Study to Evaluate the Safety and Efficacy of IV Infusion Treatment With Omecamtiv Mecarbil in Subjects With Left Ventricular Systolic Dysfunction Hospitalized for Acute Heart Failure

• Register: EUCTR
• Last refreshed on: 5 August 2014
• Main ID: EUCTR2010-021003-24-DE
• Date of registration: 02/03/2011
• Prospective Registration: Yes
• Primary sponsor: Amgen Inc
• Public title: Study to Evaluate the Safety and Efficacy of IV Infusion Treatment With Omecamtiv Mecarbil in Subjects With Left Ventricular Systolic Dysfunction Hospitalized for Acute Heart Failure
• Scientific title: A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate the Safety and Efficacy of IV Infusion Treatment With Omecamtiv Mecarbil in Subjects With Left Ventricular Systolic Dysfunction Hospitalized for Acute Heart Failure - ATOMIC- AHF Acute Treatment with Omecamtiv Mecarbil to increase Contractility - ATOMIC- AHF Acute Treatment with Omecamtiv Mecarbil to increase Contractility
• Date of first enrolment: 28/07/2011
• Target sample size: 600
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2010-021003-24
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 4

Countries of recruitment

Australia, Canada, Czech Republic, Finland, Germany, Greece, Hungary, Italy, Lithuania, Netherlands, Poland, Russian Federation, Slovakia, United Kingdom, United States

Contacts

• Name: IHQ Medical Information - Clinical
• Affiliation: Amgen (EUROPE) GmbH

• Name: IHQ Medical Information - Clinical
• Affiliation: Amgen (EUROPE) GmbH

Key inclusion & exclusion criteria

Inclusion criteria:
- Subject or subject’s legally acceptable representative has provided informed consent.
- Male or female = 18 years and = 85 years of age at the time of randomization.
- Current hospitalization for a primary reason of worsening heart failure (determined by the investigator) and requiring IV therapy for heart failure.
- History of chronic heart failure (defined as requiring treatment for heart failure for a minimum of 30 days before hospitalization).
- History of left ventricular ejection fraction (LVEF) = 40% (echocardiogram, radionuclide ventriculography, cardiac magnetic resonance imaging, or contrast ventriculography) within 12 months before randomization and without a subsequent intervening value of > 40%.
- Dyspnea due to heart failure, at rest or with minimal exertion, within 24 hours after their initial IV furosemide (or alternative IV loop diuretic) dose and at least 2 hours after having received a total of = 40 mg IV furosemide (or equivalent dose of an alternative IV loop diuretic).
- Brain-type natriuretic peptide (BNP) = 400 pg/mL or NT-proBNP = 1600 pg/mL during screening (BNP = 600 pg/mL or NT-proBNP = 2400 pg/mL if the subject has atrial fibrillation at presentation).
- Female subjects, if not postmenopausal or sterilized, must have a negative pregnancy test, must not be breastfeeding and must agree to abstain from sexual intercourse or use highly effective methods of birth control during treatment and for 5 days following the last dose of investigational product. Highly effective methods of birth control include: sterilization, birth control pills, Depo-Provera® injections, or contraceptive implants. Postmenopausal female is defined as 12 continuous months of spontaneous amenorrhea.
- Male subjects with a partner of childbearing potential must agree to inform their partner of their participation in this clinical study and, during treatment and for 5 days after the last dose of investigational product, to abstain from sexual intercourse or use highly effective methods of birth control, such as: vasectomy or a condom in combination with hormonal birth control or barrier methods used by the woman. For male subjects with pregnant partners, sexual abstinence or a condom must be used for 5 days after the last dose.
- If participating in the PK/PD substudy, subject must currently be in sinus rhythm.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 210
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 390

Exclusion criteria:
Disease-specific
- Receiving IV vasopressor (excluding dopamine = 5 µg/kg/min), inotropic or mechanical (eg, intra-aortic balloon pump counterpulsation) support between admission to the hospital and randomization.
- Subject has a pulmonary artery catheter.
- Subject requires endotracheal mechanical ventilation.
- Subject has acute coronary syndrome.
- Within 30 days prior to enrollment: cardiac resynchronization therapy (CRT) or implantable cardioverter defibrillator (ICD) implantation, hospitalization for acute coronary syndrome, coronary revascularization, transient ischemic attack or stroke, sustained ventricular arrhythmia, or major surgery.
- Likely to receive within 30 days after randomization, in the opinion of the investigator, planned revascularization, implantation of ICD, or CRT, ventricular assist device, continuous inotropic therapy, intermittent out-patient inotropic therapy, hospice care, or cardiac transplant.
- Severe aortic or mitral stenosis or heart failure primarily due to valvular heart disease.
- Hypertrophic obstructive cardiomyopathy, active myocarditis, or constrictive pericarditis, or clinically significant congenital heart disease.
- Chronic antiarrhythmic therapy, with the exception of amiodarone.
Note: For the purposes of this exclusion criterion, digoxin and betablocker therapy are not considered to be chronic anti-arrhythmic therapies.
- Routinely scheduled outpatient IV infusions for HF (eg, inotropes, vasodilators [eg, nesiritide], diuretics) or routinely scheduled ultrafiltration.
- Evidence of digitalis intoxication.
Other medical conditions
- Blood pressure (BP) > 160/100 mm Hg, systolic BP (SBP) < 90 mm Hg, or heart rate (HR) > 110 bpm or HR < 60 bpm at screening and confirmed by a repeat assessment.
- Estimated glomerular filtration rate (eGFR) calculated by the Modification of Diet in Renal Disease (MDRD) equation < 20 mL/min/1.73m2 at screening.
- Severe, concomitant non-cardiovascular disease that is expected to reduce life expectancy to less than 1 year.
- Recipient of any major organ transplant (eg, lung, liver, heart, bone marrow, renal) or receiving renal replacement therapy by dialysis.
- Receiving or has received chemotherapy and/or radiation therapy for treatment of a malignancy within 6 months prior to randomization or clinical evidence of current malignancy, with the following exceptions: localized basal or squamous cell carcinoma of the skin or cervical intraepithelial neoplasia.
- Untreated hypothyroidism or hyperthyroidism, adrenal insufficiency, active vasculitis due to collagen vascular disease.
- Hepatic impairment defined by a total bilirubin = 2 times the upper limit of normal (ULN), or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) = 5 times ULN at screening.
General or other
- Previously received omecamtiv mecarbil.
- Currently enrolled in another investigational heart failure device or drug study, or less than 30 days since ending another investigational heart failure device or drug study, or receiving other investigational agent(s) for heart failure.
- Recent (within 3 months) history of alcohol or illicit drug abuse based on self-report.
- Known sensitivity to any of the products to be administered during dosing.
- Subject previously has entered this study.
- Subject will not be available for protocol-required study visits, to the best of the subject’s or investigator’s knowledge.
- Any kind of disorde

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Acute heart failure
MedDRA version: 14.1 Level: LLT Classification code 10000803 Term: Acute heart failure System Organ Class: 100000004849

Intervention(s)

Product Name: omecamtiv mecarbil
Product Code: AMG423
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: omecamtiv mecarbil
Current Sponsor code: AMG423
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1-
Pharmaceutical form of the placebo: Concentrate for solution for injection
Route of administration of the placebo: Intravenous use

Primary Outcome(s)

Secondary Objective: • To assess the safety and tolerability of 3 dose levels of IV omecamtiv mecarbil compared with placebo in subjects with left ventricular systolic dysfunction hospitalized for AHF.
• To evaluate the effects of 48 hours treatment with IV omecamtiv mecarbil on additional measures of dyspnea, patient global assessment (PGA), change in N-terminal pro brain-type natriuretic peptide (NT-pro BNP) and short-term clinical outcomes.
• To characterize pharmacokinetics of omecamtiv mecarbil, including
omecamtiv mecarbil metabolites, following IV infusion and to evaluate
the relationship between omecamtiv mecarbil plasma concentration and
echocardiographic parameters in subjects with acute heart failure.

Primary end point(s): The primary endpoint is dyspnea symptom response defined as follows:
minimally, moderately or markedly better by 7-point Likert scale at 6 hours after investigational product initiation, AND moderately or markedly better at 24 and 48 hours after investigational product initiation without worsening heart failure event or death by 48 hours.

Main Objective: The primary objective of the study is to evaluate the effect of 48 hours of intravenous (IV) omecamtiv mecarbil compared with placebo on dyspnea in subjects with left ventricular systolic dysfunction hospitalized for acute heart failure (AHF).

Timepoint(s) of evaluation of this end point: 6hrs, 24rs and 48hrs

Secondary Outcome(s)

Secondary end point(s): - Death from any cause or worsening heart failure within 7 days of initiation of investigational product
- Worsening heart failure within 7 days of initiation of investigational product
- Dyspnea area under the curve (AUC) (baseline to day 6 or discharge, whichever comes first) as measured by subject self-assessed Numerical Rating Scale (NRS)
- Dyspnea by 7-point Likert scale at each scheduled assessment
- PGA response (minimally, moderately or markedly better by subject self-assessed 7-point Likert scale at 6 hours after investigational product initiation, AND moderately or markedly better at 24 and 48 hours after investigational product initiation)
- PGA at each scheduled assessment
- Change from baseline in NT-proBNP at each scheduled assessment
- Length of initial hospital stay
- Days alive out of hospital until day 30

Timepoint(s) of evaluation of this end point: Death from any cause or worsening HF: from the start of the IP infusion until Day 8 (7 days after IP infusion initiation)
Worsening HF: 15, 24, 48hrs and Day 4. Day of discharge if later than day 4. If subject remains hospitalised: Days 5, 6, 7 & 8.
Dyspnea AUC: 0, 6, 24, 48hrs & Day 4. Day of discharge if later than day 4. If the subject remains hospitalised: Days 5, 6 & 30
Dyspnea by 7-point Likert scale: 6, 24, 48hrs & Day 4. Day of discharge if later than day 4. If subject remains hospitalised: Days 5, 6 & 30
PGA response: 6hrs, 24hrs & 48hrs
PGA at scheduled assessments: 6, 24, 48hrs & Day 4. Day of discharge if later than day 4. If subject remains hospitalised: Days 5, 6 & 30
For remaining timepoints please see the protocol

Secondary ID(s)

20100754

Source(s) of Monetary Support

Amgen Inc