Cardiovascular Diseases, Heart Diseases, Heart Failure, Heart Failure With Preserved Ejection Fraction, Heart Failure With Reduced Ejection Fraction
Conditions
Keywords
PDE9, Heart Failure, CRD-740, HFpEF, HFrEF
Brief summary
This is a study evaluating the effectiveness of CRD-740 in patients with either Heart Failure with Reduced Ejection Fraction (HFrEF) or Heart Failure with Preserved Ejection Fraction (HFpEF) after 12 weeks of treatment. The primary objective in Part A is to assess the effect of CRD-740 compared to placebo in plasma cGMP at Week 4 in HFrEF. Part B of the study was not conducted in favor of redesigned new studies.
Interventions
DRUGCRD-740
Tablets administered orally.
DRUGPlacebo
Tablets administered orally.
Sponsors
Cardurion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Males or Females ≥18 years of age, at screening. 2. Diagnosis of clinical heart failure syndrome, New York Heart Association functional class II - III for at least 6 months prior to screening 3. For Part A: * Ejection Fraction ≤40% by echocardiography at screening. * NT-proBNP level ≥600 pg/ml at screening. Subjects with atrial fibrillation or flutter at screening are required to have an NT-proBNP level of ≥1000 pg/mL at screening. 5\. Stable doses of guideline-directed heart failure therapy for a minimum of 4 weeks prior to screening that has been individually optimized according to standard practice guidelines and no addition of guideline-directed heart failure therapy within 3 months of screening.
Exclusion criteria
2\. Recent HF exacerbation defined by hospitalization or requirement for intravenous diuretics within 60 days of screening. 3\. Subjects with planned interventions (e.g., percutaneous coronary intervention, devices) etc. occurring during their involvement in this study. 4\. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other major cardiovascular surgery or carotid angioplasty within 60 days of screening. 5\. Subjects with clinical suspicion of infiltrative cardiomyopathy (e.g., amyloid, sarcoid), hypertrophic cardiomyopathy (obstructive or non-obstructive), or HF secondary to severe valvular disease, active myocarditis, active pericarditis, or clinically significant congenital heart disease. 6\. Prior or planned orthotopic heart transplantation. 7\. Presence of or plan for mechanical circulatory support. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: The Mean Change From Baseline (Day 1) in Plasma cGMP at Week 4. | Baseline to Week 4 | Efficacy: To assess the effect of CRD-740 compared to placebo in plasma cGMP at Week 4 in subjects with CHFrEF. |
Countries
Canada, Israel, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CRD-740 Part A: Participants in Part A randomly assigned to this arm will take CRD-740 at two ascending dose levels over 12 weeks.
CRD-740: Tablets administered orally.
Part B of the study was not conducted in favor of redesigned new studies. | 40 |
| Placebo Part A: Participants in Part A randomly assigned to this arm will take placebo at two ascending dose levels over 12 weeks.
Placebo: Tablets administered orally.
Part B of the study was not conducted in favor of redesigned new studies. | 20 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Complete Study | Adverse Event | 1 | 2 |
| Complete Study | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Placebo | CRD-740 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 11 Participants | 23 Participants | 34 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 17 Participants | 26 Participants |
| Age, Continuous | 65.6 years STANDARD_DEVIATION 13.16 | 68.4 years STANDARD_DEVIATION 12.7 | 67.4 years STANDARD_DEVIATION 12.81 |
| Age, Customized Median Age | 66.0 years | 70.5 years | 69.0 years |
| Echocardiogram performed during screening No | 0 Participants | 0 Participants | 0 Participants |
| Echocardiogram performed during screening Yes | 20 Participants | 40 Participants | 60 Participants |
| EF group EF ≤ 40% | 20 Participants | 40 Participants | 60 Participants |
| EF group EF > 40% | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 4 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 36 Participants | 54 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Mean Body Mass Index (kg/m2) at Baseline | 28.38 body weight (kg)/ height (m2) STANDARD_DEVIATION 5.953 | 31.41 body weight (kg)/ height (m2) STANDARD_DEVIATION 11.483 | 30.40 body weight (kg)/ height (m2) STANDARD_DEVIATION 10.032 |
| Mean EF (%) for rEF (≤40%) subjects | 26.91 percent STANDARD_DEVIATION 6.181 | 29.16 percent STANDARD_DEVIATION 7.191 | 28.41 percent STANDARD_DEVIATION 6.901 |
| Mean Height (cm) at Baseline | 172.5 cm STANDARD_DEVIATION 10.65 | 175.6 cm STANDARD_DEVIATION 10.2 | 174.6 cm STANDARD_DEVIATION 10.36 |
| Mean Weight (kg) at Baseline | 84.07 kg STANDARD_DEVIATION 16.932 | 97.27 kg STANDARD_DEVIATION 37.582 | 92.87 kg STANDARD_DEVIATION 32.639 |
| Median Body Mass Index (kg/m2) at Baseline | 26.72 body weight (kg)/ height (m2) | 28.92 body weight (kg)/ height (m2) | 27.89 body weight (kg)/ height (m2) |
| Median EF (%) for rEF (≤40%) subjects | 25.00 percent | 26.50 percent | 25.00 percent |
| Median Height (cm) at Baseline | 170.8 cm | 175.0 cm | 173.4 cm |
| Median Weight (kg) at Baseline | 81.00 kg | 87.65 kg | 85.55 kg |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 9 Participants | 13 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 29 Participants | 44 Participants |
| Region of Enrollment Israel | 3 participants | 5 participants | 8 participants |
| Region of Enrollment United Kingdom | 4 participants | 8 participants | 12 participants |
| Region of Enrollment United States | 13 participants | 27 participants | 40 participants |
| Reproductive System Findings Test (Female only), n (%) Childbearing Potential | 0 Participants | 2 Participants | 2 Participants |
| Reproductive System Findings Test (Female only), n (%) Menopause Status | 4 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 9 Participants |
| Sex: Female, Male Male | 16 Participants | 35 Participants | 51 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 |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 40 | 0 / 20 | 0 / 38 | 0 / 19 | 0 / 36 | 0 / 19 | 0 / 40 | 0 / 20 |
| other Total, other adverse events | 1 / 40 | 1 / 20 | 3 / 38 | 1 / 19 | 4 / 36 | 1 / 19 | 5 / 40 | 3 / 20 |
| serious Total, serious adverse events | 1 / 40 | 0 / 20 | 1 / 38 | 0 / 19 | 0 / 36 | 1 / 19 | 3 / 40 | 3 / 20 |
Outcome results
Primary
Part A: The Mean Change From Baseline (Day 1) in Plasma cGMP at Week 4.
Efficacy: To assess the effect of CRD-740 compared to placebo in plasma cGMP at Week 4 in subjects with CHFrEF.
Time frame: Baseline to Week 4
Population: The modified Intention to Treat (mITT) Population will consist of all randomized subjects who received at least one dose of CRD-740 or placebo. Subjects will be analyzed according to their randomized treatment, regardless of actual treatment received, treatment compliance, or treatment duration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CRD-740 | Part A: The Mean Change From Baseline (Day 1) in Plasma cGMP at Week 4. | 19.139 AUC 0-6hr (hr*nmol/L) | Standard Deviation 26.9007 |
| Placebo | Part A: The Mean Change From Baseline (Day 1) in Plasma cGMP at Week 4. | -8.822 AUC 0-6hr (hr*nmol/L) | Standard Deviation 31.3357 |
p-value: 0.003295% CI: [7.847, 45.099]ANCOVA