E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10007558 |
E.1.2 | Term | Cardiac failure chronic |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the safety and tolerability of CLR325 in stable heart failure patients. |
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E.2.2 | Secondary objectives of the trial |
To determine the pharmacokinetics and immunogenicity of CLR325 and the active metabolite CQJ295 in heart failure patients. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Written informed consent must be obtained before any assessment is performed.
•Able to communicate well with the investigator, to understand and comply with the requirements of the study.
•Male and female patients >18 years of age.
•Patients must weigh between 50kg and 140 kg to participate in the study.
•Patients with a cardiac ejection fraction of ≤ 45% as 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 will not
require a change in their dose of ACE, ARB, β-blocker, mineralocorticoid receptor antagonist, or diuretic for 24 hours after
randomization
•At baseline, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting position after the subject has rested for at least five minutes.
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E.4 | Principal exclusion criteria |
•Presence of impaired renal function as indicated by clinically significant abnormal creatinine values (eGFR < 30 ml/min/1.73m^2 calculated using the MDRD equation).
•Patients with values of AST or ALT >100 U/L measured within
the last 3 months before randomization.
•Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV). A
positive Hepatitis B surface antigen (HBsAg) test excludes a
patient. Patients with a positive Hepatitis C antibody test should
have HCV RNA levels measured. Patients with positive
(detectable) HCV RNA should be excluded.
•Patients with a history of chronic hepatitis of any non-cardiac
etiology.
•History of any active, clinically significant cardiac tachyarrhythmia, such as recurrent atrial fibrillation with rapid ventricular response within the last year. Anticoagulation for patients with atrial fibrillation should be managed per usual clinical practice for patients undergoing right heart catheterization.
•For Echocardiography-based cohort only, patients admitted to an
inpatient setting for acute decompensated heart failure within the last
30 days.
•Patients who have received an intravenous infusion of a cardiac
inotrope (e.g.,dobutamine or milrinone) in the last 24 hours prior to
randomization.
•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 <5mm Hg on baseline echocardiogram as determined by
inferior vena cava criteria.
•Patients with any significant change in their dose of their ACE, ARB,
mineralocorticoid receptor antagonist, diuretic or β-blocker within the
last 12 hours.
•Patients with minor changes in their heart failure regimen may be eligible if deemed clinically stable by both the investigator and
sponsor.
•Patients with known significant valvular heart disease, as indicated
by the following:
- Severe aortic stenosis (Aortic Valve Area < 1.0 cm^2 or peak
gradient > 50 mmHg as determined by echocardiography)
- Severe mitral stenosis
•Patients with history of acute coronary syndrome within the last 60
days as determined by both clinical and enzymatic criteria. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Number of patients with adverse events, serious adverse events and death [ Time Frame: Day 1 to 28 ] |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
•Pharmacokinetic of CLR325 and CQJ295: area under the plasma concentration-time curve from time zero to 18 hours (AUC0-18hr) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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: renal clearance from plasma (CLr) following drug administration [ Time Frame: 0-28 hours on Day 1 ]
•Pharmacokinetic of CLR325 and CQJ295: observed maximum plasma concentration following drug administration at steady state (Cmax,ss) [ Time Frame: 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: time to reach the maximum concentration after drug administration (TMax) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 0-28 hours on Day 1 ]
•Number of patients with increase in anti-CLR325 and anti-apelin antibodies in serum [ Time Frame: Baseline, Day 10 and Day 28 ] |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 6 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Germany |
Netherlands |
Poland |
Singapore |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 6 |