Cardiac Failure, Heart Failure, Reduced Ventricular Ejection Fraction
Conditions
Brief summary
The purpose of this study is to evaluate the effects of BMS-986231 on systolic and diastolic parameters in patients with heart failure and low ejection fraction.
Interventions
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For more information regarding Bristol-Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: * Heart failure with reduced ejection fraction (LVEF on echocardiogram of 40% or less) * Stable guideline directed therapy for heart failure including oral diuretics, ACEi, ARBs, ARNi, MRAs, and β blockers as tolerated, with no dose changes of these medications in the past 2 weeks * Have screening values of NT pro-BNP ≥ 125 pg/mL (15 pmol/L) or BNP ≥ 35 pg/mL (10 pmol/L)
Exclusion criteria
* Systolic blood pressure (SBP) \< 110 mm Hg at screening or pre-randomization * Heart rate \< 50 beats per minute (bpm) or \> 90 bpm at screening or pre-randomization * Permanent Atrial Fibrillation, Atrial Flutter or having Atrial Fibrillation, Atrial Flutter * Estimated glomerular filtration rate (eGFR) \< 15 ml/min/1.73 m2 * Ventricular assist device or prior heart transplant * Prior solid organ transplant * Body weight \< 45 kg or ≥ 140 kg * Low quality echocardiographic visualization windows and image acquisition * Permanent paced rhythm (VVI, DDD or BiV pacing) Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Stroke Volume Index (SVI) Derived From the Velocity Time Integral at the Left Ventricular Outflow Tract (LVOT VTI) at the End of the 5-hour Infusion of BMS-986231, Versus Placebo | at the end of the 5-hour infusion | The objective is to evaluate the effects of BMS-986231 on the left ventricular (LV) systolic function by stroke volume index (SVI) assessed by echocardiography compared to placebo. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean LVEF, Computed by Simpson's Method at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG | at the end of the 5-hour infusion | Evaluate the effects of BMS-986231 on selected other left ventricular systolic and diastolic indices compared to placebo and NTG: LV ejection fraction |
| Mean Cardiac Power Index at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG | at the end of the 5-hour infusion | Evaluate the effects of BMS-986231 on selected other left ventricular systolic and diastolic indices compared to placebo and NTG: Mean LV power index |
| Mean SVI Derived From LVOT VTI at the End of the 5-hour Infusion of BMS-986231, Versus NTG | at the end of the 5-hour infusion | The objective is to evaluate the effects of BMS-986231 on the left ventricular (LV) systolic function by stroke volume index (SVI) assessed by echocardiography compared to NTG. |
| Mean Diastolic Indices: Annular e' Velocity at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG | at the end of the 5-hour infusion | Evaluate the effects of BMS-986231 on selected other left ventricular systolic and diastolic indices compared to placebo and NTG: Diastolic function |
| Mean LV Global Longitudinal Strain, Computed Using STE at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG | at the end of the 5-hour infusion | Evaluate the effects of BMS-986231 on selected other left ventricular systolic and diastolic indices compared to placebo and NTG: LV global longitudinal strain |
| Mean Diastolic Indices: E/A and E/e' Ratio at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG | at the end of the 5-hour infusion | Evaluate the effects of BMS-986231 on selected other left ventricular systolic and diastolic indices compared to placebo and NTG: Diastolic function |
Countries
Japan, Netherlands, United Kingdom, United States
Participant flow
Pre-assignment details
49 participants assigned to treatment and 45 treated. Reasons not treated: 2 re-randomized; 1 randomized in error, screen failure; 1 no longer met study criteria. Note: Study designed for all participants to enter all 3 arms (reassignment of arms occurs every period change).
Participants by arm
| Arm | Count |
|---|---|
| Overall Participants Inclusive of all treatments, all periods. Note: Participants crossed-over from either placebo, drug or NTG arm to the next (in various sequence) following Day 1 treatment and a minimum 5-day washout period, per arm. | 45 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Acute bradycardia and hypotension | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Hypotension | 0 | 0 | 1 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Withdrew consent due to personal reasons | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Overall Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 25 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants |
| Age, Continuous | 63.7 Years STANDARD_DEVIATION 12.35 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 43 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 40 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 40 | 0 / 42 | 0 / 44 |
| other Total, other adverse events | 2 / 40 | 12 / 42 | 10 / 44 |
| serious Total, serious adverse events | 1 / 40 | 0 / 42 | 1 / 44 |
Outcome results
Primary
Mean Stroke Volume Index (SVI) Derived From the Velocity Time Integral at the Left Ventricular Outflow Tract (LVOT VTI) at the End of the 5-hour Infusion of BMS-986231, Versus Placebo
The objective is to evaluate the effects of BMS-986231 on the left ventricular (LV) systolic function by stroke volume index (SVI) assessed by echocardiography compared to placebo.
Time frame: at the end of the 5-hour infusion
Population: Intent to Treat (ITT) population: All randomized participants who started study drug infusion in at least one treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (PBO) | Mean Stroke Volume Index (SVI) Derived From the Velocity Time Integral at the Left Ventricular Outflow Tract (LVOT VTI) at the End of the 5-hour Infusion of BMS-986231, Versus Placebo | 29.545 mL/m^2 | Standard Deviation 7.0243 |
| BMS-986231 | Mean Stroke Volume Index (SVI) Derived From the Velocity Time Integral at the Left Ventricular Outflow Tract (LVOT VTI) at the End of the 5-hour Infusion of BMS-986231, Versus Placebo | 28.721 mL/m^2 | Standard Deviation 9.0174 |
p-value: 0.02795% CI: [-4.0432, -0.257]Kenward-Roger degree of freedom
Secondary
Mean Cardiac Power Index at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG
Evaluate the effects of BMS-986231 on selected other left ventricular systolic and diastolic indices compared to placebo and NTG: Mean LV power index
Time frame: at the end of the 5-hour infusion
Population: Intent to Treat (ITT) population: All randomized participants who started study drug infusion in at least one treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (PBO) | Mean Cardiac Power Index at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG | 0.4122 watts per square meter (W/m^2) | Standard Deviation 0.14404 |
| BMS-986231 | Mean Cardiac Power Index at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG | 0.3427 watts per square meter (W/m^2) | Standard Deviation 0.10463 |
| Nitroglycerin (NTG) | Mean Cardiac Power Index at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG | 0.3568 watts per square meter (W/m^2) | Standard Deviation 0.09184 |
p-value: 0.00795% CI: [-0.16634, -0.02915]Kenward-Roger degree of freedom
p-value: 0.10395% CI: [-0.08243, 0.00814]Kenward-Roger degree of freedom
Secondary
Mean Diastolic Indices: Annular e' Velocity at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG
Evaluate the effects of BMS-986231 on selected other left ventricular systolic and diastolic indices compared to placebo and NTG: Diastolic function
Time frame: at the end of the 5-hour infusion
Population: Intent to Treat (ITT) population: All randomized participants who started study drug infusion in at least one treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (PBO) | Mean Diastolic Indices: Annular e' Velocity at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG | 7.18 cm/sec | Standard Deviation 2.467 |
| BMS-986231 | Mean Diastolic Indices: Annular e' Velocity at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG | 8.07 cm/sec | Standard Deviation 2.333 |
| Nitroglycerin (NTG) | Mean Diastolic Indices: Annular e' Velocity at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG | 7.18 cm/sec | Standard Deviation 2.143 |
Comparison: annular e' velocityp-value: 0.99495% CI: [-0.827, 0.82]Kenward-Roger degree of freedom
Comparison: annular e' velocityp-value: 0.07395% CI: [-0.049, 1.013]Kenward-Roger degree of freedom
Secondary
Mean Diastolic Indices: E/A and E/e' Ratio at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG
Evaluate the effects of BMS-986231 on selected other left ventricular systolic and diastolic indices compared to placebo and NTG: Diastolic function
Time frame: at the end of the 5-hour infusion
Population: Intent to Treat (ITT) population: All randomized participants who started study drug infusion in at least one treatment period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (PBO) | Mean Diastolic Indices: E/A and E/e' Ratio at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG | E/A ratio | 0.80 Ratio | Standard Deviation 0.278 |
| Placebo (PBO) | Mean Diastolic Indices: E/A and E/e' Ratio at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG | E/e' ratio | 9.42 Ratio | Standard Deviation 4.102 |
| BMS-986231 | Mean Diastolic Indices: E/A and E/e' Ratio at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG | E/A ratio | 0.73 Ratio | Standard Deviation 0.27 |
| BMS-986231 | Mean Diastolic Indices: E/A and E/e' Ratio at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG | E/e' ratio | 7.00 Ratio | Standard Deviation 2.464 |
| Nitroglycerin (NTG) | Mean Diastolic Indices: E/A and E/e' Ratio at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG | E/A ratio | 0.71 Ratio | Standard Deviation 0.31 |
| Nitroglycerin (NTG) | Mean Diastolic Indices: E/A and E/e' Ratio at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG | E/e' ratio | 7.81 Ratio | Standard Deviation 2.652 |
Comparison: E/A ratiop-value: 0.00395% CI: [-0.205, -0.051]Kenward-Roger degree of freedom
Comparison: E/A ratiop-value: 0.90495% CI: [-0.051, 0.057]Kenward-Roger degree of freedom
Comparison: E/e' ratiop-value: 0.00695% CI: [-2.763, -0.549]Kenward-Roger degree of freedom
Comparison: E/e' ratiop-value: 0.50395% CI: [-1.085, 0.55]Kenward-Roger degree of freedom
Secondary
Mean LVEF, Computed by Simpson's Method at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG
Evaluate the effects of BMS-986231 on selected other left ventricular systolic and diastolic indices compared to placebo and NTG: LV ejection fraction
Time frame: at the end of the 5-hour infusion
Population: Intent to Treat (ITT) population: All randomized participants who started study drug infusion in at least one treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (PBO) | Mean LVEF, Computed by Simpson's Method at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG | 31.9 Percentage of blood pumped from the LV | Standard Deviation 7.15 |
| BMS-986231 | Mean LVEF, Computed by Simpson's Method at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG | 32.8 Percentage of blood pumped from the LV | Standard Deviation 8.24 |
| Nitroglycerin (NTG) | Mean LVEF, Computed by Simpson's Method at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG | 33.5 Percentage of blood pumped from the LV | Standard Deviation 7.33 |
p-value: 0.17795% CI: [-0.62, 3.19]Kenward-Roger degree of freedom
p-value: 0.83995% CI: [-1.08, 0.88]Kenward-Roger degree of freedom
Secondary
Mean LV Global Longitudinal Strain, Computed Using STE at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG
Evaluate the effects of BMS-986231 on selected other left ventricular systolic and diastolic indices compared to placebo and NTG: LV global longitudinal strain
Time frame: at the end of the 5-hour infusion
Population: Intent to Treat (ITT) population: All randomized participants who started study drug infusion in at least one treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (PBO) | Mean LV Global Longitudinal Strain, Computed Using STE at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG | -11.98 Percentage of blood pumped from the LV | Standard Deviation 2.86 |
| BMS-986231 | Mean LV Global Longitudinal Strain, Computed Using STE at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG | -11.94 Percentage of blood pumped from the LV | Standard Deviation 3.458 |
| Nitroglycerin (NTG) | Mean LV Global Longitudinal Strain, Computed Using STE at the End of the 5-hour Infusion of BMS-986231, Versus Placebo and NTG | -11.36 Percentage of blood pumped from the LV | Standard Deviation 3.067 |
p-value: 0.70595% CI: [-0.67, 0.976]Kenward-Roger degree of freedom
p-value: 0.10595% CI: [-1.504, 0.151]Kenward-Roger degree of freedom
Secondary
Mean SVI Derived From LVOT VTI at the End of the 5-hour Infusion of BMS-986231, Versus NTG
The objective is to evaluate the effects of BMS-986231 on the left ventricular (LV) systolic function by stroke volume index (SVI) assessed by echocardiography compared to NTG.
Time frame: at the end of the 5-hour infusion
Population: Intent to Treat (ITT) population: All randomized participants who started study drug infusion in at least one treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BMS-986231 | Mean SVI Derived From LVOT VTI at the End of the 5-hour Infusion of BMS-986231, Versus NTG | 28.721 mL/m^2 | Standard Deviation 9.0174 |
| Nitroglycerin (NTG) | Mean SVI Derived From LVOT VTI at the End of the 5-hour Infusion of BMS-986231, Versus NTG | 27.811 mL/m^2 | Standard Deviation 7.9712 |
p-value: 0.84695% CI: [-1.8176, 2.2042]Kenward-Roger degree of freedom