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

Primary Purpose

Heart Failure With Reduced Ejection Fraction, Dilated Cardiomyopathy

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

MYK-491

Placebo

About this trial

This is an interventional treatment trial for Heart Failure With Reduced Ejection Fraction

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Jacksonville Center for Clinical Research
Prism Reseach
St. Louis Heart and Vascular Cardiology
Newark Beth Israel Medical Center
Duke University Medical Center
Ohio State University Medical Center
Oregon Health & Science University
University of Pennsylvania Heart and Vascular Center
Tennessee Center for Clinical Trials
Hopital Europeen Georges-Pompidou
Charite Research Organization
Groningen UMC
D&A Research
Wojewodzki Szpital Specjalistyczny we Wroclawiu, Oddzial Kardiologiczny z Pododdzialem Intensywnego Nadzoru Kardiologicznego i Pododdzialem Leczenia Zaburzen Rytmu Serca
Wojewodzki Szpital Specjalistyczny Im M Kopernika
Karolinska University Hospital
Queen Elizabeth University Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Arm Label

Part 1/SAD and Part 2/MAD - drug

Part 1/SAD and Part 2/MAD - placebo

Arm Description

Part 1/SAD: Crossover, Single ascending dose of MYK-491/placebo Part 2/MAD: Parallel, multiple ascending dose of MYK-491/placebo

Outcomes

Primary Outcome Measures

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).

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.

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.

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.

Mean Change From Baseline in Vital Signs Part 1 - MAD Cohorts

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.

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

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.

Number of Participants With a Troponin I Increase - MAD Cohorts

Number of Participants With Clinically Significant Laboratory Abnormalities

Number of participants with clinically significant laboratory abnormalities.

Number of Participants With Clinically Significant Physical Examinations Abnormalities

Number of participants with clinically significant physical examinations abnormalities.

Secondary Outcome Measures

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.

Danicamtiv Time of Maximum Observed Plasma Concentration (Tmax)

Time of maximum observed plasma concentration (Tmax) for Danicamtiv.

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-∞))=from time 0 to infinity. 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)

Apparent first-order terminal elimination half-life (t1/2).

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.

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.

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

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

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

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

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

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

Full Information

NCT ID

NCT03447990

First Posted

February 14, 2018

Last Updated

January 9, 2023

Sponsor

Bristol-Myers Squibb

1. Study Identification

Unique Protocol Identification Number

NCT03447990

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2023

Overall Recruitment Status

Completed

Study Start Date

February 6, 2018 (Actual)

Primary Completion Date

October 24, 2019 (Actual)

Study Completion Date

October 24, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Bristol-Myers Squibb

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Heart Failure With Reduced Ejection Fraction, Dilated Cardiomyopathy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Model Description

This is a a two part study. The first part is a randomized, crossover, double-blind, placebo-controlled, two cohort, sequential ascending single dose study. All patients will receive placebo and active doses of MYK-491. The second part is a randomized, parallel, double-blind, placebo-controlled, sequential ascending multiple dose study. All patients will receive placebo and/or active doses of MYK-491.

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

52 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Part 1/SAD and Part 2/MAD - drug

Arm Type

Other

Arm Description

Part 1/SAD: Crossover, Single ascending dose of MYK-491/placebo Part 2/MAD: Parallel, multiple ascending dose of MYK-491/placebo

Arm Title

Part 1/SAD and Part 2/MAD - placebo

Arm Type

Other

Arm Description

Part 1/SAD: Crossover, Single ascending dose of MYK-491/placebo Part 2/MAD: Parallel, multiple ascending dose of MYK-491/placebo

Intervention Type

Drug

Intervention Name(s)

MYK-491

Intervention Description

Single Ascending Dose and Multiple Ascending Dose of MYK-491

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Single Ascending Dose and Multiple Ascending Dose of placebo

Primary Outcome Measure Information:

Title

Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Description

Number of participants with any grade of treatment-emergent adverse events (TEAEs) and any grade of serious adverse events (SAEs).

Time Frame

From first dose to 30 days post last dose (Up to 2 months)

Title

Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts

Description

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.

Time Frame

Baseline, day 1-16, 2 hours pre-dose and at 3-, 5-, 9-, 12-, 24-, and 36-hours post-dose

Title

Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - MAD Cohorts

Description

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.

Time Frame

Baseline, Day 1-16, 2 hours pre-dose and at 7-, 24-, and 48-hours post final dose

Title

Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts

Description

Time Frame

Baseline and at 6-hours post-dose

Title

Mean Change From Baseline in Vital Signs Part 1 - MAD Cohorts

Description

Time Frame

Baseline and at 6-hours post-dose

Title

Mean Change From Baseline in Vital Signs Part 2 - SAD Cohorts

Description

Mean change from baseline in heart rate (HR) vital signs. Baseline is defined as the last non-missing value prior to the corresponding period.

Time Frame

Baseline and at 6-hours post-dose

Title

Mean Change From Baseline in Vital Signs Part 2 - MAD Cohorts

Description

Mean change from baseline in heart rate (HR) vital signs. Baseline is defined as the last non-missing value prior to first randomized dose

Time Frame

Baseline and at 6-hours post-dose

Title

Number of Participants With a Troponin I Increase - SAD Cohorts

Description

Time Frame

Baseline, day 1-3, 2 hours pre-dose and at 3-, 5-, 9-, 12-, 24-, and 36-hours post-dose

Title

Number of Participants With a Troponin I Increase - MAD Cohorts

Description

Time Frame

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

Title

Number of Participants With Clinically Significant Laboratory Abnormalities

Description

Number of participants with clinically significant laboratory abnormalities.

Time Frame

From first dose to 30 days post last dose (Up to 2 months)

Title

Number of Participants With Clinically Significant Physical Examinations Abnormalities

Description

Number of participants with clinically significant physical examinations abnormalities.

Time Frame

From first dose to 30 days post last dose (Up to 2 months)

Secondary Outcome Measure Information:

Title

Danicamtiv Maximum Observed Plasma Concentration (Cmax)

Description

Maximum observed plasma concentration (Cmax) for Danicamtiv. Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported.

Time Frame