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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000803 |
E.1.2 | Term | Acute heart failure |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10019280 |
E.1.2 | Term | Heart failures |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064081 |
E.1.2 | Term | Heart failure NYHA class III |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064082 |
E.1.2 | Term | Heart failure NYHA class IV |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010684 |
E.1.2 | Term | Congestive heart failure |
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 evaluate the safety and tolerability of TRV120027 administered as a continuous intravenous infusion of increasing dose levels in subjects with heart failure (HF) while undergoing invasive hemodynamic monitoring
• To explore the effects of TRV120027 on pulmonary capillary wedge pressure (PCWP) in subjects with HF |
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E.2.2 | Secondary objectives of the trial |
• To explore the effects of TRV120027 on other hemodynamic parameters in subjects with HF
• To evaluate the dose-response and concentration-response of TRV120027 administered as a continuous intravenous infusion of increasing dose levels in subjects with HF
• To evaluate the effects of TRV120027 on measures of neurohormonal activation
• To evaluate the renal effects of TRV120027 in subjects with HF |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF).
2) Male or female, age ≥ 18 and ≤ 65 years. Males must agree to use appropriate birth control measures including condoms for at least 1 week following participation in the study (Section 7.3). Females must be of non-childbearing potential as defined below.
a) Pre-menopausal females with documented (medical report verification) hysterectomy or bilateral oophrectomy, or
b) Post-menopausal females with at least 12 months of spontaneous amenorrhea; or 6 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels ≥ 40 IU/L or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy.
3) Diagnosis of congestive heart failure made at least 3 months prior to screening and confirmed with at least one elevated BNP (or NT-proBNP) concentration (greater than laboratory reference range) performed within 3 months of IMP administration (may be obtained during screening).
4) Ejection fraction ≤ 35% as measured using any quantitative imaging modality (e.g. echocardiography, radionuclide imaging, MRI, CT) within 3 months prior to screening.
5) NYHA Class III or IV heart failure, and in the opinion of the investigator, right-heart catheterization is clinically indicated.
6) Systolic blood pressure at screening taken after at least 10 minutes at rest must be ≥ 100 mmHg. Heart rate at screening taken after at least 10 minutes at rest must be < 90 bpm. The blood pressure and/or heart rate may be repeated if the Investigator believes that including the subject will not pose unacceptable risk to the subject or compromise interpretation of the tolerability or pharmacodynamic data.
7) Oxygen saturation ≥ 94% on room air (≥ 92% for high altitude locations).
8) Weight ≤ 125 kg at baseline.
9) For males, serum creatinine ≤ 1.8 mg/dL (≤ 160 μmol/L); for females, serum creatinine ≤ 1.5 mg/dL (133 μmol/L).
10) Clinical laboratory tests within the lab reference ranges or within clinically acceptable limits as determined by the Investigator.
11) Baseline mean PCWP ≥ 20 mmHg with three consecutive measures where the highest and lowest values are within 4 mmHg of each other. |
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E.4 | Principal exclusion criteria |
Subjects will be excluded if any of the following apply:
1) Any significant disease or condition that would interfere with the interpretation of safety or efficacy in this study as determined by the Investigator based on medical history, physical examination or laboratory tests.
2) Presence of clinically significant anemia at screening.
3) Any other serious life threatening disease, for example uncontrolled or poorly controlled seizure disorder, poorly controlled diabetes mellitus, chronic obstructive pulmonary disease, that may impair the interpretation of safety or efficacy data from the study.
4) Contraindication to the placement of a PAC, or placement of PAC not feasible
5) Medications:
a) Has received an intravenous vasodilator (e.g. nitroglycerin, nitroprusside, nesiritide) within 24 hours of initiating IMP.
b) Has received any dose of an intravenous inotrope or chronotrope (e.g. milrinone, dobutamine) within 48 hours of initiating IMP.
c) Use of a phosphodiesterase type-5 (PDE5) inhibitor (e.g. sildenafil, vardenafil, tadalafil) within 1 week of initiating IMP.
d) Use of angiotensin receptor blocking drugs within 7 days of initiating IMP.
e) Use of any investigational medication within 30 days or 5 half-lives (whichever is longer) within 30 days prior to IMP administration.
6) Uncorrected and hemodynamically significant aortic or mitral stenosis, or aortic regurgitation.
7) Clinical signs or symptoms of cardiogenic shock.
8) Current signs or symptoms of acute myocardial ischemia.
9) Acute coronary syndrome (ACS) or coronary revascularization in the past 3 months.
10) Complex congenital heart disease.
11) Primary myocardial infiltrative disease (e.g. hypertrophic cardiomyopathy, amyloidosis, sarcoidosis, hemochromatosis).
12) Sustained or uncontrolled ventricular arrhythmia. Inclusion of patients with atrial fibrillation with a heart rate ≤ 90 bpm is permitted.
13) Ventricular assist device or intra-aortic balloon pump in place.
14) Ultrafiltration at time of randomization.
15) Post-cardiac or renal transplant.
16) Major surgery within 8 weeks prior to IMP administration.
17) Stroke in the past 6 months.
18) Allergy or intolerance of angiotensin receptor blockers or ACE inhibitors.
19) Illicit drug use within 6 months of IMP initiation.
20) Pregnant or lactating. |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Safety and tolerability will be evaluated by measuring vital signs (heart rate, systolic and diastolic blood pressure, respiratory rate, and O2 saturation), 12-lead ECGs, cardiac telemetry, measurements of hemodynamic parameters, clinical laboratory assessments, physical exams, and adverse events.
• The effective dose range will be characterized using PCWP as the primary pharmacodynamic endpoint. PCWP will be measured at baseline, at multiple time points during each dose level, and after discontinuation of the infusion. The effect of TRV120027 on PCWP will be compared to baseline and to placebo at each measurement time point. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Timepoints for primary endpoint: PCWP
During infusion: Hours 1-5: 30 & 45-59 minutes into the hour; Hours 6, 8, 10, 12, 14: 45-59 minutes into the hour; Post-infusion: Hour 15: 30 minutes into the hour and Hour 16, 17 and 18: 0 minutes into the hour
Timepoints for Safety & tolerability
Multiple measurements of vital signs (1/h during the infusion and in the washout phase, at least every 2 hours in the observation phase), lab tests (1/h in the first 5 hours of the infusion, at hour 10 and at hour 14; at the end of the washout phase and the end of the post-washout observation phase), ECGs (5 x during infusion, and 2 x post infusion), monitoring of telemetry, specific questioning for adverse assessments, etc. See protocol for details.
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E.5.2 | Secondary end point(s) |
• Other PD measures of interest include pulmonary arterial pressure (systolic, diastolic and mean PAP), pulmonary vascular resistance (PVR), systemic vascular resistance (SVR), right atrial pressure (RAP), heart rate (HR) and cardiac index (CI). Each of these parameters will be measured at baseline and at each dose level. These parameters will be measured at multiple time points at the final dose level, and after discontinuation of the infusion. The effect of TRV120027 on each of these parameters will be compared to baseline and to placebo at each measurement time point.
• PK parameters including (but not limited to) area under the plasma drug concentration versus time curve (AUC0-t, AUC0-∞, AUC0-τ), maximum observed plasma concentration (Cmax), time to maximum observed plasma concentration (tmax), terminal half-life (t½), clearance (CL) will be analyzed and correlated to PD effects, as data permit.
• Serum brain natriuretic peptide (BNP) and plasma renin activity, and angiotensin II (Ang II) may be measured at baseline, at the end of the infusion, and after discontinuing the infusion and compared to baseline and to placebo.
• The renal effects of TRV120027 will be evaluated by measuring urine volume (Uvol), serum creatinine (SCr), plasma cystatin C, and urinary NGAL and comparing the baseline (SCr, cystatin C and NGAL only) and placebo values at each measurement time point.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
PD measures
Each of these parameters will be measured at baseline and at each dose level. These parameters will be measured at multiple time points at the final dose level, and after discontinuation of the infusion. The effect of TRV120027 on each of these parameters will be compared to baseline and to placebo at each measurement time point.
PK parameters
10 samples in total:
Predose
During infusion: end of hours 1, 2, 3, 4, 5, 14
Following completion of infusion: 2 samples within 15 minutes and 1 sample 1 hour after end infusion
Serum brain natriuretic peptide (BNP) and plasma renin activity, and angiotensin II (Ang II) may be measured at baseline, at the end of the infusion, and after discontinuing
the infusion and compared to baseline and to placebo.
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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 |
evaluation of hemodynamic parameters, neurohormonal activation, renal effects |
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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 | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
multiple cohort, adaptive dose-rising |
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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 | 6 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 12 |
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 |
Czech Republic |
Poland |
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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Please see study protocol. |
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |