Clinical trial NCT03447990: 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
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Heart Failure With Reduced Ejection Fraction
Dilated Cardiomyopathy
Lead sponsor: Bristol-Myers Squibb
Sponsor class: INDUSTRY
First posted: 2018-02-27
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: From first dose to 30 days post last dose (Up to 2 months)
measure: Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts
timeFrame: Baseline, day 1-16, 2 hours pre-dose and at 3-, 5-, 9-, 12-, 24-, and 36-hours post-dose
measure: Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - MAD Cohorts
timeFrame: Baseline, Day 1-16, 2 hours pre-dose and at 7-, 24-, and 48-hours post final dose
measure: Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts
timeFrame: Baseline and at 6-hours post-dose
measure: Mean Change From Baseline in Vital Signs Part 1 - MAD Cohorts
timeFrame: Baseline and at 6-hours post-dose
measure: Mean Change From Baseline in Vital Signs Part 2 - SAD Cohorts
timeFrame: Baseline and at 6-hours post-dose
measure: Mean Change From Baseline in Vital Signs Part 2 - MAD Cohorts
timeFrame: Baseline and at 6-hours post-dose
measure: Number of Participants With a Troponin I Increase - SAD Cohorts
timeFrame: Baseline, day 1-3, 2 hours pre-dose and at 3-, 5-, 9-, 12-, 24-, and 36-hours post-dose
measure: Number of Participants With a Troponin I Increase - MAD Cohorts
timeFrame: 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
measure: Number of Participants With Clinically Significant Laboratory Abnormalities
timeFrame: From first dose to 30 days post last dose (Up to 2 months)
measure: Number of Participants With Clinically Significant Physical Examinations Abnormalities
timeFrame: From first dose to 30 days post last dose (Up to 2 months)
Secondary outcomes:
measure: Danicamtiv Maximum Observed Plasma Concentration (Cmax)
timeFrame: 1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose
measure: Danicamtiv Time of Maximum Observed Plasma Concentration (Tmax)
timeFrame: 1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose
measure: Area Under the Plasma Concentration-Time Curve (AUC)
timeFrame: 1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose
measure: Apparent First-order Terminal Elimination Half-life (t1/2)
timeFrame: 1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose
measure: Danicamtiv Accumulation Ratio for Maximum Observed Plasma Concentration AR(Cmax) - MAD Cohorts
timeFrame: 1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose
measure: Accumulation Ratio for Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours AR(AUC(0-12)) - MAD Cohorts
timeFrame: 1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose
measure: Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 1 - SAD Cohorts
timeFrame: Baseline, predose and at 3, 6, 9, and 24 hours post dose
measure: Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 2 - SAD Cohorts
timeFrame: Baseline, predose and at 3, 6, 9, and 24 hours post dose
measure: Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 3 - SAD Cohorts
timeFrame: Baseline, predose and at 3, 6, 9, and 24 hours post dose
measure: Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 1 - MAD Cohorts
timeFrame: Baseline, predose, and at 7 hours post dose on day 1,2,3, 4, 7, 9, 10, and 11
measure: Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 2 - MAD Cohorts
timeFrame: Baseline, predose, and at 7 hours post dose on day 1,2,3, 4, 7, 9, 10, and 11
measure: Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 3 - MAD Cohorts
timeFrame: Baseline, predose, and at 7 hours post dose on day 1,2,3, 4, 7, 9, 10, and 11
Other outcomes:
Locations:
city: Jacksonville
country: United States
facility: Jacksonville Center for Clinical Research
state: Florida
city: Saint Paul
country: United States
facility: Prism Reseach
state: Minnesota
city: Saint Louis
country: United States
facility: St. Louis Heart and Vascular Cardiology
state: Missouri
city: Newark
country: United States
facility: Newark Beth Israel Medical Center
state: New Jersey
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania Heart and Vascular Center
state: Pennsylvania
city: Tullahoma
country: United States
facility: Tennessee Center for Clinical Trials
state: Tennessee
city: Paris
country: France
facility: Hopital Europeen Georges-Pompidou
city: Berlin
country: Germany
facility: Charite Research Organization
city: Groningen
country: Netherlands
facility: Groningen UMC
city: Sneek
country: Netherlands
facility: D&A Research
city: Wrocław
country: Poland
facility: Wojewodzki Szpital Specjalistyczny we Wroclawiu, Oddzial Kardiologiczny z Pododdzialem Intensywnego Nadzoru Kardiologicznego i Pododdzialem Leczenia Zaburzen Rytmu Serca
city: Łódź
country: Poland
facility: Wojewodzki Szpital Specjalistyczny Im M Kopernika
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital
state: Scotland
Study officials:
References: