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Interleukin-1 Blockade in HF With Preserved EF (D-HART2)

Primary Purpose

Heart Failure With Normal Ejection Fraction

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Anakinra
Placebo
Sponsored by
Virginia Commonwealth University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Heart Failure With Normal Ejection Fraction focused on measuring heart failure, HFpEF, diastole, diastolic heart failure, inflammation, interleukin-1, C-reactive protein

Eligibility Criteria

21 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • Virginia Commonwealth University

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Anakinra

Placebo

Arm Description

Anakinra 100 mg given subcutaneously once daily for 12 weeks

Matching Placebo

Outcomes

Primary Outcome Measures

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.
Change in Ventilatory Eefficiency
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 Outcome Measures

Echocardiographic Assessment of Diastolic and Systolic Function (Left Ventricular Ejection Fraction)
Structural and functional echocardiographic parameters include left and right ventricular dimensions, mass, systolic and diastolic function. (Change in e')
Change in Diastolic and Contractile Reserve (e' Velocity and E/e' Ratio)
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.
Change in Inflammation (C Reactive Protein Levels)
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)
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.
Change in Quality of Life Questionnaire-Duke Activity Status Index (DASI)
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.
Hospital Admission for Acute Decompensated Heart Failure
Number of participants admitted to hospital for acute decompensated heart failure

Full Information

First Posted
June 20, 2014
Last Updated
May 18, 2018
Sponsor
Virginia Commonwealth University
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT02173548
Brief Title
Interleukin-1 Blockade in HF With Preserved EF
Acronym
D-HART2
Official Title
Interleukin-1 Blockade in Heart Failure With Preserved Ejection Fraction (HFpEF): a Randomized Placebo-controlled Double Blinded Study (D-HART2)
Study Type
Interventional

2. Study Status

Record Verification Date
May 2018
Overall Recruitment Status
Completed
Study Start Date
September 2014 (undefined)
Primary Completion Date
April 11, 2017 (Actual)
Study Completion Date
June 1, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Virginia Commonwealth University
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure With Normal Ejection Fraction
Keywords
heart failure, HFpEF, diastole, diastolic heart failure, inflammation, interleukin-1, C-reactive protein

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
31 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Anakinra
Arm Type
Active Comparator
Arm Description
Anakinra 100 mg given subcutaneously once daily for 12 weeks
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Matching Placebo
Intervention Type
Drug
Intervention Name(s)
Anakinra
Other Intervention Name(s)
Kineret
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Change in Aerobic Exercise Capacity
Description
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.
Time Frame
Baseline to 12 weeks
Title
Change in Ventilatory Eefficiency
Description
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.
Time Frame
Baseline to 12 weeks
Secondary Outcome Measure Information:
Title
Echocardiographic Assessment of Diastolic and Systolic Function (Left Ventricular Ejection Fraction)
Description
Structural and functional echocardiographic parameters include left and right ventricular dimensions, mass, systolic and diastolic function. (Change in e')
Time Frame
12 weeks
Title
Change in Diastolic and Contractile Reserve (e' Velocity and E/e' Ratio)
Description
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.
Time Frame
Baseline to 12 weeks
Title
Change in Inflammation (C Reactive Protein Levels)
Description
The change C reactive protein (CRP) levels will be reported at 12 weeks. Higher C reactive protein levels indicate greater inflammation.
Time Frame
Baseline to 12 weeks
Title
Change in Quality of Life Questionnaire-Minnesota Living With Heart Failure Questionnaire (MLWHF)
Description
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.
Time Frame
Baseline to 24 weeks
Title
Change in Quality of Life Questionnaire-Duke Activity Status Index (DASI)
Description
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.
Time Frame
Baseline to 12 weeks
Title
Hospital Admission for Acute Decompensated Heart Failure
Description
Number of participants admitted to hospital for acute decompensated heart failure
Time Frame
24 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Symptoms and signs of heart failure (NYHA II-III) and prior hospitalization for heart failure Recent Imaging Study (<12 months) showing LVEF>50% and Left Ventricular End Diastolic Volume Index (LVEDVI) <97ml/m2 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) 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Antonio Abbate, MD, PhD
Organizational Affiliation
Virginia Commonwealth University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Benjamin Van Tassell, PharmD
Organizational Affiliation
Virginia Commonwealth University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Virginia Commonwealth University
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
30354558
Citation
Van Tassell BW, Trankle CR, Canada JM, Carbone S, Buckley L, Kadariya D, Del Buono MG, Billingsley H, Wohlford G, Viscusi M, Oddi-Erdle C, Abouzaki NA, Dixon D, Biondi-Zoccai G, Arena R, Abbate A. IL-1 Blockade in Patients With Heart Failure With Preserved Ejection Fraction. Circ Heart Fail. 2018 Aug;11(8):e005036. doi: 10.1161/CIRCHEARTFAILURE.118.005036.
Results Reference
derived
PubMed Identifier
28475816
Citation
Van Tassell BW, Buckley LF, Carbone S, Trankle CR, Canada JM, Dixon DL, Abouzaki N, Oddi-Erdle C, Biondi-Zoccai G, Arena R, Abbate A. Interleukin-1 blockade in heart failure with preserved ejection fraction: rationale and design of the Diastolic Heart Failure Anakinra Response Trial 2 (D-HART2). Clin Cardiol. 2017 Sep;40(9):626-632. doi: 10.1002/clc.22719. Epub 2017 May 5.
Results Reference
derived

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Interleukin-1 Blockade in HF With Preserved EF

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