v4 Study Evaluating the Safety, Tolerability and Preliminary Pharmacokinetics and Pharmacodynamics of MYK-491
- Conditions
- Heart Failure With Reduced Ejection FractionDilated Cardiomyopathy
- Interventions
- Drug: MYK-491Drug: Placebo
- Registration Number
- NCT03447990
- Lead Sponsor
- Bristol-Myers Squibb
- Brief Summary
The purpose of this Phase 1b/2a study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of MYK-491 in patients with stable heart failure.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 52
- Has stable chronic heart failure with reduced ejection fraction
- Has adequate acoustic windows for echocardiography
Key
- Any significant structural cardiac abnormalities on Screening TTE
- At Screening, symptomatic hypotension or hypertension or bradycardia.
- Routinely scheduled outpatient intravenous (IV) infusions for heart failure (e.g., inotropes, vasodilators [e.g., nesiritide], diuretics) or routinely scheduled ultrafiltration.
- Presence of protocol specified laboratory abnormalities at Screening.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part 1/SAD and Part 2/MAD - drug MYK-491 Part 1/SAD: Crossover, Single ascending dose of MYK-491/placebo Part 2/MAD: Parallel, multiple ascending dose of MYK-491/placebo Part 1/SAD and Part 2/MAD - placebo Placebo Part 1/SAD: Crossover, Single ascending dose of MYK-491/placebo Part 2/MAD: Parallel, multiple ascending dose of MYK-491/placebo
- Primary Outcome Measures
Name Time Method Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) From first dose to 30 days post last dose (Up to 2 months) Number of participants with any grade of treatment-emergent adverse events (TEAEs) and any grade of serious adverse events (SAEs).
Number of Participants With a Troponin I Increase - MAD Cohorts Baseline, pre-dose and 7hr post dose on treatment day 1, day 2, day 5 and pre-dose and at 7-, 24-, and 48-hours post final dose Number of participants with a troponin increase is defined as when one of the following conditions was met (1) if the participant's troponin I value was normal prior to dosing (≤0.03 ng/mL), an elevated level on at least one measurement after start of dosing \>2×ULN for the specific assay (\>0.06 ng/mL) through Day 16. (2) If the participant's troponin I value was above the ULN for the specific assay prior to dosing, an increase \>0.03 ng/mL compared to baseline on at least one measurement after start of dosing through Day 16.
Number of Participants With Clinically Significant Laboratory Abnormalities From first dose to 30 days post last dose (Up to 2 months) Number of participants with clinically significant laboratory abnormalities.
Number of Participants With Clinically Significant Physical Examinations Abnormalities From first dose to 30 days post last dose (Up to 2 months) Number of participants with clinically significant physical examinations abnormalities.
Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts Baseline, day 1-16, 2 hours pre-dose and at 3-, 5-, 9-, 12-, 24-, and 36-hours post-dose Number of participants with change from baseline in ECGs QTcF, PR, and QRS intervals. Baseline is defined as the last non-missing value prior to the corresponding period.
Mean Change From Baseline in Vital Signs Part 1 - MAD Cohorts Baseline and at 6-hours post-dose Mean change from baseline in supine systolic blood pressure (SBP) and supine diastolic blood pressure (DBP) vital signs. Baseline is defined as the last non-missing value prior to first randomized dose
Mean Change From Baseline in Vital Signs Part 2 - SAD Cohorts Baseline and at 6-hours post-dose Mean change from baseline in heart rate (HR) vital signs. Baseline is defined as the last non-missing value prior to the corresponding period.
Mean Change From Baseline in Vital Signs Part 2 - MAD Cohorts Baseline and at 6-hours post-dose Mean change from baseline in heart rate (HR) vital signs. Baseline is defined as the last non-missing value prior to first randomized dose
Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - MAD Cohorts Baseline, Day 1-16, 2 hours pre-dose and at 7-, 24-, and 48-hours post final dose Number of participants with change from baseline in ECGs QTcF, PR, and QRS intervals. Baseline is defined as the last non-missing value prior to first randomized dose.
Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts Baseline and at 6-hours post-dose Mean change from baseline in supine systolic blood pressure (SBP) and supine diastolic blood pressure (DBP) vital signs. Baseline is defined as the last non-missing value prior to the corresponding period.
Number of Participants With a Troponin I Increase - SAD Cohorts Baseline, day 1-3, 2 hours pre-dose and at 3-, 5-, 9-, 12-, 24-, and 36-hours post-dose Number of participants with a troponin increase is defined as when one of the following conditions was met (1) if the participant's troponin I value was normal prior to dosing (≤0.03 ng/mL), an elevated level on at least one measurement after start of dosing \>2×ULN for the specific assay (\>0.06 ng/mL) through Day 16. (2) If the participant's troponin I value was above the ULN for the specific assay prior to dosing, an increase \>0.03 ng/mL compared to baseline on at least one measurement after start of dosing through Day 16.
- Secondary Outcome Measures
Name Time Method Danicamtiv Maximum Observed Plasma Concentration (Cmax) 1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose Maximum observed plasma concentration (Cmax) for Danicamtiv. Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported.
Apparent First-order Terminal Elimination Half-life (t1/2) 1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose Apparent first-order terminal elimination half-life (t1/2).
Accumulation Ratio for Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours AR(AUC(0-12)) - MAD Cohorts 1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose Accumulation ratio for area under the plasma concentration-time curve from time 0 to 12 hours AR(AUC(0-12)) for Danicamtiv. Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported.
Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 1 - SAD Cohorts Baseline, predose and at 3, 6, 9, and 24 hours post dose Mean change from baseline in TTE parameter systolic ejection time (SET) according to Danicamtiv plasma concentration ranges. Baseline is defined as the last non-missing value prior to the corresponding period. Reporting arms are not mutually exclusive
Danicamtiv Accumulation Ratio for Maximum Observed Plasma Concentration AR(Cmax) - MAD Cohorts 1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose Accumulation ratio for maximum observed plasma concentration AR(Cmax) for Danicamtiv. Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported.
Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 3 - SAD Cohorts Baseline, predose and at 3, 6, 9, and 24 hours post dose Mean change from baseline in TTE parameter left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) according to Danicamtiv plasma concentration ranges. Baseline is defined as the last non-missing value prior to the corresponding period. Reporting arms are not mutually exclusive
Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 2 - MAD Cohorts Baseline, predose, and at 7 hours post dose on day 1,2,3, 4, 7, 9, 10, and 11 Mean change from baseline in TTE parameter left ventricular stroke volume (LVSV) according to Danicamtiv plasma concentration ranges. Baseline is defined as the last non-missing value prior to first randomized dose. Reporting arms are not mutually exclusive
Danicamtiv Time of Maximum Observed Plasma Concentration (Tmax) 1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose Time of maximum observed plasma concentration (Tmax) for Danicamtiv.
Area Under the Plasma Concentration-Time Curve (AUC) 1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose Area under the plasma concentration-time curve (AUC) for Danicamtiv including the following time points: (AUC(0-12))=from time 0 to 12 hours; (AUC(0-24))=from time 0 to 24 hours; (AUC(0-48))=from time 0 to 48 hours; (AUClast)=from time 0 up to the last measurable concentration; (AUC(0-∞))=from time 0 to infinity. Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported.
Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 2 - SAD Cohorts Baseline, predose and at 3, 6, 9, and 24 hours post dose Mean change from baseline in TTE parameter left ventricular stroke volume (LVSV) according to Danicamtiv plasma concentration ranges. Baseline is defined as the last non-missing value prior to the corresponding period. Reporting arms are not mutually exclusive
Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 1 - MAD Cohorts Baseline, predose, and at 7 hours post dose on day 1,2,3, 4, 7, 9, 10, and 11 Mean change from baseline in TTE parameter systolic ejection time (SET) according to Danicamtiv plasma concentration ranges. Baseline is defined as the last non-missing value prior to first randomized dose. Reporting arms are not mutually exclusive
Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 3 - MAD Cohorts Baseline, predose, and at 7 hours post dose on day 1,2,3, 4, 7, 9, 10, and 11 Mean change from baseline in TTE parameter left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) according to Danicamtiv plasma concentration ranges. Baseline is defined as the last non-missing value prior to first randomized dose. Reporting arms are not mutually exclusive
Trial Locations
- Locations (17)
Newark Beth Israel Medical Center
🇺🇸Newark, New Jersey, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Ohio State University Medical Center
🇺🇸Columbus, Ohio, United States
Queen Elizabeth University Hospital
🇬🇧Glasgow, Scotland, United Kingdom
Wojewodzki Szpital Specjalistyczny we Wroclawiu, Oddzial Kardiologiczny z Pododdzialem Intensywnego Nadzoru Kardiologicznego i Pododdzialem Leczenia Zaburzen Rytmu Serca
🇵🇱Wrocław, Poland
Groningen UMC
🇳🇱Groningen, Netherlands
D&A Research
🇳🇱Sneek, Netherlands
Jacksonville Center for Clinical Research
🇺🇸Jacksonville, Florida, United States
Prism Reseach
🇺🇸Saint Paul, Minnesota, United States
Tennessee Center for Clinical Trials
🇺🇸Tullahoma, Tennessee, United States
Karolinska University Hospital
🇸🇪Stockholm, Sweden
Wojewodzki Szpital Specjalistyczny Im M Kopernika
🇵🇱Łódź, Poland
St. Louis Heart and Vascular Cardiology
🇺🇸Saint Louis, Missouri, United States
University of Pennsylvania Heart and Vascular Center
🇺🇸Philadelphia, Pennsylvania, United States
Hopital Europeen Georges-Pompidou
🇫🇷Paris, France
Charite Research Organization
🇩🇪Berlin, Germany
Oregon Health & Science University
🇺🇸Portland, Oregon, United States