v4 Study Evaluating the Safety, Tolerability and Preliminary Pharmacokinetics and Pharmacodynamics of MYK-491

Heart Failure With Reduced Ejection Fraction Clinical Trial

Official title:

Randomized, Double-blind, Placebo-controlled, Two-Part, Adaptive Design Study of Safety, Tolerability, Preliminary Pharmacokinetics, and Pharmacodynamics of Single and Multiple Ascending Oral Doses of MYK-491 in Patients With Stable Heart Failure With Reduced Ejection Fraction

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03447990
• Other study ID #: MYK-491-003
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: February 6, 2018
• Est. completion date: October 24, 2019

Study information

• Verified date: January 2023
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 52
• Est. completion date: October 24, 2019
• Est. primary completion date: October 24, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Key Inclusion Criteria:

• Has stable chronic heart failure with reduced ejection fraction
• Has adequate acoustic windows for echocardiography

Key Exclusion Criteria:

• 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.

Related Conditions & MeSH terms

• Cardiomyopathies
• Cardiomyopathy, Dilated
• Dilated Cardiomyopathy
• Heart Failure
• Heart Failure With Reduced Ejection Fraction

Intervention

Drug:
• MYK-491
Single Ascending Dose and Multiple Ascending Dose of MYK-491
• Placebo
Single Ascending Dose and Multiple Ascending Dose of placebo

Locations

Country	Name	City	State
France	Hopital Europeen Georges-Pompidou	Paris
Germany	Charite Research Organization	Berlin
Netherlands	Groningen UMC	Groningen
Netherlands	D&A Research	Sneek
Poland	Wojewodzki Szpital Specjalistyczny Im M Kopernika	Lódz
Poland	Wojewodzki Szpital Specjalistyczny we Wroclawiu, Oddzial Kardiologiczny z Pododdzialem Intensywnego Nadzoru Kardiologicznego i Pododdzialem Leczenia Zaburzen Rytmu Serca	Wroclaw
Sweden	Karolinska University Hospital	Stockholm
United Kingdom	Queen Elizabeth University Hospital	Glasgow	Scotland
United States	Ohio State University Medical Center	Columbus	Ohio
United States	Duke University Medical Center	Durham	North Carolina
United States	Jacksonville Center for Clinical Research	Jacksonville	Florida
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	University of Pennsylvania Heart and Vascular Center	Philadelphia	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	St. Louis Heart and Vascular Cardiology	Saint Louis	Missouri
United States	Prism Reseach	Saint Paul	Minnesota
United States	Tennessee Center for Clinical Trials	Tullahoma	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  France,  Germany,  Netherlands,  Poland,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	Number of participants with any grade of treatment-emergent adverse events (TEAEs) and any grade of serious adverse events (SAEs).	From first dose to 30 days post last dose (Up to 2 months)
Primary	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	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.	Baseline, day 1-16, 2 hours pre-dose and at 3-, 5-, 9-, 12-, 24-, and 36-hours post-dose
Primary	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - MAD Cohorts	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.	Baseline, Day 1-16, 2 hours pre-dose and at 7-, 24-, and 48-hours post final dose
Primary	Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts	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.	Baseline and at 6-hours post-dose
Primary	Mean Change From Baseline in Vital Signs Part 1 - MAD Cohorts	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	Baseline and at 6-hours post-dose
Primary	Mean Change From Baseline in Vital Signs Part 2 - SAD Cohorts	Mean change from baseline in heart rate (HR) vital signs. Baseline is defined as the last non-missing value prior to the corresponding period.	Baseline and at 6-hours post-dose
Primary	Mean Change From Baseline in Vital Signs Part 2 - MAD Cohorts	Mean change from baseline in heart rate (HR) vital signs. Baseline is defined as the last non-missing value prior to first randomized dose	Baseline and at 6-hours post-dose
Primary	Number of Participants With a Troponin I Increase - SAD Cohorts	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.	Baseline, day 1-3, 2 hours pre-dose and at 3-, 5-, 9-, 12-, 24-, and 36-hours post-dose
Primary	Number of Participants With a Troponin I Increase - MAD Cohorts	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.	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
Primary	Number of Participants With Clinically Significant Laboratory Abnormalities	Number of participants with clinically significant laboratory abnormalities.	From first dose to 30 days post last dose (Up to 2 months)
Primary	Number of Participants With Clinically Significant Physical Examinations Abnormalities	Number of participants with clinically significant physical examinations abnormalities.	From first dose to 30 days post last dose (Up to 2 months)
Secondary	Danicamtiv Maximum Observed Plasma Concentration (Cmax)	Maximum observed plasma concentration (Cmax) for Danicamtiv. Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported.	1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose
Secondary	Danicamtiv Time of Maximum Observed Plasma Concentration (Tmax)	Time of maximum observed plasma concentration (Tmax) for Danicamtiv.	1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose
Secondary	Area Under the Plasma Concentration-Time Curve (AUC)	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(0-8))=from time 0 to infinity. Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported.	1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose
Secondary	Apparent First-order Terminal Elimination Half-life (t1/2)	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
Secondary	Danicamtiv Accumulation Ratio for Maximum Observed Plasma Concentration AR(Cmax) - MAD Cohorts	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.	1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose
Secondary	Accumulation Ratio for Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours AR(AUC(0-12)) - MAD Cohorts	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.	1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose
Secondary	Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 1 - SAD Cohorts	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	Baseline, predose and at 3, 6, 9, and 24 hours post dose
Secondary	Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 2 - SAD Cohorts	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	Baseline, predose and at 3, 6, 9, and 24 hours post dose
Secondary	Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 3 - SAD Cohorts	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	Baseline, predose and at 3, 6, 9, and 24 hours post dose
Secondary	Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 1 - MAD Cohorts	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	Baseline, predose, and at 7 hours post dose on day 1,2,3, 4, 7, 9, 10, and 11
Secondary	Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 2 - MAD Cohorts	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	Baseline, predose, and at 7 hours post dose on day 1,2,3, 4, 7, 9, 10, and 11
Secondary	Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 3 - MAD Cohorts	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	Baseline, predose, and at 7 hours post dose on day 1,2,3, 4, 7, 9, 10, and 11