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.

Inclusion Criteria:

1. Male and female subjects 18 years old or older
2. Symptomatic stable HF (NYHA class II-III) with reduced left ventricular ejection fraction (LVEF≤40%, measured within 6 months of enrollment - no changes in cardiac medications or new device implantation within past 2 months)
3. Peak exercise limited by shortness of breath and/or fatigue associated with a respiratory exchange ratio (RER) > 1.00 (reflecting maximal aerobic effort)
4. Reduced peak aerobic exercise capacity (peak VO2) to less than 80% of predicted value by age/gender at Baseline
5. Plasma CRP or hsCRP levels > 2 mg/L at Screening
6. Acceptable overall medical condition to be safely enrolled in and to complete the study (with specific regard to cardiovascular, renal and hepatic conditions) in the opinion of the Principal Investigator
7. Ability to provide written, informed consent prior to initiation of any study-related procedures, and ability, in the opinion of the Principal Investigator, to understand and comply with all the requirements of the study

Exclusion Criteria:

1. Women of childbearing potential, or men whose sexual partner(s) is a woman of childbearing potential who:

   1. Are or intend to become pregnant (including use of fertility drugs) during the study
   2. Are nursing
   3. Are not using an acceptable, highly effective method of contraception until all follow-up procedures are complete. (Acceptable, highly effective forms of contraception are defined as: oral contraception, intrauterine device, systemic [injectable or patch] contraception, double barrier methods, naturally or surgically sterile, strict abstinence or partner has been sterilized. If hormonal-based birth control is being used, subject or subject's sexual partner(s) must be on a stable-dose for ≥ 3 months prior to the Baseline visit and maintained at the same dosing level throughout the study.)

2. Abnormal blood pressure or heart rate response, angina or ECG changes (ischemia or arrhythmias) occurring during CPX

3. Presence or known history of autoimmune conditions (e.g., systemic lupus erythematosus, hypophysitis, etc.)

4. History or evidence of active tuberculosis (TB) infection at Baseline visit or one of the risk factors for tuberculosis such as but not limited or exclusive to:

   1. History of any of the following: residence in a congregate setting (e.g., jail or prison, homeless shelter, or chronic care facility), substance abuse (e.g., injection or non-injection), health-care workers with unprotected exposure to subjects who are at high risk of TB or subjects with TB disease before the identification and correct airborne precautions of the subject or
   2. Close contact (i.e., share the same air space in a household or other enclosed environment for a prolonged period (days or weeks, not minutes or hours)) with a person with active pulmonary TB disease within the last 12 months.

5. Use of any prohibited concomitant medications/therapies over the periods defined in Section 5.6.3 or planned use of any prohibited concomitant medications/therapies during the Treatment Period

6. Any other concomitant medical or psychiatric condition(s), disease(s) or prior surgery(ies) that, in the opinion of the Principal Investigator, would impair the subject from safely participating in the trial and/or completing protocol requirements, including but not limited to:

   1. physical inability to walk on a treadmill
   2. decompensated HF (edema, NYHA IV)
   3. significant ischemic heart disease, angina
   4. arterial hypotension (blood pressure [BP] systolic < 90 mmHg)
   5. arterial hypertension (resting BP systolic > 160 mmHg)
   6. atrial fibrillation with rapid ventricular response
   7. severe valvular disease
   8. severe chronic obstructive or restrictive pulmonary disease
   9. moderate-severe anemia (Hgb < 10 g/dL)
   10. severe diabetic neuropathy or myopathy

7. Active or recent (within 2 weeks) infection prior to the Baseline visit

8. History of or known positive for HIV, Hepatitis B surface antigen or antibodies to Hepatitis C Virus

9. Known history of renal impairment and/or creatinine clearance less than 50 mL/min calculated by Cockcroft-Gault method

10. Active malignancy or recent malignancy with chemotherapy treatment within the past 6 months

11. Enrollment in any trial and/or use of any investigational product or device within the immediate 30-day period prior to the Baseline visit

12. Previous exposure to the investigational product

This is a randomized, blinded, placebo-controlled study. Treatment allocation (to active or placebo treatment groups) will be blinded to all study participants, personnel, and investigators. Only the randomization statistician, drug labeling personnel and the medical monitor will be unblinded to the treatment assignment (in the event of an emergency, a scratch off label can be removed unmasking the treatment assignment to the PI and Medical Monitor).