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

• ClinicalTrials.gov Identifier: NCT02173548
• Recruitment Status: Completed
• First Posted: June 25, 2014
• Results First Posted: June 19, 2018
• Last Update Posted: June 19, 2018
• Sponsor: Virginia Commonwealth University
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Virginia Commonwealth University

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

Condition or disease	Intervention/treatment	Phase
Heart Failure With Normal Ejection Fraction	Drug: Anakinra; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 31 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Interleukin-1 Blockade in Heart Failure With Preserved Ejection Fraction (HFpEF): a Randomized Placebo-controlled Double Blinded Study (D-HART2)
• Study Start Date: September 2014
• Actual Primary Completion Date: April 11, 2017
• Actual Study Completion Date: June 1, 2017

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Anakinra; Anakinra 100 mg given subcutaneously once daily for 12 weeks	Drug: Anakinra; Other Name: Kineret
Placebo Comparator: Placebo; Matching Placebo	Drug: Placebo

Outcome Measures

Primary Outcome Measures :

1. Change in Aerobic Exercise Capacity [ Time Frame: 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.
2. Change in Ventilatory Eefficiency [ Time Frame: 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 Outcome Measures :

1. Echocardiographic Assessment of Diastolic and Systolic Function (Left Ventricular Ejection Fraction) [ Time Frame: 12 weeks ]
   Structural and functional echocardiographic parameters include left and right ventricular dimensions, mass, systolic and diastolic function. (Change in e')
2. Change in Diastolic and Contractile Reserve (e' Velocity and E/e' Ratio) [ Time Frame: 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.
3. Change in Inflammation (C Reactive Protein Levels) [ Time Frame: 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.
4. Change in Quality of Life Questionnaire-Minnesota Living With Heart Failure Questionnaire (MLWHF) [ Time Frame: 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.
5. Change in Quality of Life Questionnaire-Duke Activity Status Index (DASI) [ Time Frame: 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.
6. Hospital Admission for Acute Decompensated Heart Failure [ Time Frame: 24 weeks ]
   Number of participants admitted to hospital for acute decompensated heart failure

Eligibility Criteria

• Ages Eligible for Study: 21 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Virginia

Virginia Commonwealth University

Richmond, Virginia, United States, 23298

Sponsors and Collaborators

Virginia Commonwealth University

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Antonio Abbate, MD, PhD; Virginia Commonwealth University
• Principal Investigator: Benjamin Van Tassell, PharmD; Virginia Commonwealth University

  Study Documents (Full-Text)

Documents provided by Virginia Commonwealth University:

Study Protocol and Statistical Analysis Plan  [PDF] April 20, 2016

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

• Responsible Party: Virginia Commonwealth University
• ClinicalTrials.gov Identifier: NCT02173548
• Other Study ID Numbers: HM20000118; 1R34HL118348-01A1 ( U.S. NIH Grant/Contract )
• First Posted: June 25, 2014
• Results First Posted: June 19, 2018
• Last Update Posted: June 19, 2018
• Last Verified: May 2018

Keywords provided by Virginia Commonwealth University:

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

Additional relevant MeSH terms:

Heart Failure; Heart Diseases; Cardiovascular Diseases; Interleukin 1 Receptor Antagonist Protein; Antirheumatic Agents