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    Summary
    EudraCT Number:2010-020376-37
    Sponsor's Protocol Code Number:CP120027.2001
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-01-26
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedCzechia - SUKL
    A.2EudraCT number2010-020376-37
    A.3Full title of the trial
    A Randomized, Double-Blind, Placebo-Controlled, Adaptive, Ascending
    Dose-Titration Study to Evaluate the Safety, Tolerability,
    Pharmacokinetics, and Invasive Hemodynamics of TRV120027 in
    Patients with Stable Heart Failure
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to Evaluate the Effects of TRV120027 in Patients With Heart Failure
    A.4.1Sponsor's protocol code numberCP120027.2001
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01187836
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorTrevena, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportTrevena, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPSI Pharma Support Poland Sp. z o.o.
    B.5.2Functional name of contact pointProject Management
    B.5.3 Address:
    B.5.3.1Street Addressul. 1-go Sierpnia 6A
    B.5.3.2Town/ cityWarsaw
    B.5.3.3Post code02-134
    B.5.3.4CountryPoland
    B.5.4Telephone number+48 (22) 210 02 00
    B.5.5Fax number+48 (22) 210 02 20
    B.5.6E-mailmarek.perz@psi-cro.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTRV120027
    D.3.2Product code TRV120027
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeTRV120027
    D.3.9.3Other descriptive nameTRV120027, MPS-418
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Heart failure
    E.1.1.1Medical condition in easily understood language
    Heart failure
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10000803
    E.1.2Term Acute heart failure
    E.1.2System Organ Class 10007541 - Cardiac disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level HLGT
    E.1.2Classification code 10019280
    E.1.2Term Heart failures
    E.1.2System Organ Class 10007541 - Cardiac disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10064081
    E.1.2Term Heart failure NYHA class III
    E.1.2System Organ Class 10007541 - Cardiac disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10064082
    E.1.2Term Heart failure NYHA class IV
    E.1.2System Organ Class 10007541 - Cardiac disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10010684
    E.1.2Term Congestive heart failure
    E.1.2System Organ Class 10007541 - Cardiac disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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
    E.2.2Secondary 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
    E.2.3Trial contains a sub-study No
    E.3Principal 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.
    E.4Principal 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.
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(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.
    E.5.2Secondary 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.
    E.5.2.1Timepoint(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.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    evaluation of hemodynamic parameters, neurohormonal activation, renal effects
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    multiple cohort, adaptive dose-rising
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial6
    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.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA12
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If 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
    E.8.7Trial 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
    Please see study protocol.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 27
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 13
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 35
    F.4.2.2In the whole clinical trial 40
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    No special care is foreseen after the subject has ended his/her participation in the study.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2011-02-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-01-19
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2012-04-06
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