Interleukin-1 Blockade in HF With Preserved EF

Interleukin-1 Blockade in Heart Failure With Preserved Ejection Fraction (HFpEF): a Randomized Placebo-controlled Double Blinded Study (D-HART2)

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02173548

Acronym

D-HART2

Enrollment

Registered

2014-06-25

Start date

2014-09-30

Completion date

2017-06-01

Last updated

2018-06-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Heart Failure With Normal Ejection Fraction

Keywords

heart failure, HFpEF, diastole, diastolic heart failure, inflammation, interleukin-1, C-reactive protein

Brief summary

* Heart Failure with Preserved Ejection Fraction (HFpEF) is a common form of heart failure * Standard treatment for heart failure, show less than ideal results in HFpEF * Evidence of systemic inflammation is common in all forms of heart failure, including HFpEF * The main hypothesis of this study is that systemic inflammation contributes to heart failure symptoms and exercise limitations in patients with HFpEF * The main objective is to treat patients with HFpEF and evidence of systemic inflammation with an anti-inflammatory drug targeting Interleukin-1 (or placebo) to determine effects on cardiovascular function

Detailed description

Heart Failure with Preserved Ejection Fraction (HFpEF) is a common form of heart failure, characterized by symptoms of congestion and impaired exercise tolerance, secondary to impaired left ventricular filling (diastole) in absence of a significant impairment in contractility (LVEF\>50%) or significant valvular abnormalities, shunts or intra- or extra-cavitary obstruction. The standard treatment for patient with heart failure is very effective in Heart Failure with Reduced Ejection Fraction (HFrEF), but it not very effective in HFpEF. Evidence of systemic inflammation is common in all forms of heart failure, including HFpEF, and predicts worse outcomes. C reactive protein (CRP) is the preferred inflammatory biomarker used as risk predictor for cardiovascular disease. Patients with heart failure (HFpEF or HFrEF) with elevated CRP levels are more likely to be severely limited by heart failure symptoms, are more likely to be admitted to the hospital for heart failure, and are more likely to die of cardiac causes. Preclinical studies show that a key mediator of systemic inflammation, Interleukin-1 (IL-1), impairs cardiac and vascular function, and may contribute to the pathogenesis of heart failure. The main hypothesis of this study is that systemic inflammation, and IL-1 in particular, contributes to heart failure symptoms and exercise limitations in patients with HFpEF. The main objective is to treat patients with HFpEF and evidence of systemic inflammation with an IL-1 blocker, anakinra (recombinant human IL-1 receptor antagonist)(or placebo) to determine effects on exercise capacity measured as peak oxygen consumption at maximal cardiopulmonary exercise testing.

Interventions

DRUGAnakinra

DRUGPlacebo

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

21 Years to No maximum

Healthy volunteers

Inclusion criteria

1. Symptoms and signs of heart failure (NYHA II-III) and prior hospitalization for heart failure 2. Recent Imaging Study (\<12 months) showing LVEF\>50% and Left Ventricular End Diastolic Volume Index (LVEDVI) \<97ml/m2 3. Evidence of abnormal LV relaxation, filling, diastolic distensibility, and diastolic stiffness as shown by one of the following a. Invasive Hemodynamic measurements i. mean Pulmonary Capillary Wedge Pressure (mPCW) \>12 ii. Left Ventricular End Diastolic Pressure (LVEDP) \>16 mmHg b. Tissue Doppler Echocardiogram i. E/E' \>15 ii. E/E' 8-15 and one of the following: Left Ventricular Hypertrophy (LVH), Atrial fibrillation, Left Atrial Enlargement (LAE), E/A \<0.5 + DT (Deceleration Time) \>280, c. Biomarkers i. Brain Natriuretic Peptide (BNP) \>200pg/ml (not due to a concomitant disease such as pulmonary arterial hypertension, pulmonary embolism, acute renal failure, or other) 4. CRP \> 2.0 mg/L

Exclusion criteria

* Age \<21 * Concomitant conditions or treatments which would affect completion of the study or interpretation of the study tests including but not limited to the following conditions: * physical inability to walk or run on a treadmill * angina or evidence of spontaneous or inducible ischemia * uncontrolled arterial hypertension * atrial fibrillation (or other arrhythmias) * moderate to severe valvular heart disease * chronic pulmonary disease * anemia (Hgb\<10 g/dl) * Angina, uncontrolled hypertension or electrocardiograph (ECG) changes (i.e. ischemia, arrhythmias) that limit maximum exertion during cardiopulmonary exercise testing * Anticipated need for cardiac resynchronization therapy (CRT) or automated-implantable cardioverter defibrillator (AICD) or coronary revascularization or cardiac surgery * Active infection including chronic infection * Active cancer (or prior diagnosis of cancer within the past 10 years) * Recent (\<14 days) or active use of immunosuppressive drugs (including but not limited to high-dose corticosteroids \[\>1\_mg/kg of prednisone equivalent\], Tumor Necrosis Factor (TNF)-α blockers, cyclosporine) not including Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) or corticosteroids used for IV dye allergy only) * Chronic auto-immune or auto-inflammatory disease (including but not limited to rheumatoid arthritis, systemic lupus erythematosus) * Neutropenia (absolute neutrophil count\<1,800/mm3 \[or \<1,000/mm3 in African-American patients\]) * Severe impairment in renal function (estimated glomerular filtration rate \<30 ml/kg\*min) * Recent or planned use of vaccination with live attenuated viruses * Allergy to rubber or latex * Allergy to products derived from Escherichia coli * Pregnancy or breastfeeding * Inability to give informed consent

Design outcomes

Primary

Measure	Time frame	Description
Change in Aerobic Exercise Capacity	Baseline to 12 weeks	Absolute changes in aerobic exercise capacity (peak VO2) after 12 weeks treatment. This will compare patients treated with anakinra and provide a randomized, double-blinded assessment of the effects of IL-1β blockade on aerobic exercise performance.
Change in Ventilatory Eefficiency	Baseline to 12 weeks	Absolute changes in ventilatory efficiency (VE/VCO2 \[carbon dioxide\] slope) after 12 weeks treatment. This will compare patients treated with anakinra vs placebo, and provide a randomized, double-blinded assessment of the effects of IL-1β blockade on aerobic exercise performance.

Secondary

Measure	Time frame	Description
Change in Inflammation (C Reactive Protein Levels)	Baseline to 12 weeks	The change C reactive protein (CRP) levels will be reported at 12 weeks. Higher C reactive protein levels indicate greater inflammation.
Change in Quality of Life Questionnaire-Minnesota Living With Heart Failure Questionnaire (MLWHF)	Baseline to 24 weeks	The Minnesota Living with Heart Failure questionnaire (MLWHF) is a 21-question graded questionnaire that has been extensively used to measure impairment in quality of life in patients with HF, with higher scores reflecting increased burden of HF symptoms. The questionnaire will be administered in accordance with cardiopulmonary test (CPET) and echocardiography. Scores range from zero to 105 with lower scores indicating better quality of life.
Echocardiographic Assessment of Diastolic and Systolic Function (Left Ventricular Ejection Fraction)	12 weeks	Structural and functional echocardiographic parameters include left and right ventricular dimensions, mass, systolic and diastolic function. (Change in e')
Hospital Admission for Acute Decompensated Heart Failure	24 weeks	Number of participants admitted to hospital for acute decompensated heart failure
Change in Quality of Life Questionnaire-Duke Activity Status Index (DASI)	Baseline to 12 weeks	Two independent questionnaires will be used to assess quality of life and HF symptoms. The Duke Activity Status Index (DASI) questionnaire is a 12-question, yes/no, instrument that allows for the calculation of perceived functional capacity, in which each question describes a different physical activity and the questions are weighted according to their degree of physical exertion. Higher scores indicate greater functional capacity. The questionnaire will be administered at 0, 4, 12 and 24 weeks in accordance with cardiopulmonary test (CPET) and echocardiography. Scores range from zero to 58.2 with higher scores indicating higher functional status.
Change in Diastolic and Contractile Reserve (e' Velocity and E/e' Ratio)	Baseline to 12 weeks	Exercise stress echocardiography will be performed at baseline and 12 weeks to measure diastolic and contractile reserve. We will perform an assessment before initiation of exercise and immediately after cessation of peak exercise.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Anakinra Anakinra 100 mg given subcutaneously once daily for 12 weeks Anakinra	21
Placebo Matching Placebo Placebo	10
Total	31

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Lost to Follow-up	0	2
Overall Study	Withdrawal by Subject	1	0

Baseline characteristics

Characteristic	Anakinra	Placebo	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	21 Participants	10 Participants	31 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	11 Participants	4 Participants	15 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	10 Participants	6 Participants	16 Participants
Region of Enrollment United States	21 participants	10 participants	28 participants
Sex: Female, Male Female	13 Participants	5 Participants	18 Participants
Sex: Female, Male Male	8 Participants	5 Participants	13 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 20	0 / 10
other Total, other adverse events	4 / 20	2 / 10
serious Total, serious adverse events	1 / 20	1 / 10

Outcome results

Primary

Change in Aerobic Exercise Capacity

Absolute changes in aerobic exercise capacity (peak VO2) after 12 weeks treatment. This will compare patients treated with anakinra and provide a randomized, double-blinded assessment of the effects of IL-1β blockade on aerobic exercise performance.