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Study of Dapansutrile Capsules in Heart Failure

Primary Purpose

Systolic Heart Failure

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
dapansutrile capsules
Placebo capsules
Sponsored by
Olatec Therapeutics LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Systolic Heart Failure focused on measuring heart failure, systolic heart failure

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Virginia Commonwealth University - Pauley Heart Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

dapansutrile capsules

Placebo Capsules

Arm Description

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

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

Outcomes

Primary Outcome Measures

Adverse events
Adverse events experienced by the patient will be recorded.

Secondary Outcome Measures

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.
Transthoracic Doppler ECG - Left Ventricle Ejection Fraction
Changes in left ventricular ejection fraction will be analyzed.
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.
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.
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).
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).
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.
Vital signs - Pulse
Changes in pulse will be analyzed.
Vital signs - Blood Pressure
Changes in systolic and diastolic blood pressure will be analyzed.
Vital signs - Temperature
Changes in body temperature will be analyzed.
Vital signs - Respiratory Rate
Changes in respiratory rate will be analyzed.
Safety Laboratory Measurements - Chemistry
Changes in blood chemistry will be analyzed.
Safety Laboratory Measurements - Hematology
Changes in complete blood count will be analyzed.
Physical Examination
A full or targeted physical examination of the patient's major body systems
12-lead electrocardiogram
Electrodes will be placed on the patient to obtain a recording of the electrical activity of the heart.

Full Information

First Posted
December 21, 2017
Last Updated
January 6, 2020
Sponsor
Olatec Therapeutics LLC
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1. Study Identification

Unique Protocol Identification Number
NCT03534297
Brief Title
Study of Dapansutrile Capsules in Heart Failure
Official Title
A Phase 1b, Randomized, Double-Blinded, Dose Escalation, Single Center, Repeat-Dose Safety and Pharmacodynamics Study of Orally Administered Dapansutrile Capsules in Subjects With NYHA II-III Systolic Heart Failure
Study Type
Interventional

2. Study Status

Record Verification Date
January 2020
Overall Recruitment Status
Completed
Study Start Date
May 16, 2018 (Actual)
Primary Completion Date
November 21, 2019 (Actual)
Study Completion Date
November 21, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Olatec Therapeutics LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Systolic Heart Failure
Keywords
heart failure, systolic heart failure

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Model Description
Subjects will be assigned to receive either dapansutrile capsules or placebo capsules in a 4:1 ratio within each Cohort.
Masking
ParticipantCare ProviderInvestigator
Masking Description
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).
Allocation
Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
dapansutrile capsules
Arm Type
Experimental
Arm Description
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
Arm Title
Placebo Capsules
Arm Type
Placebo Comparator
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
dapansutrile capsules
Other Intervention Name(s)
OLT1177 capsules
Intervention Description
Hard opaque capsules containing 100 mg of API.
Intervention Type
Drug
Intervention Name(s)
Placebo capsules
Intervention Description
Hard opaque capsules containing 0 mg of API.
Primary Outcome Measure Information:
Title
Adverse events
Description
Adverse events experienced by the patient will be recorded.
Time Frame
Screening through Day 42 follow-up
Secondary Outcome Measure Information:
Title
Cardiopulmonary exercise test
Description
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
Title
Transthoracic Doppler ECG - Left Ventricle Ejection Fraction
Description
Changes in left ventricular ejection fraction will be analyzed.
Time Frame
Day 14
Title
Transthoracic Doppler ECG - Left Ventricular Filling Pressure
Description
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
Title
Bioimpedance analysis
Description
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
Title
Kansas City Cardiomyopathy Questionnaire - Clinical Summary Score
Description
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
Title
Kansas City Cardiomyopathy Questionnaire - Overall Summary Score
Description
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
Title
Duke Activity Status Index
Description
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
Title
Vital signs - Pulse
Description
Changes in pulse will be analyzed.
Time Frame
Day 14
Title
Vital signs - Blood Pressure
Description
Changes in systolic and diastolic blood pressure will be analyzed.
Time Frame
Day 14
Title
Vital signs - Temperature
Description
Changes in body temperature will be analyzed.
Time Frame
Day 14
Title
Vital signs - Respiratory Rate
Description
Changes in respiratory rate will be analyzed.
Time Frame
Day 14
Title
Safety Laboratory Measurements - Chemistry
Description
Changes in blood chemistry will be analyzed.
Time Frame
Day 14
Title
Safety Laboratory Measurements - Hematology
Description
Changes in complete blood count will be analyzed.
Time Frame
Day 14
Title
Physical Examination
Description
A full or targeted physical examination of the patient's major body systems
Time Frame
Day 14
Title
12-lead electrocardiogram
Description
Electrodes will be placed on the patient to obtain a recording of the electrical activity of the heart.
Time Frame
Day 8
Other Pre-specified Outcome Measures:
Title
Pharmacokinetics
Description
Blood sample for determination of dapansutrile blood concentrations.
Time Frame
Baseline (pre and post dose), Day 4, Day 8, Day 14 and Day 28
Title
Pharmacodynamics / Biomarkers
Description
Blood sample for determination of levels of inflammatory biomarkers
Time Frame
Baseline (pre and post dose), Day 4, Day 8, Day 14 and Day 28

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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 Exclusion Criteria: 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) arterial hypertension (resting BP systolic > 160 mmHg) atrial fibrillation with rapid ventricular response severe valvular disease severe chronic obstructive or restrictive pulmonary disease moderate-severe anemia (Hgb < 10 g/dL) severe diabetic neuropathy or myopathy Active or recent (within 2 weeks) infection prior to the Baseline visit History of or known positive for HIV, Hepatitis B surface antigen or antibodies to Hepatitis C Virus Known history of renal impairment and/or creatinine clearance less than 50 mL/min calculated by Cockcroft-Gault method Active malignancy or recent malignancy with chemotherapy treatment within the past 6 months Enrollment in any trial and/or use of any investigational product or device within the immediate 30-day period prior to the Baseline visit Previous exposure to the investigational product
Facility Information:
Facility Name
Virginia Commonwealth University - Pauley Heart Center
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
33235030
Citation
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.
Results Reference
derived

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Study of Dapansutrile Capsules in Heart Failure

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