Study of Dapansutrile Capsules in Heart Failure

NCT03534297 | Completed Phase 1 FDA Drug

• 1 other identifier: OLT1177-06
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Systolic Heart Failure

Keywords

heart failure; systolic heart failure

Outcome Measures

Primary Outcomes (1)

• Adverse events

  Adverse events experienced by the patient will be recorded.

  Screening through Day 42 follow-up

Secondary Outcomes (15)

• Cardiopulmonary exercise test

  Day 14

• Transthoracic Doppler ECG - Left Ventricle Ejection Fraction

  Day 14

• Transthoracic Doppler ECG - Left Ventricular Filling Pressure

  Day 14

• Bioimpedance analysis

  Day 14

• Kansas City Cardiomyopathy Questionnaire - Clinical Summary Score

  Day 14

Other Outcomes (2)

• Pharmacokinetics

  Baseline (pre and post dose), Day 4, Day 8, Day 14 and Day 28

• Pharmacodynamics / Biomarkers

  Baseline (pre and post dose), Day 4, Day 8, Day 14 and Day 28

Study Arms (2)

dapansutrile capsules

EXPERIMENTAL

A total of 8 patients in each cohort will receive dapansutrile capsules: * Cohort 1 will receive 5x 100 mg dapansutrile capsules QD for 14 days * Cohort 2 will receive 5x 100 mg dapansutrile capsules BID for 14 days * Cohort 3 will receive 5x 100 mg dapansutrile capsules QID for 14 days

Drug: dapansutrile capsules

Placebo Capsules

PLACEBO COMPARATOR

A total of 2 patients in each cohort will receive placebo capsules: * Cohort 1 will receive 5 placebo capsules QD for 14 days * Cohort 2 will receive 5 placebo capsules BID for 14 days * Cohort 3 will receive 5 placebo capsules QID for 14 days

Drug: Placebo capsules

Interventions

dapansutrile capsules DRUG

Hard opaque capsules containing 100 mg of API.

Also known as: OLT1177 capsules

dapansutrile capsules

Placebo capsules DRUG

Hard opaque capsules containing 0 mg of API.

Placebo Capsules

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and female subjects 18 years old or older
• 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)
• Peak exercise limited by shortness of breath and/or fatigue associated with a respiratory exchange ratio (RER) \> 1.00 (reflecting maximal aerobic effort)
• Reduced peak aerobic exercise capacity (peak VO2) to less than 80% of predicted value by age/gender at Baseline
• Plasma CRP or hsCRP levels \> 2 mg/L at Screening
• 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
• 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

You may not qualify if:

• Women of childbearing potential, or men whose sexual partner(s) is a woman of childbearing potential who:
• Are or intend to become pregnant (including use of fertility drugs) during the study
• Are nursing
• 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.)
• Abnormal blood pressure or heart rate response, angina or ECG changes (ischemia or arrhythmias) occurring during CPX
• Presence or known history of autoimmune conditions (e.g., systemic lupus erythematosus, hypophysitis, etc.)
• 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:
• 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
• 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.
• 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
• 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:
• physical inability to walk on a treadmill
• decompensated HF (edema, NYHA IV)
• significant ischemic heart disease, angina
• arterial hypotension (blood pressure \[BP\] systolic \< 90 mmHg)

Sponsors & Collaborators

• Olatec Therapeutics LLC: lead

Study Sites (1)

Virginia Commonwealth University - Pauley Heart Center

Richmond, Virginia, 23298, United States

Location

Related Publications (2)

• de Baat A, Trinh B, Ellingsgaard H, Donath MY. Physiological role of cytokines in the regulation of mammalian metabolism. Trends Immunol. 2023 Aug;44(8):613-627. doi: 10.1016/j.it.2023.06.002. Epub 2023 Jul 7.

  PMID: 37423882 DERIVED

• Wohlford GF, Van Tassell BW, Billingsley HE, Kadariya D, Canada JM, Carbone S, Mihalick VL, Bonaventura A, Vecchie A, Chiabrando JG, Bressi E, Thomas G, Ho AC, Marawan AA, Dell M, Trankle CR, Turlington J, Markley R, Abbate A. Phase 1B, Randomized, Double-Blinded, Dose Escalation, Single-Center, Repeat Dose Safety and Pharmacodynamics Study of the Oral NLRP3 Inhibitor Dapansutrile in Subjects With NYHA II-III Systolic Heart Failure. J Cardiovasc Pharmacol. 2020 Oct 24;77(1):49-60. doi: 10.1097/FJC.0000000000000931.

  PMID: 33235030 DERIVED

MeSH Terms

Conditions

Heart Failure, Systolic; Heart Failure

Interventions

dapansutrile

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: 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).
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Subjects will be assigned to receive either dapansutrile capsules or placebo capsules in a 4:1 ratio within each Cohort.

Study Record Dates

• First Submitted: December 21, 2017
• First Posted: May 23, 2018
• Study Start: May 16, 2018
• Primary Completion: November 21, 2019
• Study Completion: November 21, 2019
• Last Updated: January 9, 2020

Record last verified: 2020-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)