chronic heart failure
Conditions
Interventions
Part A:
The planning of the study is as follows:
Group Day Treatment Formulation Condition How often
A-1 1 BMS-986224 1 mg or placebo capsule fasting once
A-2 1 BMS-986224 5 mg or placebo capsule f
the dose levels for these groups
will be determined based on results from the previous group(s) and will not be
higher than 90 mg. The dose levels in the other groups may be adapted to a
lower dose
Sponsors
Britsol-Myers Squibb International Corporation
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: Part A and B - Males and females, ages 18 to 55 years, inclusive, female subjects should be of non childbearing potential, at screening. - BMI of 18.0 to 30.0 kg/m2, inclusive, at Screening. BMI = weight (kg)/height m2.;Part C 1. Signed written informed consent. 2. Subjects must be willing to participate in the study and sign the ICF. 3. Subjects must be willing and able to complete all study-specific procedures and visits. 4. Males and females, ages 18 years or older, at screening; female subjects should be of non childbearing potential (see Inclusion Criterion 12). 5. BMI of 18.0 to 35.0 kg/m2, inclusive, at screening. BMI = weight (kg)/height m2. 6. New York Heart Association class II or III. 7. Left ventricular EF = 300 pg/mL (35 pmol/L) or BNP >= 100 pg/mL (29 pmol/L). 11. Regular sinus rhythm at screening and no history of atrial fibrillation in the past 12 months. 12. Postmenopausal women (12 months or more amenorrhea and over 45 years of age in the absence of other biological or physiological causes). Females under 55 years of age require FSH >40 mIU/mL at screening. 13. Women must not be breastfeeding. 14. Males that meet one of the following: Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of the study and a minimum of 3 months after dosing has been completed. In addition, male subjects must be willing to refrain from sperm donation during this time.
Exclusion criteria
Exclusion criteria: Suffering from hepatitis B, hepatitis C, cancer or HIV/AIDS. In case of participation in another drug study within 90 days before the start of this study. Being a blood donor (Part A & B)/Loss of more than 100 mL blood (Part C) within 60 days prior to the first study drug administration. In case of donating more than 1.5 liters of blood (male subjects)/1 liter (female subjects) in the 10 months prior the first study drug administration. We refer to section 9.3.2 if the protocol for a complete overview of all the exclusion criteria.;Part C: 1. Current or recent (within 3 months of study treatment administration) gastrointestinal disease that could affect absorption. Patients who suffer from an episode of acute gastroenteritis without an underlying chronic GI condition can be enrolled if the acute event occurred more than 1 month prior to the first dose of study drug. 2. Major surgery within 4 weeks of (first) study treatment administration. 3. Loss of more than 100 mL of blood within 2 months prior to the first drug administration. Loss of more than 1.5 L of blood (for male subjects) / more than 1.0 L of blood (for female subjects) in the 10 months prior to the first drug administration in the current study. 4. Inability to be venipunctured and/or tolerate venous access. 5. Not applicable per Protocol Amendment 4: Subjects who have smoked or used smoking cessation or nicotine containing products (including, but not limited to, e-cigarettes, pipes, cigars, chewing tobacco, nicotine patches, nicotine lozenges, or nicotine gum, varenicline, bupropion) within 3 months of the first dose of study drug. 6. Abuse or drug addiction (including cannabis products) within one year from screening. 7. Positive drug screen (opiates, methadone, cocaine, amphetamines [including ecstasy], cannabinoids or barbiturates) at screening or admission to the CRU. Any positive drug screen test will be discussed with the Medical Monitor for further assessment. If justified in the opinion of the PI and Medical Monitor, the patient can be eligible for the study, despite a positive urinary drug screen. 8. Average intake of more than 21 units of alcohol per week (1 unit of alcohol equals approximately 250 mL of beer, 100 mL of wine or 35 mL of spirits). 9. Participation in a drug study or exposure to investigational drug or placebo within 2 months prior to the first drug administration in the current study. 10. Any contraindication to MRI scanning (eg, claustrophobia, implantable devices, etc). 11. Systolic blood pressure >180 mmHg or 90 bpm at screening or pre-randomization. A patient is eligible if clinically stable as per PI*s assessment and if heart rate at rest is at least 50 bpm, up to a maximum of 90 bpm, on vital signs taken at both the screening visit and the Day -1 visit (or pre dose Day 1 if patient admits to the clinic on Day 1 instead of Day -1), regardless of the heart rate reported on ECG. 13. Atrial arrhythmia (fibrillation, flutter) at screening or pre-randomization. 14. Significant ventricular arrhythmia (eg more than one couplet, triplets, or any VT-runs of 6 consecutive beats or more) on baseline or screening ECG. Note that a history of (ie, anterior to screening) couplets, triplets or non-sustained VT (<6 consecutive beats) does not exclude a patient from participation. 15. Presence of pacemakers/implantable cardioverter-de
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part A: The primary objective of this study is to assess the safety and tolerability of single oral doses of BMS-986224 in healthy subjects. Part B: To assess the safety and tolerability of multiple oral doses of BMS-986224 in healthy subjects (including Japanese subjects). Part C: To assess the safety and tolerability of multiple oral doses of BMS-986224 in chronic heart failure patients. | — |
Secondary
| Measure | Time frame |
|---|---|
| Part A: - To assess the single-dose PK of orally administered BMS-986224 and primary metabolite, BMT-328934, in healthy subjects. - To assess the effect of food on BMS-986224 PK following single dose of the drug in capsule (DIC) formulation. - To assess the effect of a strong CYP3A4 inhibitor (itraconazole) on the single-dose PK of BMS-986224 in healthy subjects. - To assess the pharmacodynamic (PD) effects of single doses of BMS-986224 in healthy subjects as measured by cardiac magnetic resonance imaging (MRI) (including EF, Left Ventricular Stroke Volume [LVSV], End Diastolic Volume [EDV], End Systolic Volume [ESV], LV mass, Cardiac Output [CO] and Cardiac Index [CI]). Part B: To assess the PK of BMS-986224 and BMT-328934 following multiple oral doses of BMS-986224 in healthy subjects (including Japanese subjects). Part C: - To assess the PK of BMS-986224 and BMT-328934 following multiple oral doses of BMS-986224 in chronic heart failure patients. - To assess the PD effects of single and multiple doses of BMS-986224 in chronic heart failure patients as measured by cardiac MRI (including EF, LVSV, EDV, ESV, LV mass, CO and CI). | — |
Countries
Netherlands
Outcome results
None listed