Heart Failure
Conditions
Keywords
Heart failure with preserved ejection fraction, Diastolic heart failure, Aerobic exercise performance
Brief summary
This will be a randomized, double-blind, crossover pilot study to measure the safety and feasibility of Interleukin-1 (IL-1) blockade with Anakinra in patients with stable heart failure with preserved ejection fraction.
Interventions
DRUGAnakinra
Anakinra 100 mg daily subcutaneous injection
DRUGPlacebo
Placebo daily subcutaneous injection
Sponsors
American Heart Association
Virginia Commonwealth University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
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
* Symptoms and signs of congestive heart failure * Recent Imaging Study (\<12 months) showing Left Ventricular Ejection Fraction (LVEF) \>50% and Left Ventricular End Diastolic Volume Index (LVEDVI) \<97ml/m2 * Evidence of abnormal Left Ventricular (LV) relaxation, filling, diastolic distensibility, and diastolic stiffness as shown by one of the following: 1. Invasive Hemodynamic measurements * mean Pulmonary Capillary Wedge pressure (mPCW) \>12 * Left Ventricular End Diastolic Pressure (LVEDP) \>16 mmHg 2. Tissue Doppler Echocardiogram * E/E' \>15 * E/E' 8-15 and one of the following * Left Ventricular Hypertrophy (LVH) * Atrial Fibrillation * Left Atrial Enlargement * E/A \<0.5 + Deceleration Time (DT) \>280 (if \>50yrs of age) 3. Biomarkers * Brain Natriuretic Peptide (BNP) \>200pg/mL
Exclusion criteria
* Age \<18 * Recent changes (previous 3 months) in HF maintenance medications (beta-blockers, angiotensin converting enzyme \[ACE\] inhibitors, aldosterone antagonists, vasodilators, cardiac glycosides, diuretics) * Hospitalization for worsening Heart Failure (HF) or acute decompensated HF within the previous 12months * Anticipated need for cardiac resynchronization therapy (CRT) or automated-implantable cardioverter defibrillator (AICD) * Angina or electrocardiograph (ECG) changes that limit maximum exertion during cardiopulmonary exercise testing * Active infection including chronic infection * Active cancer * Recent (\<14 days) use of anti-inflammatory drugs (not including Non-Steroidal Anti-Inflammatory Drugs \[NSAIDs\]), Chronic inflammatory disorder (including but not limited to rheumatoid arthritis, systemic lupus erythematosus), malignancy, or any comorbidity limiting survival or ability to complete the study * Pregnancy (determined by urine pregnancy test in women of childbearing potential) * Inability to give informed consent * Other conditions limiting completion of cardiopulmonary exercise test or completion of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peak Oxygen Consumption (Peak VO2) | 14 days | The primary endpoint is the change in peak oxygen consumption among stable heart failure patients (n = 12) following 14-days treatment with daily doses of Anakinra 100 mg (SC, subcutaneous). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Exercise Time | 14 days | Interval change from baseline in duration of exercise during a standardized cardiopulmonary exercise test upon completion of 2 weeks treatment |
Other
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events | 28 days | Additional endpoints will include assessment of adverse events and hospitalizations during 4-week duration of study. |
| Correlation Between Endpoints | 28 days | Correlation between interval change in peak VO2 and high sensitivity C-reactive protein |
| Ventilatory Efficiency (VE/VCO2 [Carbon Dioxide] Slope) | 14 days | Interval change from baseline in ventilatory efficiency (VE/VCO2 slope) upon completion of 2 weeks treatment. |
| Inflammatory Biomarkers | 28 days | Interval change from baseline in high-sensitivity C-reactive protein upon completion of 2 weeks treatment. |
| Heart Failure Symptoms (DASI) | 28 days | Interval change from baseline in Heart Failure (HF) symptoms as measured by Duke Activity Status Index (DASI) upon completion of 2 weeks treatment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants Baseline measures for all study participants | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants |
| Age, Continuous | 61 years |
| Gender Female | 11 Participants |
| Gender Male | 1 Participants |
| Region of Enrollment United States | 12 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 12 | 0 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 |
Outcome results
Primary
Peak Oxygen Consumption (Peak VO2)
The primary endpoint is the change in peak oxygen consumption among stable heart failure patients (n = 12) following 14-days treatment with daily doses of Anakinra 100 mg (SC, subcutaneous).
Time frame: 14 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anakinra | Peak Oxygen Consumption (Peak VO2) | 1.1 ml*kg^-1*min^-1 |
| Placebo | Peak Oxygen Consumption (Peak VO2) | -0.1 ml*kg^-1*min^-1 |
p-value: 0.009ANOVA
Secondary
Exercise Time
Interval change from baseline in duration of exercise during a standardized cardiopulmonary exercise test upon completion of 2 weeks treatment
Time frame: 14 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anakinra | Exercise Time | 0.05 minutes |
| Placebo | Exercise Time | 0.4 minutes |
p-value: 0.87ANOVA
Other Pre-specified
Adverse Events
Additional endpoints will include assessment of adverse events and hospitalizations during 4-week duration of study.
Time frame: 28 days
Other Pre-specified
Correlation Between Endpoints
Correlation between interval change in peak VO2 and high sensitivity C-reactive protein
Time frame: 28 days
Other Pre-specified
Heart Failure Symptoms (DASI)
Interval change from baseline in Heart Failure (HF) symptoms as measured by Duke Activity Status Index (DASI) upon completion of 2 weeks treatment.
Time frame: 28 days
Other Pre-specified
Inflammatory Biomarkers
Interval change from baseline in high-sensitivity C-reactive protein upon completion of 2 weeks treatment.
Time frame: 28 days
Other Pre-specified
Ventilatory Efficiency (VE/VCO2 [Carbon Dioxide] Slope)
Interval change from baseline in ventilatory efficiency (VE/VCO2 slope) upon completion of 2 weeks treatment.
Time frame: 14 days