This is a Phase 1b randomized, double-blinded, single-center safety and pharmacodynamics study of sequential cohort, dose-escalating, repeat-dosing of dapansutrile or placebo (4:1 ratio) in subjects with stable systolic heart failure (HF) with LVEF≤40% symptomatic for NYHA functional classification II-III who show signs of systemic inflammation (high sensitivity plasma C reactive protein \[hsCRP\] \> 2 mg/L). A total of 30 subjects will be enrolled in 3 sequential cohorts by randomized allocation (8 active and 2 placebo within each cohort). Progression to cohort 2 with dose escalation will occur following the Day 28 visit of the last subject in the first cohort. Progression to cohort 3 with dose escalation will occur following the Day 8 visit of the last subject in the second cohort. Subjects will be screened and evaluated twice for eligibility: 1) at the time of Screening (up to 28 days prior to enrollment); and 2) at the Baseline visit, prior to randomization. Following enrollment, Baseline assessments will be conducted and the first dose of investigational product (either dapansutrile capsules or placebo capsules) will be administered at the clinical site upon completion of all assessment and collection of baseline parameters. Subjects will then self-administer investigational product once, twice or four times daily, depending on cohort, for up to fourteen (14) consecutive days beginning at the Baseline visit and continuing through the planned Day 14 visit. Subjects will return to the study clinic on Days 4, 8, 14 and 28 for follow-up visits. Additionally, subjects will be contacted for telephone follow-up on Day 42.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
30
Hard opaque capsules containing 100 mg of API.
Hard opaque capsules containing 0 mg of API.
Virginia Commonwealth University - Pauley Heart Center
Richmond, Virginia, United States
Adverse events
Adverse events experienced by the patient will be recorded.
Time frame: Screening through Day 42 follow-up
Cardiopulmonary exercise test
Physician-supervised maximal aerobic exercise test will be administered using a metabolic cart that is interfaced with a motorized treadmill. Change in peak oxygen consumption in each group will be assessed.
Time frame: Day 14
Transthoracic Doppler ECG - Left Ventricle Ejection Fraction
Changes in left ventricular ejection fraction will be analyzed.
Time frame: Day 14
Transthoracic Doppler ECG - Left Ventricular Filling Pressure
Changes in estimated left ventricular filling pressure, measured as ratio of early diastolic transmitral pulsed wave Doppler flow velocity (E) to tissue Doppler velocity of the mitral annulus (e') will be analyzed.
Time frame: Day 14
Bioimpedance analysis
Bioimpedance is a non-invasive, quick and safe technique that allows to estimate body composition compartments (total body water, intracellular water, extracellular water, fat mass, fat-free mass, lean mass). Change in total body water will be assessed.
Time frame: Day 14
Kansas City Cardiomyopathy Questionnaire - Clinical Summary Score
Change in KCCQ score, a 23-item, self-administered instrument that independently measures a patient's perception of their health status, which includes heart failure symptoms. This scale is quantified in six domains: physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. Each domain is scored on a 0-100 scale with 100 being better and 0 being worse. Two summary scores are calculated: the Clinical Summary Score (mean of symptom and physical function domain scores) and the Overall Summary Score (mean of the symptom, physical function, social limitations and quality of life scores).
Time frame: Day 14
Kansas City Cardiomyopathy Questionnaire - Overall Summary Score
Change in KCCQ score, a 23-item, self-administered instrument that independently measures a patient's perception of their health status, which includes heart failure symptoms. This scale is quantified in six domains: physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. Each domain is scored on a 0-100 scale with 100 being better and 0 being worse. Two summary scores are calculated: the Clinical Summary Score (mean of symptom and physical function domain scores) and the Overall Summary Score (mean of the symptom, physical function, social limitations and quality of life scores).
Time frame: Day 14
Duke Activity Status Index
Change in Duke Activity Status Index, a self-administered questionnaire that measures a patient's functional capacity. The index consists of 12 "yes or no" questions, which are summed and used to calculate VO2peak and METS.
Time frame: Day 14
Vital signs - Pulse
Changes in pulse will be analyzed.
Time frame: Day 14
Vital signs - Blood Pressure
Changes in systolic and diastolic blood pressure will be analyzed.
Time frame: Day 14
Vital signs - Temperature
Changes in body temperature will be analyzed.
Time frame: Day 14
Vital signs - Respiratory Rate
Changes in respiratory rate will be analyzed.
Time frame: Day 14
Safety Laboratory Measurements - Chemistry
Changes in blood chemistry will be analyzed.
Time frame: Day 14
Safety Laboratory Measurements - Hematology
Changes in complete blood count will be analyzed.
Time frame: Day 14
Physical Examination
A full or targeted physical examination of the patient's major body systems
Time frame: Day 14
12-lead electrocardiogram
Electrodes will be placed on the patient to obtain a recording of the electrical activity of the heart.
Time frame: Day 8
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