Heart Failure
Conditions
Brief summary
This study will assess the safety, tolerability, and pharmacodynamics of CK-1827452 infusion in patients with stable heart failure.
Interventions
DRUGCK-1827452
IV infusion for 1 hour at 0.125 mg/kg/h followed by 1 hour at 0.0625 mg/kg/h
DRUGPlacebo
IV infusion for 2 hours
Sponsors
Cytokinetics
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patient is male, or female of non-childbearing potential (two years post-menopausal or surgically sterilized) 2. Female patients must have a negative urine pregnancy test prior to entry into the study 3. Patient is 18 years old or greater 4. Patient has given signed informed consent 5. Patient is considered to be in suitable health in the opinion of the investigator, as determined by: * A pre-study physical examination with no clinical abnormalities which in the opinion of the investigator would preclude participation in the study other than physical symptoms or signs consistent with stable heart failure * An electrocardiogram (ECG) with no abnormalities in the opinion of the investigator that would impair assessment of stopping criteria 6. Patient has pre-study clinical laboratory findings that are within normal range, or if outside of the normal range, should not preclude participation in the study in the opinion of the investigator (see
Exclusion criteria
, below, for exceptions) 7. Patient has a documented diagnosis of heart failure with an ejection fraction of less than 40% 8. Patient has been on a stable dose of a beta blocker and an ACE (angiotensin-converting enzyme) inhibitor or an ARB (angiotensin II receptor blocker) for at least 4 weeks. If prescribed, diuretics must have been administered according to a consistent regimen for at least 4 weeks 9. Patient is currently in sinus rhythm 10. Patient has interpretable echocardiographic images on a screening echocardiogram
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline of Systolic Ejection Time at Various CK-1827452 Plasma Concentrations | 4 days | Pooled analysis of the echocardiographic measure systolic ejection time from echocardiograms taken at all timepoints. The systolic ejection time is the period during which the aortic valve is open and blood is flowing across the valve. Echocardiograms from cohorts 1,2,3,4 and 5 (564 echocardiograms) were binned into either placebo group or 1 of 6 groups based on plasma concentration of CK-1827452. |
| Change From Baseline of Fractional Shortening at Various CK-1827452 Plasma Concentrations | 4 days | Pooled analysis of the echocardiographic measure fractional shortening from echocardiograms taken at all timepoints. Fractional shortening is the percentage of change from baseline in the left ventricular cavity dimension with systole. Echocardiograms from cohorts 1,2,3,4 and 5 (564 echocardiograms) were binned into either placebo group or 1 of 6 groups based on plasma concentration of CK-1827452. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CK-1827452 Maximum Observed Plasma Concentration (Cmax) | 2 days | Determined by evaluation of plasma concentrations from blood samples collected prior to dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 12, 24 and 48 hours after initiation of study drug infusion |
| CK-1827452 Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Plasma Concentration (AUClast) | 2 days | Determined by evaluation of plasma concentrations from blood samples collected prior to dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 12, 24 and 48 hours after initiation of study drug infusion |
Countries
Georgia, Russia, United Kingdom, United States
Participant flow
Recruitment details
The recruitment period was from April 2007 to January 2009.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 4 treatment periods with a 2 hour infusion. The 4 treatment periods consist of 3 escalating dose levels of CK-1827452 and 1 placebo treatment randomized into the dose escalation sequence. Treatment periods occur at least 7 days apart. | 8 |
| Cohort 2 4 treatment periods with a 2 hour infusion. The 4 treatment periods consist of 3 escalating dose levels of CK-1827452 and 1 placebo treatment randomized into the dose escalation sequence. Treatment periods occur at least 7 days apart. | 9 |
| Cohort 3 4 treatment periods with a 24 hour infusion. The 4 treatment periods consist of 3 escalating dose levels of CK-1827452 and 1 placebo treatment randomized into the dose escalation sequence. Treatment periods occur at least 7 days apart. | 10 |
| Cohort 4 4 treatment periods with a 24 hour infusion. The 4 treatment periods consist of 3 escalating dose levels of CK-1827452 and 1 placebo treatment randomized into the sequence. Treatment periods occur at least 7 days apart. | 8 |
| Cohort 5 2 treatment periods with a 72 hour infusion. The 2 treatment periods are randomly assigned and consist of 1 dose level of CK-1827452 (with dose de-escalation possible depending on tolerability) and 1 placebo treatment. Treatment period 2 occurs at least 7 days after the conclusion of period 1. | 10 |
| Total | 45 |
Baseline characteristics
| Characteristic | Cohort 5 | Total | Cohort 1 | Cohort 2 | Cohort 3 | Cohort 4 |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 15 Participants | 3 Participants | 2 Participants | 4 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 30 Participants | 5 Participants | 7 Participants | 6 Participants | 5 Participants |
| Age, Continuous | 57.0 years STANDARD_DEVIATION 14 | 57.5 years STANDARD_DEVIATION 13.2 | 59.0 years STANDARD_DEVIATION 11.9 | 56.0 years STANDARD_DEVIATION 14.3 | 62.0 years STANDARD_DEVIATION 8.2 | 52.6 years STANDARD_DEVIATION 18 |
| Region of Enrollment Georgia | 2 participants | 2 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Region of Enrollment Russian Federation | 1 participants | 11 participants | 0 participants | 4 participants | 4 participants | 2 participants |
| Region of Enrollment United Kingdom | 5 participants | 29 participants | 8 participants | 5 participants | 6 participants | 5 participants |
| Region of Enrollment United States | 2 participants | 3 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Sex: Female, Male Female | 2 Participants | 6 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants |
| Sex: Female, Male Male | 8 Participants | 39 Participants | 8 Participants | 8 Participants | 10 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 41 | 1 / 8 | 0 / 9 | 1 / 16 | 4 / 6 | 0 / 8 | 1 / 1 | 6 / 18 | 4 / 18 | 1 / 16 | 1 / 2 | 2 / 8 |
| serious Total, serious adverse events | 0 / 41 | 0 / 8 | 0 / 9 | 0 / 16 | 0 / 6 | 0 / 8 | 1 / 1 | 1 / 18 | 1 / 18 | 0 / 16 | 0 / 2 | 0 / 8 |
Outcome results
Primary
Change From Baseline of Fractional Shortening at Various CK-1827452 Plasma Concentrations
Pooled analysis of the echocardiographic measure fractional shortening from echocardiograms taken at all timepoints. Fractional shortening is the percentage of change from baseline in the left ventricular cavity dimension with systole. Echocardiograms from cohorts 1,2,3,4 and 5 (564 echocardiograms) were binned into either placebo group or 1 of 6 groups based on plasma concentration of CK-1827452.
Time frame: 4 days
Population: Pharmacodynamic Population. 4-way crossover design for cohorts 1-4 and 2-way crossover for cohort 5 requires multiple dosing events per participant. Also, multiple PK/PD assessments occur per dosing event.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| >0-100 ng/mL | Change From Baseline of Fractional Shortening at Various CK-1827452 Plasma Concentrations | Fractional Shortening Percent Change from Baseline | 1 Percentage of change | Standard Error 1 |
| >0-100 ng/mL | Change From Baseline of Fractional Shortening at Various CK-1827452 Plasma Concentrations | # of Echocardiographic Observations (no units) | 81 Percentage of change | Standard Error 0 |
| >100-200 ng/mL | Change From Baseline of Fractional Shortening at Various CK-1827452 Plasma Concentrations | Fractional Shortening Percent Change from Baseline | 1 Percentage of change | Standard Error 1 |
| >100-200 ng/mL | Change From Baseline of Fractional Shortening at Various CK-1827452 Plasma Concentrations | # of Echocardiographic Observations (no units) | 56 Percentage of change | Standard Error 0 |
| >200-300 ng/mL | Change From Baseline of Fractional Shortening at Various CK-1827452 Plasma Concentrations | Fractional Shortening Percent Change from Baseline | 3 Percentage of change | Standard Error 1 |
| >200-300 ng/mL | Change From Baseline of Fractional Shortening at Various CK-1827452 Plasma Concentrations | # of Echocardiographic Observations (no units) | 37 Percentage of change | Standard Error 0 |
| >300-400 ng/mL | Change From Baseline of Fractional Shortening at Various CK-1827452 Plasma Concentrations | Fractional Shortening Percent Change from Baseline | 3 Percentage of change | Standard Error 1 |
| >300-400 ng/mL | Change From Baseline of Fractional Shortening at Various CK-1827452 Plasma Concentrations | # of Echocardiographic Observations (no units) | 23 Percentage of change | Standard Error 0 |
| >400-500 ng/mL | Change From Baseline of Fractional Shortening at Various CK-1827452 Plasma Concentrations | # of Echocardiographic Observations (no units) | 17 Percentage of change | Standard Error 0 |
| >400-500 ng/mL | Change From Baseline of Fractional Shortening at Various CK-1827452 Plasma Concentrations | Fractional Shortening Percent Change from Baseline | 2 Percentage of change | Standard Error 1 |
| >500 ng/mL | Change From Baseline of Fractional Shortening at Various CK-1827452 Plasma Concentrations | Fractional Shortening Percent Change from Baseline | 5 Percentage of change | Standard Error 1 |
| >500 ng/mL | Change From Baseline of Fractional Shortening at Various CK-1827452 Plasma Concentrations | # of Echocardiographic Observations (no units) | 44 Percentage of change | Standard Error 0 |
Comparison: Placebo corrected change from baseline least squares mean +/- the standard error of the meanp-value: 0.366595% CI: [-1, 2]ANCOVA
Comparison: Placebo corrected change from baseline least squares mean +/- the standard error of the meanp-value: <0.035795% CI: [0, 3]ANCOVA
Comparison: Placebo corrected change from baseline least squares mean +/- the standard error of the meanp-value: 0.000495% CI: [1, 5]ANCOVA
Comparison: Placebo corrected change from baseline least squares mean +/- the standard error of the meanp-value: 0.008695% CI: [1, 4]ANCOVA
Comparison: Placebo corrected change from baseline least squares mean +/- the standard error of the meanp-value: 0.03295% CI: [0, 5]ANCOVA
Comparison: Placebo corrected change from baseline least squares mean +/- the standard error of the meanp-value: <0.000195% CI: [3, 6]ANCOVA
Comparison: All available concentration data are used in the model as a continuous variable.~p-value based on individual plasma concentration of CK-1827452 vs. corresponding fractional shortening PD assessment (not binned based on plasma concentration)p-value: <0.0001ANCOVA
Primary
Change From Baseline of Systolic Ejection Time at Various CK-1827452 Plasma Concentrations
Pooled analysis of the echocardiographic measure systolic ejection time from echocardiograms taken at all timepoints. The systolic ejection time is the period during which the aortic valve is open and blood is flowing across the valve. Echocardiograms from cohorts 1,2,3,4 and 5 (564 echocardiograms) were binned into either placebo group or 1 of 6 groups based on plasma concentration of CK-1827452.
Time frame: 4 days
Population: Pharmacodynamic Population. 4-way crossover design for cohorts 1-4 and 2-way crossover for cohort 5 requires multiple dosing events per participant. Also, multiple PK/PD assessments occur per dosing event.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| >0-100 ng/mL | Change From Baseline of Systolic Ejection Time at Various CK-1827452 Plasma Concentrations | # of Echocardiographic Observations (no units) | 84 msec | Standard Error 0 |
| >0-100 ng/mL | Change From Baseline of Systolic Ejection Time at Various CK-1827452 Plasma Concentrations | Ejection Fraction msec Change from Baseline | 1 msec | Standard Error 4 |
| >100-200 ng/mL | Change From Baseline of Systolic Ejection Time at Various CK-1827452 Plasma Concentrations | # of Echocardiographic Observations (no units) | 62 msec | Standard Error 0 |
| >100-200 ng/mL | Change From Baseline of Systolic Ejection Time at Various CK-1827452 Plasma Concentrations | Ejection Fraction msec Change from Baseline | 18 msec | Standard Error 4 |
| >200-300 ng/mL | Change From Baseline of Systolic Ejection Time at Various CK-1827452 Plasma Concentrations | # of Echocardiographic Observations (no units) | 42 msec | Standard Error 0 |
| >200-300 ng/mL | Change From Baseline of Systolic Ejection Time at Various CK-1827452 Plasma Concentrations | Ejection Fraction msec Change from Baseline | 47 msec | Standard Error 5 |
| >300-400 ng/mL | Change From Baseline of Systolic Ejection Time at Various CK-1827452 Plasma Concentrations | # of Echocardiographic Observations (no units) | 24 msec | Standard Error 0 |
| >300-400 ng/mL | Change From Baseline of Systolic Ejection Time at Various CK-1827452 Plasma Concentrations | Ejection Fraction msec Change from Baseline | 58 msec | Standard Error 6 |
| >400-500 ng/mL | Change From Baseline of Systolic Ejection Time at Various CK-1827452 Plasma Concentrations | # of Echocardiographic Observations (no units) | 20 msec | Standard Error 0 |
| >400-500 ng/mL | Change From Baseline of Systolic Ejection Time at Various CK-1827452 Plasma Concentrations | Ejection Fraction msec Change from Baseline | 59 msec | Standard Error 6 |
| >500 ng/mL | Change From Baseline of Systolic Ejection Time at Various CK-1827452 Plasma Concentrations | # of Echocardiographic Observations (no units) | 46 msec | Standard Error 0 |
| >500 ng/mL | Change From Baseline of Systolic Ejection Time at Various CK-1827452 Plasma Concentrations | Ejection Fraction msec Change from Baseline | 80 msec | Standard Error 5 |
Comparison: Placebo corrected change from baseline least squares mean +/- the standard error of the meanp-value: 0.884295% CI: [-7, 8]ANCOVA
Comparison: Placebo corrected change from baseline least squares mean +/- the standard error of the meanp-value: <0.000195% CI: [10, 27]ANCOVA
Comparison: Placebo corrected change from baseline least squares mean +/- the standard error of the meanp-value: <0.000195% CI: [38, 56]ANCOVA
Comparison: Placebo corrected change from baseline least squares mean +/- the standard error of the meanp-value: <0.000195% CI: [46, 70]ANCOVA
Comparison: All available concentration data are used in the model as a continuous variable.~p-value based on individual plasma concentration of CK-1827452 vs. corresponding systolic ejection time PD assessment (not binned based on plasma concentration)p-value: <0.0001ANCOVA
Comparison: Placebo corrected change from baseline least squares mean +/- the standard error of the meanp-value: <0.000195% CI: [47, 72]ANCOVA
Comparison: Placebo corrected change from baseline least squares mean +/- the standard error of the meanp-value: <0.000195% CI: [71, 89]ANCOVA
Secondary
CK-1827452 Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Plasma Concentration (AUClast)
Determined by evaluation of plasma concentrations from blood samples collected prior to dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 12, 24 and 48 hours after initiation of study drug infusion
Time frame: 2 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| >0-100 ng/mL | CK-1827452 Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Plasma Concentration (AUClast) | 1102.2 hour x nanogram/milliliter | Standard Deviation 257.6 |
| >100-200 ng/mL | CK-1827452 Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Plasma Concentration (AUClast) | 2314.3 hour x nanogram/milliliter | Standard Deviation 640.9 |
| >200-300 ng/mL | CK-1827452 Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Plasma Concentration (AUClast) | 4252.7 hour x nanogram/milliliter | Standard Deviation 1296.7 |
| >300-400 ng/mL | CK-1827452 Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Plasma Concentration (AUClast) | 6060.7 hour x nanogram/milliliter | Standard Deviation 1741.7 |
| >400-500 ng/mL | CK-1827452 Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Plasma Concentration (AUClast) | 8495.7 hour x nanogram/milliliter | Standard Deviation 3178.3 |
| >500 ng/mL | CK-1827452 Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Plasma Concentration (AUClast) | 3982.7 hour x nanogram/milliliter | Standard Deviation 1070.2 |
| Cohort 3: 0.5 mg/kg/h + 0.05 mg/kg/h | CK-1827452 Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Plasma Concentration (AUClast) | 8120.5 hour x nanogram/milliliter | Standard Deviation 2268.9 |
| Cohort 3: 1.0 mg/kg/h + 0.1 mg/kg/h | CK-1827452 Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Plasma Concentration (AUClast) | 18450.7 hour x nanogram/milliliter | Standard Deviation 4747.8 |
| Cohort 4: 0.25 mg.kg.h + 0.125 mg/kg/h + 0.025 mg/kg/h | CK-1827452 Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Plasma Concentration (AUClast) | 4399.0 hour x nanogram/milliliter | Standard Deviation 1483.2 |
| Cohort 4: 0.5 mg/kg/h + 0.25 mg/kg/h + 0.05 mg/kg/h | CK-1827452 Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Plasma Concentration (AUClast) | 10624.8 hour x nanogram/milliliter | Standard Deviation 5168.3 |
| Cohort 4: 1.0 mg/kg/h + 0.5 mg/kg/h + 0.1 mg/kg/h | CK-1827452 Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Plasma Concentration (AUClast) | 19394.3 hour x nanogram/milliliter | Standard Deviation 4230.6 |
| Cohort 5: 1.0 mg/kg/h + 0.5 mg/kg/h + 0.1 mg/kg/h | CK-1827452 Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Plasma Concentration (AUClast) | 59044.6 hour x nanogram/milliliter | Standard Deviation 17693.2 |
| Cohort 5: 0.75 mg/kg/h + 0.375 mg/kg/h + 0.075 mg/kg/h | CK-1827452 Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Plasma Concentration (AUClast) | 43605.5 hour x nanogram/milliliter | Standard Deviation 3551 |
Secondary
CK-1827452 Maximum Observed Plasma Concentration (Cmax)
Determined by evaluation of plasma concentrations from blood samples collected prior to dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 12, 24 and 48 hours after initiation of study drug infusion
Time frame: 2 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| >0-100 ng/mL | CK-1827452 Maximum Observed Plasma Concentration (Cmax) | 96.1 nanogram/milliliter | Standard Deviation 27.8 |
| >100-200 ng/mL | CK-1827452 Maximum Observed Plasma Concentration (Cmax) | 195.0 nanogram/milliliter | Standard Deviation 69.4 |
| >200-300 ng/mL | CK-1827452 Maximum Observed Plasma Concentration (Cmax) | 347.1 nanogram/milliliter | Standard Deviation 108.6 |
| >300-400 ng/mL | CK-1827452 Maximum Observed Plasma Concentration (Cmax) | 558.1 nanogram/milliliter | Standard Deviation 156.5 |
| >400-500 ng/mL | CK-1827452 Maximum Observed Plasma Concentration (Cmax) | 635.9 nanogram/milliliter | Standard Deviation 158 |
| >500 ng/mL | CK-1827452 Maximum Observed Plasma Concentration (Cmax) | 165.3 nanogram/milliliter | Standard Deviation 51.4 |
| Cohort 3: 0.5 mg/kg/h + 0.05 mg/kg/h | CK-1827452 Maximum Observed Plasma Concentration (Cmax) | 279.9 nanogram/milliliter | Standard Deviation 55 |
| Cohort 3: 1.0 mg/kg/h + 0.1 mg/kg/h | CK-1827452 Maximum Observed Plasma Concentration (Cmax) | 633.0 nanogram/milliliter | Standard Deviation 161.5 |
| Cohort 4: 0.25 mg.kg.h + 0.125 mg/kg/h + 0.025 mg/kg/h | CK-1827452 Maximum Observed Plasma Concentration (Cmax) | 177.9 nanogram/milliliter | Standard Deviation 103.4 |
| Cohort 4: 0.5 mg/kg/h + 0.25 mg/kg/h + 0.05 mg/kg/h | CK-1827452 Maximum Observed Plasma Concentration (Cmax) | 403.3 nanogram/milliliter | Standard Deviation 226.2 |
| Cohort 4: 1.0 mg/kg/h + 0.5 mg/kg/h + 0.1 mg/kg/h | CK-1827452 Maximum Observed Plasma Concentration (Cmax) | 681.4 nanogram/milliliter | Standard Deviation 159.2 |
| Cohort 5: 1.0 mg/kg/h + 0.5 mg/kg/h + 0.1 mg/kg/h | CK-1827452 Maximum Observed Plasma Concentration (Cmax) | 884.5 nanogram/milliliter | Standard Deviation 316.2 |
| Cohort 5: 0.75 mg/kg/h + 0.375 mg/kg/h + 0.075 mg/kg/h | CK-1827452 Maximum Observed Plasma Concentration (Cmax) | 726.9 nanogram/milliliter | Standard Deviation 62.4 |