, Germany, 93053
      • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 169609
    • Novartis Investigative Site
• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Novartis Investigative Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Novartis Investigative Site
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Novartis Investigative Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Novartis Investigative Site
  • Texas
    • Houston, Texas, United States, 77030
      • Novartis Investigative Site
  • Washington
    • Tacoma, Washington, United States, 98405
      • 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:

• 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CLR325; 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; CLR325 Concentrate for solution for infusion
Placebo Comparator: Placebo; 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; Normal saline

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• A Plain Language Trial Summary is available on novartisclinicatrials.com

Study record dates

Study Major Dates

• Study Start (Actual): May 17, 2016
• Primary Completion (Actual): January 14, 2019
• Study Completion (Actual): January 14, 2019

Study Registration Dates

• First Submitted: February 26, 2016
• First Submitted That Met QC Criteria: February 26, 2016
• First Posted (Estimate): March 2, 2016

Study Record Updates

• Last Update Posted (Actual): January 5, 2021
• Last Update Submitted That Met QC Criteria: December 9, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: Apelin; Chronic heart failure; CLR325
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: CCLR325X2202; 2016-001387-12 (EudraCT Number)

Plan for Individual participant data (IPD)

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

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