Chronic Stable Heart Failure
Conditions
Keywords
Apelin, CLR325, Chronic heart failure
Brief summary
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.
Interventions
DRUGCLR325
CLR325 Concentrate for solution for infusion
OTHERPlacebo
Normal saline
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Adverse Events, Serious Adverse Events and Death | Day 1 to 28 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From From Time Zero to 28 Hours (AUC0-28hrs) | 0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1 | 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. |
| Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) | 0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1 | 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. |
| Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) | 0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1 | 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. |
| Pharmacokinetic of CLR325: Clearance From Plasma (CL) Following Drug Administration | 0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1 | 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. |
| Pharmacokinetic of CLR325 and CQJ295: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax,ss) | 0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1 | 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. |
| Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From Time Zero to 18 Hours (AUC0-18hr) | 0, 0.5, 3, 5, 8, 10, 12, and 18 hours post start of CLR325 infusion on Day 1 | 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. |
| Pharmacokinetic of CLR325 and CQJ295: Time to Reach the Maximum Concentration After Drug Administration (TMax) | 0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1 | 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. |
| Pharmacokinetic of CLR325: Volume of Distribution at Steady State Following Intravenous Administration (Vss) | 0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1 | 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. |
| Pharmacokinetic of CLR325 and CQJ295: Amount of Drug (or Defined Metabolite) Excreted Into the Urine From Time (Ae 0-28 Hours) | 0-28 hours on Day 1 | 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. |
| Pharmacokinetic of CLR325 and CQJ295: Renal Clearance From Plasma (CLr) Following Drug Administration | 0-28 hours on Day 1 | 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. |
| Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | Baseline (BL), Day 10 (D10) and Day 28 (D28) | 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. |
| Pharmacokinetic of CLR325 and CQJ295: Terminal Elimination Half-life (T1/2) | 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1 | 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. |
Countries
Belgium, Germany, Netherlands, Singapore, United States
Participant flow
Recruitment details
This study was conducted in 11 centers in 5 countries: Belgium (1), Germany (2), Netherlands (1), Singapore (1) and USA (6).
Pre-assignment details
Patients were assigned to one of the 2 treatment arms in fixed randomization ratio (CLR325: Placebo): * Cohort 1: Single dose of CLR325 2.5 mcg/kg/min (i.v.) or placebo (i.v.) * Cohort 2: Single dose of CLR325 0.25 mcg/kg/min (i.v.) or placebo (i.v.) * Cohort 3: Single dose of CLR325 8 mcg/kg/min (i.v.) or placebo (i.v.)
Participants by arm
| Arm | Count |
|---|---|
| CLR325 0.25 mcg/kg/Min Patients randomized to this arm received single dose of CLR325 0.25 mcg/kg/min (i.v.) in double blind manner. | 4 |
| CLR325 2.5 mcg/kg/Min Patients randomized to this arm received single dose of CLR325 2.5 mcg/kg/min (i.v.) in double blind manner. | 6 |
| CLR325 8 mcg/kg/Min Patients randomized to this arm received single dose of CLR325 8 mcg/kg/min (i.v.) in double blind manner. | 6 |
| Placebo Patients randomized to this arm received single dose of Placebo (i.v.) in double blind manner. | 10 |
| Total | 26 |
Baseline characteristics
| Characteristic | CLR325 0.25 mcg/kg/Min | CLR325 2.5 mcg/kg/Min | CLR325 8 mcg/kg/Min | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 56.5 Years STANDARD_DEVIATION 3.1 | 55.2 Years STANDARD_DEVIATION 13 | 63.5 Years STANDARD_DEVIATION 11.8 | 54.2 Years STANDARD_DEVIATION 9.2 | 56.9 Years STANDARD_DEVIATION 10.4 |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Black | 0 Participants | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized Caucasian | 4 Participants | 3 Participants | 4 Participants | 8 Participants | 19 Participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 3 Participants |
| Sex: Female, Male Male | 3 Participants | 6 Participants | 4 Participants | 10 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 6 | 0 / 6 | 0 / 10 |
| other Total, other adverse events | 1 / 4 | 2 / 6 | 4 / 6 | 7 / 10 |
| serious Total, serious adverse events | 0 / 4 | 2 / 6 | 2 / 6 | 0 / 10 |
Outcome results
Primary
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.
Time frame: Day 1 to 28
Population: The Safety population, which consisted of all patients who had been exposed to at least one infusion of study drug or placebo, was considered.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CLR325 0.25 mcg/kg/Min | Number of Patients With Adverse Events, Serious Adverse Events and Death | On-treatment Adverse Event (AEs) | 1 Participants |
| CLR325 0.25 mcg/kg/Min | Number of Patients With Adverse Events, Serious Adverse Events and Death | On-treatment Deaths | 0 Participants |
| CLR325 0.25 mcg/kg/Min | Number of Patients With Adverse Events, Serious Adverse Events and Death | On-treatment Serious Adverse Event (SAEs) | 0 Participants |
| CLR325 2.5 mcg/kg/Min | Number of Patients With Adverse Events, Serious Adverse Events and Death | On-treatment Adverse Event (AEs) | 2 Participants |
| CLR325 2.5 mcg/kg/Min | Number of Patients With Adverse Events, Serious Adverse Events and Death | On-treatment Deaths | 0 Participants |
| CLR325 2.5 mcg/kg/Min | Number of Patients With Adverse Events, Serious Adverse Events and Death | On-treatment Serious Adverse Event (SAEs) | 2 Participants |
| CLR325 8 mcg/kg/Min | Number of Patients With Adverse Events, Serious Adverse Events and Death | On-treatment Serious Adverse Event (SAEs) | 2 Participants |
| CLR325 8 mcg/kg/Min | Number of Patients With Adverse Events, Serious Adverse Events and Death | On-treatment Adverse Event (AEs) | 4 Participants |
| CLR325 8 mcg/kg/Min | Number of Patients With Adverse Events, Serious Adverse Events and Death | On-treatment Deaths | 0 Participants |
| Placebo | Number of Patients With Adverse Events, Serious Adverse Events and Death | On-treatment Adverse Event (AEs) | 7 Participants |
| Placebo | Number of Patients With Adverse Events, Serious Adverse Events and Death | On-treatment Deaths | 0 Participants |
| Placebo | Number of Patients With Adverse Events, Serious Adverse Events and Death | On-treatment Serious Adverse Event (SAEs) | 0 Participants |
Secondary
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.
Time frame: Baseline (BL), Day 10 (D10) and Day 28 (D28)
Population: The Safety population, which consisted of all patients who had been exposed to at least one infusion of study drug or placebo, was considered. Only subjest with or without anitbody detected were included in the analysis.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| CLR325 0.25 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D28 anti-Apelin antibody | Antibody detected = Yes | 0 Participants |
| CLR325 0.25 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D10 anti-CLR325 antibody | Antibody detected = Yes | 0 Participants |
| CLR325 0.25 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | BL anti-Apelin antibody | Antibody detected = Yes | 0 Participants |
| CLR325 0.25 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D10 anti-Apelin antibody | Antibody detected = Yes | 0 Participants |
| CLR325 0.25 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | BL anti-CLR325 antibody | Antibody detected = No | 4 Participants |
| CLR325 0.25 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D10 anti-CLR325 antibody | Antibody detected = No | 3 Participants |
| CLR325 0.25 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D28 anti-CLR325 antibody | Antibody detected = No | 3 Participants |
| CLR325 0.25 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D10 anti-Apelin antibody | Antibody detected = No | 0 Participants |
| CLR325 0.25 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | BL anti-CLR325 antibody | Antibody detected = Yes | 0 Participants |
| CLR325 0.25 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | BL anti-Apelin antibody | Antibody detected = No | 1 Participants |
| CLR325 0.25 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D28 anti-CLR325 antibody | Antibody detected = Yes | 0 Participants |
| CLR325 0.25 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D28 anti-Apelin antibody | Antibody detected = No | 1 Participants |
| CLR325 2.5 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | BL anti-CLR325 antibody | Antibody detected = No | 5 Participants |
| CLR325 2.5 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | BL anti-Apelin antibody | Antibody detected = Yes | 0 Participants |
| CLR325 2.5 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | BL anti-Apelin antibody | Antibody detected = No | 1 Participants |
| CLR325 2.5 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D10 anti-Apelin antibody | Antibody detected = No | 0 Participants |
| CLR325 2.5 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | BL anti-CLR325 antibody | Antibody detected = Yes | 0 Participants |
| CLR325 2.5 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D10 anti-CLR325 antibody | Antibody detected = Yes | 0 Participants |
| CLR325 2.5 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D10 anti-CLR325 antibody | Antibody detected = No | 4 Participants |
| CLR325 2.5 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D28 anti-Apelin antibody | Antibody detected = Yes | 0 Participants |
| CLR325 2.5 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D10 anti-Apelin antibody | Antibody detected = Yes | 0 Participants |
| CLR325 2.5 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D28 anti-Apelin antibody | Antibody detected = No | 0 Participants |
| CLR325 2.5 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D28 anti-CLR325 antibody | Antibody detected = Yes | 0 Participants |
| CLR325 2.5 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D28 anti-CLR325 antibody | Antibody detected = No | 5 Participants |
| CLR325 8 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | BL anti-Apelin antibody | Antibody detected = No | 1 Participants |
| CLR325 8 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D10 anti-Apelin antibody | Antibody detected = No | 1 Participants |
| CLR325 8 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | BL anti-Apelin antibody | Antibody detected = Yes | 0 Participants |
| CLR325 8 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D28 anti-Apelin antibody | Antibody detected = No | 1 Participants |
| CLR325 8 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D10 anti-Apelin antibody | Antibody detected = Yes | 0 Participants |
| CLR325 8 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | BL anti-CLR325 antibody | Antibody detected = Yes | 0 Participants |
| CLR325 8 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D28 anti-CLR325 antibody | Antibody detected = No | 5 Participants |
| CLR325 8 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D10 anti-CLR325 antibody | Antibody detected = No | 6 Participants |
| CLR325 8 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D10 anti-CLR325 antibody | Antibody detected = Yes | 0 Participants |
| CLR325 8 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | BL anti-CLR325 antibody | Antibody detected = No | 5 Participants |
| CLR325 8 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D28 anti-CLR325 antibody | Antibody detected = Yes | 0 Participants |
| CLR325 8 mcg/kg/Min | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D28 anti-Apelin antibody | Antibody detected = Yes | 0 Participants |
| Placebo | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | BL anti-CLR325 antibody | Antibody detected = Yes | 0 Participants |
| Placebo | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | BL anti-CLR325 antibody | Antibody detected = No | 10 Participants |
| Placebo | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D10 anti-Apelin antibody | Antibody detected = Yes | 0 Participants |
| Placebo | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D10 anti-Apelin antibody | Antibody detected = No | 1 Participants |
| Placebo | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D10 anti-CLR325 antibody | Antibody detected = Yes | 0 Participants |
| Placebo | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D10 anti-CLR325 antibody | Antibody detected = No | 7 Participants |
| Placebo | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D28 anti-Apelin antibody | Antibody detected = Yes | 0 Participants |
| Placebo | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D28 anti-Apelin antibody | Antibody detected = No | 0 Participants |
| Placebo | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D28 anti-CLR325 antibody | Antibody detected = No | 9 Participants |
| Placebo | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | BL anti-Apelin antibody | Antibody detected = Yes | 0 Participants |
| Placebo | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | BL anti-Apelin antibody | Antibody detected = No | 0 Participants |
| Placebo | Number of Patients With Increase in Anti-CLR325 and Anti-apelin Antibodies in Serum | D28 anti-CLR325 antibody | Antibody detected = Yes | 0 Participants |
Secondary
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.
Time frame: 0-28 hours on Day 1
Population: Participants from the Pharmacokinetic (PK) analysis set, defined as all randomized participants who received at least one dose of study drug and one evaluable PK concentration measurement, with data available for analysis were considered.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| CLR325 0.25 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Amount of Drug (or Defined Metabolite) Excreted Into the Urine From Time (Ae 0-28 Hours) | CLR325 | NA ng | — |
| CLR325 0.25 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Amount of Drug (or Defined Metabolite) Excreted Into the Urine From Time (Ae 0-28 Hours) | CQJ295 | NA ng | — |
| CLR325 2.5 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Amount of Drug (or Defined Metabolite) Excreted Into the Urine From Time (Ae 0-28 Hours) | CLR325 | 19500000 ng | Geometric Coefficient of Variation 125.2 |
| CLR325 2.5 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Amount of Drug (or Defined Metabolite) Excreted Into the Urine From Time (Ae 0-28 Hours) | CQJ295 | 7620000 ng | Geometric Coefficient of Variation 27.2 |
| CLR325 8 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Amount of Drug (or Defined Metabolite) Excreted Into the Urine From Time (Ae 0-28 Hours) | CLR325 | 41300000 ng | Geometric Coefficient of Variation 253.3 |
| CLR325 8 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Amount of Drug (or Defined Metabolite) Excreted Into the Urine From Time (Ae 0-28 Hours) | CQJ295 | 4040000 ng | — |
Secondary
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.
Time frame: 0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1
Population: Participants from the Pharmacokinetic (PK) analysis set, defined as all randomized participants who received at least one dose of study drug and one evaluable PK concentration measurement, with data available for analysis were considered.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| CLR325 0.25 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From From Time Zero to 28 Hours (AUC0-28hrs) | CLR325 | 1460 ng*hr/mL | Geometric Coefficient of Variation 12.8 |
| CLR325 0.25 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From From Time Zero to 28 Hours (AUC0-28hrs) | CQJ295 | NA ng*hr/mL | — |
| CLR325 2.5 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From From Time Zero to 28 Hours (AUC0-28hrs) | CLR325 | 21500 ng*hr/mL | Geometric Coefficient of Variation 32.9 |
| CLR325 2.5 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From From Time Zero to 28 Hours (AUC0-28hrs) | CQJ295 | 838 ng*hr/mL | Geometric Coefficient of Variation 106.2 |
| CLR325 8 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From From Time Zero to 28 Hours (AUC0-28hrs) | CLR325 | 100000 ng*hr/mL | Geometric Coefficient of Variation 28.2 |
| CLR325 8 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From From Time Zero to 28 Hours (AUC0-28hrs) | CQJ295 | 8390 ng*hr/mL | Geometric Coefficient of Variation 43.5 |
Secondary
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.
Time frame: 0, 0.5, 3, 5, 8, 10, 12, and 18 hours post start of CLR325 infusion on Day 1
Population: Participants from the Pharmacokinetic (PK) analysis set, defined as all randomized participants who received at least one dose of study drug and one evaluable PK concentration measurement, with data available for analysis were considered.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| CLR325 0.25 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From Time Zero to 18 Hours (AUC0-18hr) | CLR 325 | 1220 ng*hr/mL | Geometric Coefficient of Variation 10.4 |
| CLR325 0.25 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From Time Zero to 18 Hours (AUC0-18hr) | CQJ295 | NA ng*hr/mL | — |
| CLR325 2.5 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From Time Zero to 18 Hours (AUC0-18hr) | CLR 325 | 18500 ng*hr/mL | Geometric Coefficient of Variation 31.6 |
| CLR325 2.5 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From Time Zero to 18 Hours (AUC0-18hr) | CQJ295 | 623 ng*hr/mL | Geometric Coefficient of Variation 102.3 |
| CLR325 8 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From Time Zero to 18 Hours (AUC0-18hr) | CLR 325 | 79700 ng*hr/mL | Geometric Coefficient of Variation 32.5 |
| CLR325 8 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From Time Zero to 18 Hours (AUC0-18hr) | CQJ295 | 5560 ng*hr/mL | Geometric Coefficient of Variation 46.7 |
Secondary
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.
Time frame: 0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1
Population: Participants from the Pharmacokinetic (PK) analysis set, defined as all randomized participants who received at least one dose of study drug and one evaluable PK concentration measurement, with data available for analysis were considered.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| CLR325 0.25 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) | CLR325 | 1510 ng*hr/mL | Geometric Coefficient of Variation 4.7 |
| CLR325 2.5 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) | CLR325 | 21900 ng*hr/mL | Geometric Coefficient of Variation 34 |
| CLR325 2.5 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) | CQJ295 | 843 ng*hr/mL | Geometric Coefficient of Variation 49.9 |
| CLR325 8 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) | CLR325 | 103000 ng*hr/mL | Geometric Coefficient of Variation 26.1 |
| CLR325 8 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) | CQJ295 | 9660 ng*hr/mL | Geometric Coefficient of Variation 38.5 |
Secondary
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.
Time frame: 0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1
Population: Participants from the Pharmacokinetic (PK) analysis set, defined as all randomized participants who received at least one dose of study drug and one evaluable PK concentration measurement, with data available for analysis were considered.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| CLR325 0.25 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) | CLR325 | 1450 ng*hr/mL | Geometric Coefficient of Variation 13 |
| CLR325 0.25 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) | CQJ295 | 3.10 ng*hr/mL | — |
| CLR325 2.5 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) | CLR325 | 21500 ng*hr/mL | Geometric Coefficient of Variation 32.9 |
| CLR325 2.5 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) | CQJ295 | 836 ng*hr/mL | Geometric Coefficient of Variation 107.1 |
| CLR325 8 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) | CLR325 | 100000 ng*hr/mL | Geometric Coefficient of Variation 28.2 |
| CLR325 8 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) | CQJ295 | 8380 ng*hr/mL | Geometric Coefficient of Variation 43.6 |
Secondary
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.
Time frame: 0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1
Population: Participants from the Pharmacokinetic (PK) analysis set, defined as all randomized participants who received at least one dose of study drug and one evaluable PK concentration measurement, with data available for analysis were considered.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| CLR325 0.25 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax,ss) | CLR325 | 103 ng/mL | Geometric Coefficient of Variation 11.2 |
| CLR325 0.25 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax,ss) | CQJ295 | NA ng/mL | — |
| CLR325 2.5 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax,ss) | CLR325 | 1370 ng/mL | Geometric Coefficient of Variation 36 |
| CLR325 2.5 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax,ss) | CQJ295 | 54.2 ng/mL | Geometric Coefficient of Variation 91 |
| CLR325 8 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax,ss) | CLR325 | 6080 ng/mL | Geometric Coefficient of Variation 38.4 |
| CLR325 8 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax,ss) | CQJ295 | 468 ng/mL | Geometric Coefficient of Variation 54 |
Secondary
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.
Time frame: 0-28 hours on Day 1
Population: Participants from the Pharmacokinetic (PK) analysis set, defined as all randomized participants who received at least one dose of study drug and one evaluable PK concentration measurement, with data available for analysis were considered.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| CLR325 0.25 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Renal Clearance From Plasma (CLr) Following Drug Administration | CLR325 | NA mL/hr | — |
| CLR325 0.25 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Renal Clearance From Plasma (CLr) Following Drug Administration | CQJ295 | NA mL/hr | — |
| CLR325 2.5 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Renal Clearance From Plasma (CLr) Following Drug Administration | CLR325 | 904 mL/hr | Geometric Coefficient of Variation 199.4 |
| CLR325 2.5 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Renal Clearance From Plasma (CLr) Following Drug Administration | CQJ295 | 5620 mL/hr | Geometric Coefficient of Variation 71.7 |
| CLR325 8 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Renal Clearance From Plasma (CLr) Following Drug Administration | CLR325 | 411 mL/hr | Geometric Coefficient of Variation 395.1 |
| CLR325 8 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Renal Clearance From Plasma (CLr) Following Drug Administration | CQJ295 | 258 mL/hr | — |
Secondary
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.
Time frame: 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1
Population: Participants from the Pharmacokinetic (PK) analysis set, defined as all randomized participants who received at least one dose of study drug and one evaluable PK concentration measurement, with data available for analysis were considered.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CLR325 0.25 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Terminal Elimination Half-life (T1/2) | CLR325 | 1.86 hr | Standard Deviation 0.197 |
| CLR325 2.5 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Terminal Elimination Half-life (T1/2) | CLR325 | 2.99 hr | Standard Deviation 0.52 |
| CLR325 2.5 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Terminal Elimination Half-life (T1/2) | CQJ295 | 3.12 hr | Standard Deviation 0.275 |
| CLR325 8 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Terminal Elimination Half-life (T1/2) | CLR325 | 2.96 hr | Standard Deviation 0.992 |
| CLR325 8 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Terminal Elimination Half-life (T1/2) | CQJ295 | 5.73 hr | Standard Deviation 3.38 |
Secondary
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.
Time frame: 0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1
Population: Participants from the Pharmacokinetic (PK) analysis set, defined as all randomized participants who received at least one dose of study drug and one evaluable PK concentration measurement, with data available for analysis were considered.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| CLR325 0.25 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Time to Reach the Maximum Concentration After Drug Administration (TMax) | CLR325 | 14.0 hr |
| CLR325 0.25 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Time to Reach the Maximum Concentration After Drug Administration (TMax) | CQJ295 | 0 hr |
| CLR325 2.5 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Time to Reach the Maximum Concentration After Drug Administration (TMax) | CLR325 | 12.0 hr |
| CLR325 2.5 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Time to Reach the Maximum Concentration After Drug Administration (TMax) | CQJ295 | 15.1 hr |
| CLR325 8 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Time to Reach the Maximum Concentration After Drug Administration (TMax) | CLR325 | 14.9 hr |
| CLR325 8 mcg/kg/Min | Pharmacokinetic of CLR325 and CQJ295: Time to Reach the Maximum Concentration After Drug Administration (TMax) | CQJ295 | 17.9 hr |
Secondary
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.
Time frame: 0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1
Population: Participants from the Pharmacokinetic (PK) analysis set, defined as all randomized participants who received at least one dose of study drug and one evaluable PK concentration measurement, with data available for analysis were considered.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| CLR325 0.25 mcg/kg/Min | Pharmacokinetic of CLR325: Clearance From Plasma (CL) Following Drug Administration | 15200 mL/hr | Geometric Coefficient of Variation 6.1 |
| CLR325 2.5 mcg/kg/Min | Pharmacokinetic of CLR325: Clearance From Plasma (CL) Following Drug Administration | 13200 mL/hr | Geometric Coefficient of Variation 54.9 |
| CLR325 8 mcg/kg/Min | Pharmacokinetic of CLR325: Clearance From Plasma (CL) Following Drug Administration | 7460 mL/hr | Geometric Coefficient of Variation 15.4 |
Secondary
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.
Time frame: 0, 0.5, 3, 5, 8, 10, 12, 18, 20, 24, and 28 hours post start of CLR325 infusion on Day 1
Population: Participants from the Pharmacokinetic (PK) analysis set, defined as all randomized participants who received at least one dose of study drug and one evaluable PK concentration measurement, with data available for analysis were considered.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| CLR325 0.25 mcg/kg/Min | Pharmacokinetic of CLR325: Volume of Distribution at Steady State Following Intravenous Administration (Vss) | 51600 mL | Geometric Coefficient of Variation 19.6 |
| CLR325 2.5 mcg/kg/Min | Pharmacokinetic of CLR325: Volume of Distribution at Steady State Following Intravenous Administration (Vss) | 32500 mL | Geometric Coefficient of Variation 47.6 |
| CLR325 8 mcg/kg/Min | Pharmacokinetic of CLR325: Volume of Distribution at Steady State Following Intravenous Administration (Vss) | 28000 mL | Geometric Coefficient of Variation 33.3 |