Clinical trial NCT02173548
Conditions: Heart Failure With Normal Ejection Fraction
Keywords: heart failure HFpEF diastole diastolic heart failure inflammation interleukin-1 C-reactive protein
Sponsor: Virginia Commonwealth University
Start date: 2014-09-01; Completion date: 2017-06-01
Enrollment: 31 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: Anakinra 100 mg given subcutaneously once daily for 12 weeks arm 2: Matching Placebo
Interventions: intervention 1: Anakinra intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Title: Interleukin-1 Blockade in HF with Preserved EF (D-HART2) 
PI: Antonio Abbate, MD 
NCT #: NCT02173548 
 
Unique Protocol ID: HM20000118 
 
Document approval date: April 20, 2016 
 
Document Type: Protocol and SAP 


 
VCU Clinical Study Protocol  
  
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Interleukin-1 Blockade in Heart Failure with 
Preserved Ejection Fraction (HFpEF) 
 
 
 
 
 
A Randomized Placebo-controlled Double-blinded Study 
 
 
 
 
 
D-HART2 study 
 
 
 
 
 
 
 
 
 
 
    STUDY PROTOCOL 
 
 
 
 
 
 
 
 
Principal Investigator(s): Antonio 
Abbate, MD, PhD; Benjamin W. 
Van Tassell, PharmD 
 
 
 
 
 
Virginia Commonwealth University 
 
 
 
 
 
 
 
1 


VCU Clinical Study Protocol 
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Prior versions and edits: 
 
Edits to Version 1: 08132014 
• 
Blood pressure measurement through ccNexfin finger cuff, section 7.8 and 7.13: The 
ccNexfin “finger cuff” has been added for continuous blood pressure monitoring throughout 
the exercise protocol. Patients will also undergo brief blood pressure cuff inflation/deflation 
to measure flow-mediated dilatation prior to exercise. 
• 
Bioelectrical Impedance (Bio-Impedance) to measure body composition, section 7.9 
and 7.13: Four electrodes will applied to the skin, a small amount of electricity will be ran 
through the body to measure bioelectrical impendance (bio-impendance) to determine body 
composition. 
 
Edits to Version 2: 09072014 
• 
Personnel: The list has been updated. 
• 
Sections 5.2 and 7.12 – The description of the biomarkers has been clarified in more detail. 
• 
Section 7.1 – It is now explained that the patient will receive the investigational drug in 2 
batches, one for 5 weeks and a second one for 7 weeks. 
• 
Section 7.6 – The timing of follow up visits has been clarified in more detail. 
• 
Section 8.3.1 – The definition of “related” and “unrelated” to research has been clarified in 
more detail. 
 
Edits to Version 3 04062015: 
• 
Personnel have been updated. 
• 
The University of Virginia has been removed from the list of potential alternate sites as site 
initiation will no longer be an option. 
• 
Health Diagnostic Laboratories is now known as True Health Diagnostic Laboratories and 
this change has been updated. 
• 
The procedures for the whole blood assay have been removed as this analysis is not being 
conducted during the study. 
• 
“Any abnormal laboratory test” will no longer be considered an adverse event. 
• 
The definition of Adverse Events (AEs) has been revised, and reporting plan clarified. 
 
Edits to Version 4 11282015: 
• 
Screening will be performed in the whole VCU Health System, not just in the VCU Pauley 
Heart Center, as previously described (Section 6.1). 
• 
Requirement for “prior hospitalization for heart failure” has been removed from inclusion 
criteria (Section 6.2, and Appendix B forms). 


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TABLE OF CONTENTS 
 
 
1) 
Personnel 
 
2) 
Protocol summary 
 
3) 
Schematic of study design 
 
4) 
Background information and significance 
 
5) 
Objectives 
 
5.1 
Primary Endpoint(s) 
 
5.2 
Secondary Endpoints 
 
6) 
Enrollment in the study 
 
6.1 
Screening 
 
6.2 
Inclusion & Exclusion criteria 
 
7) 
Study design 
 
7.1 
Treatment with Anakinra 
 
7.2 
Allocation concealment 
 
7.3 
Patient Compliance 
 
7.4 
Concomitant Medications 
 
7.5 
Standard Medical Management 
 
7.6 
Cardiopulmonary exercise test 
 
7.7 
Echocardiogram 
 
7.8 
Blood pressure measurement through ccNexfin finger cuff 
 
7.9 
Bio-Impedance measurement 
 
7.10 
Exercise-stress echocardiogram 
 
7.11 
Questionnaires 
 
7.12 
Biomarkers 
 
7.13 
Study Schedule 
 
7.14 
Cost coverage analysis 
 
8) 
Assessment of safety 
 
8.1 
Specification of safety parameters 
 
8.2 
Data Collection and transfer 
 
8.3 
Methods of Timing for Assessing, Recording, and Analyzing Safety 
 
Parameters 


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8.4 
Reporting procedures 
 
8.5 
AE/SAE data collection 
 
8.6 
The data and safety monitoring (DSMB) plan 
 
8.7 
Regulatory reporting 
 
8.8 
Type and duration of follow up of subjects after adverse events 
 
8.9 
Halting rules 
 
9) 
Adjudication of clinical events 
 
9.1 
Event-adjudicating committee 
 
9.2 
Definition of the events 
 
9.3 
Implications of the findings of the event-adjudicating committee 
 
10) 
Discontinuation of treatment and withdrawal 
 
10.1 
Reasons for discontinuation of treatment or withdrawal from the study 
 
10.2 
Handling of withdrawals 
 
10.3 
Termination of the study 
 
11) 
Recruitment strategies 
 
12) 
Statistical considerations 
 
12.1 
Study hypothesis 
 
12.2 
Sample size consideration 
 
12.3 
Statistical analysis 
 
13) 
Literature cited 
 
Appendix: DSMB Chapter for D-HART2 


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1)  
PERSONNEL 
 
 
Name 
Role 
Institution/ Division 
Antonio Abbate, MD/PhD 
Benjamin Van Tassel, PharmD 
Co-Principal Investigator 
Co-Principal Investigator 
VCU, Cardiology 
VCU, School of Pharmacy 
 
 
Ross Arena, PhD 
Investigator 
University of Illinois, Chicago, IL 
 
Justin Canada, EPC 
Exercise Physiologist 
VCU, Physical Therapy 
Salvatore Carbone, MS 
Robin Sculthorpe, PharmD 
Research Assistant 
Investigational Pharmacy 
VCU, Cardiology 
VCU, School of Pharmacy 
 
 
Michael C. Kontos, MD 
Event Adjudicating Committee VCU, Cardiology 
Keyur Shah, MD 
Event Adjudicating Committee VCU, Cardiology 
Elizabeth Miller, MD 
Event Adjudicating Committee VCU, General Medicine 
 
 
Dominick Angiolillo, MD 
DSMB Chair 
University of Florida, Cardiology 
Richard Cooke, MD 
DSMB member 
VCU, Heart Failure 
Gonzalo Bearman, MD 
DMSB member 
VCU, Infectious disease 
Ion Jovin, MD 
DSMB member 
VCU, Cardiology / McGuire VA 
Jeffrey Kushinka, MD 
DSMB member 
VCU, General Internal Medicine 
Christine DeWilde, RN 
DSMB coordinator 
VCU, Pulmonary 
 
 
Juan Lu, PhD 
Kenneth Ellenbogen, MD 
John (Ian) Nixon, MD 
Charles A. Dinarello, MD 
Consultant 
Consultant 
Consultant 
Consultant 
VCU, Biostatistics 
VCU, Cardiology 
VCU, Cardiology 
University of Colorado 
Pierluigi Tricoci, MD 
Filippo Crea, MD 
Giuseppe Biondi-Zoccai, MD 
Consultant 
Consultant 
Consultant 
Duke University 
Catholic University, Rome, Italy 
Sapienza University, Rome, Italy 
Abbreviations: DSMB=Data Safety Monitoring Board 


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2)  
PROTOCOL SUMMARY 
 
 
 
 
Title: 
Interleukin-1  Blockade  in  Heart  Failure  with  Preserved  Ejection 
Fraction (HFpEF) 
 
Population:                             60  patients  with  a  clinical  diagnosis  of  heart  failure,  a  recent 
imaging   study   documenting   LV   ejection   fraction   >50%   and 
evidence of diastolic dysfunction, and CRP >2 mg/L 
 
Site(s): 
Virginia Commonwealth University, Richmond, VA 
 
 
 
Study Duration: 
24 months 
 
 
 
Description:                           Phase II clinical trial of Anakinra for the treatment of heart failure 
with  preserved  ejection  fraction,  impaired  left  ventricular 
relaxation, and increased systemic inflammation (CRP>2 mg/L) 
 
Objectives:                             To determine the effects of IL-1 blockade with Anakinra on peak of 
aerobic exercise capacity (peak VO2) and ventilatory efficiency 
(VE/VCO2) measured  with a cardiopulmonary  test in patients with 
heart failure with preserved ejection fraction 
 
Study Design:                        Single-center,   randomized,   double-blinded,   placebo-controlled 
clinical trial with allocation to Anakinra 100 mg daily or placebo in 
2:1 ratio for 12 weeks 
 
Estimated Time to 
Complete Enrollment:  
15 months 


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3) 
SCHEMATIC OF STUDY DESIGN 
 
 
 
 
 
HFpEF( 
(n=60)( 
Anakinra( 
(n=40)( 
 
 
 
Placebo( 
(n=20)( 
 
Follow%up( 
 
 
 
 
Follow%up( 
 
 
CPX 
CPX 
CPX 
CPX 
 
Echo 
 
Echo- 
stress 
Echo 
Echo 
 
Echo- 
stress 
Echo 
 
Biomarkers 
Biomarkers 
Biomarkers 
Biomarkers 
 
Event(s) 
Adjudication 
Event(s) 
Adjudication 
 
 
 
 
 
Abbreviations: CPX=Cardiopulmonary Exercise Test; Echo=echocardiography; Echo-stress=dobutamine stress 
echocardiography;  HFpEF=Heart Failure with Preserved Ejection Fraction 
 
 
 
 
4) BACKGROUND INFORMATION AND SIGNIFICANCE 
 
Heart failure (HF) is a condition in which the heart can no longer pump enough blood to the rest 
of the body or it is unable to do so without significantly increasing the filling pressure. HF is 
characterized by dyspnea, fatigue, and declining cardiac function. Poor exercise capacity is a 
common finding among HF patients and imposes a significant detriment to quality of life. 
Quantifiable measures of exercise capacity such as peak oxygen consumption (peak VO2) and 
the  minute  ventilation  and  carbon  dioxide  production  slope  (VE/VCO2)  represent  strong 
independent predictors of HF mortality and hospitalization. 
 
Despite the clear improvements in the treatment of cardiovascular disease over the past several 
decades, the incidence and prevalence of HF have not decreased, survival has marginally 
improved,  and morbidity  remains  unacceptably  high.[1-3]  There is an urgent need to develop 
novel therapeutic approaches to alleviate symptoms, improve functional capacity and quality of 
life, slow disease progression, and reduce hospitalization. 
 
Interleukin-1 (IL-1) is a key pro-inflammatory mediator in innate immunity that induces synthesis 
and   expression   of   multiple   secondary   inflammatory   mediators   (i.e.   Interleukin-6   [IL-6], 


VCU Clinical Study Protocol 
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Peak VO2 
(mL/min/kg) 
VE/VCO2 
Exercise time (min) 
CRP (mg/L) 
 
 
Interleukin-18 [IL-18], C reactive protein [CRP]).[4]  Early descriptions also noted that very small 
concentrations of IL-1 could induce a sepsis-like syndrome associated with cardiac dysfunction 
and described the fine regulation of the synthesis and release of this cytokine.[5]  Two related 
genes code for two different proteins IL-1α and IL-1β, both binding the same IL-1 receptor (type 
I). IL-1β is the main form of circulating IL-1, binding to the membrane IL-1 receptor in the same 
cell (autocrine), neighboring cells (paracrine), or entering the circulation targeting distant cells 
(endocrine). IL-1α, on the other hand, is mostly expressed as a membrane-bound protein or 
released  from  the  cytoplasm  during  cell  death.  An  additional  gene  codes  for  IL-1  receptor 
antagonist (IL-1Ra), a protein that binds to the IL-1 receptor but does not exert agonist activity, 
and functions as a naturally occurring anti-inflammatory protein.[4] 
 
Exogenous also IL-1β induces a reversible and dose-dependent contractile dysfunction in vitro 
or in vivo in the mouse.[4,6]  These observations formed the basis for an open-label, single-arm, 
proof-of-concept study to test the safety and feasibility of IL-1 blockade in patients with stable 
HFrEF and elevated CRP (>2 mg/L), and determine the effects on aerobic exercise capacity 
(ClinicalTrials.gov NCT01300650).[7]  We enrolled patients (n=8) with stable chronic HFrEF as 
evidenced  by  no  recent  hospitalizations  (within  previous  12  months),  no  recent  medication 
changes (within 3 months), and screening CRP >2 mg/L. Patients received 14 days treatment 
with daily anakinra 100 mg subcutaneous injection starting after the baseline cardiopulmonary 
exercise testing (CPX) to evaluate the co-primary endpoints of peak VO2 and VE/VCO2 slope at 
the beginning and end of the study. Of the 8 patients enrolled, 1 experienced flu-like symptoms 
during the study and withdrew after 8 days of injections (symptoms resolved spontaneously with 
3 days of discontinuation). All 7 patients who completed the protocol experienced improvement 
in peak VO2  after 14 days anakinra treatment; 6 out of 7 patients experienced improvement in 
the VE/VCO2 slope after 14 days anakinra treatment (Figure 2). Patients also experienced 
significant improvements in secondary endpoints of total exercise time and oxygen utilization 
efficiency score. To verify the achievement of IL-1 blockade, we found a 80-90% reduction in 
median plasma of CRP, IL-6, and IL-1β, without measurable changes in TNFα. While there was 
no significant  association  between  peak  VO2 and CRP,  there  appeared  to be trend  toward 
improved peak VO2 with lower CRP (Figure 2). No significant changes occurred in resting heart 
rate  (HR),  maximum  HR,  resting  blood  pressure,  maximum  blood  pressure,  or  heart  rate 
recovery between baseline and 2 weeks CPX. 
 
 
P=0.016 
100 
P=0.031 
10 
20 
80 
60 
8 
15 
40 
6 
 
10 
4 
20 
5 
2 
P=0.016 
 
10 
 
8 
 
6 
Baseline 
 
4 
 
2 
P=0.016  
 
 
 
 
 
P=0.016 
 
0 
10 
14 days 
0 
0 
5 
10 
15 
20 
Peak VO2 (mL/kg/min) 
 
Figure 2. Treatment with anakinra for 14 days led to an improvement in aerobic exercise capacity and a reduction in CRP 
levels in an open-label proof of concept study in patients with HFrEF. Modified from Van Tassell et al. PLOSONE 2012. 
 
 
 
 
 
8 


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1 ng 100 ng 
IL-1β 
CHF 
effects  of  recombinant  murine  Interleukin-1β     (IL-1β)  on  measures  of  systolic  and  diastolic  left 
% 
Control 
1 ng 100 ng 
IL-1β 
CHF 
R2  Linear =  0.651 
VO2  (mL/kg/min)  
 
 
The role of IL-1 in HFpEF 
or  diastolic  dysfunction  is 
less  established.  
IL-1β 
 
Fractional shortening    Isovolumetric relaxation time 
* 
* 
40 
* 
24 
60
 
 
Contractile reserve 
induces 
cellular 
20 
hypertrophy  and  changes 
in calcium handling in vitro, 
* 
* 
12 
 
 
ms 
40 
 
20 
* 
* 
% 
1 ng 100 ng 
mechanisms  
involved 
in 
the 
pathogenesis  
of 
 
 
Figure  3. The 
Control 
Control 
 
IL-1β 
 
CHF 
HFpEF.[8] 
Similar 
effects 
ventricular function are shown, panels A and B respectively, and on contractile reserve (after isoproterenol 10 ng), 
panel C, in comparison to mice with heart failure (CHF). Modified from Van Tassell et al. PLOSONE 2012. 
are induced by other inflammatory  mediators downstream of IL-1β.[9]  We have recently found 
that in the mouse in vivo IL-1β induces reversible and dose-dependent alterations in diastolic 
function (Figure 3). Moreover, IL-1β also blunts the contractile response to β-adrenergic stimuli 
(isoproterenol), an additional mechanism potentially involved in exercise intolerance in HFpEF. 
 
From a clinical standpoint, patients with chronic IL-1-mediated diseases such as patients with 
rheumatoid arthritis are more likely to have left ventricular hypertrophy and diastolic 
dysfunction.[10,11]  In a study of 23 patients with rheumatoid arthritis, a single dose of anakinra 
100 mg improved left ventricular diastolic function as well as coronary flow reserve and flow- 
mediated brachial artery vasodilatation,[12]  suggesting that IL-1 blockade may represent a viable 
treatment   strategy.   More   recently,   studies   in   patients   with   critical   illness,   a   condition 
characterized by intense inflammation, more than 50% of patients had impaired diastolic 
dysfunction,[13]   and  the  presence  of  diastolic  dysfunction  was  transient  and  correlated  with 
inflammatory biomarkers.[9] 
 
In our own pilot feasibility study of patients with 
HFpEF, elevated CRP levels (a marker of IL-1 
activity)  correlated  with  reduced  exercise 
capacity (peak VO2)(Figure 4). 
 
In the current proposal, we propose that IL-1 
contributes 
to the exercise 
intolerance 
that 
characterizes patients with HFpEF by modulating 
cardiac   relaxation,   contractile   reserve   and/or 
other  endothelial  function,  and  we  propose  to 
investigate  IL-1  blockade  with  anakinra  as  a 
 
2 0  
 
 
1 5  
 
 
1 0  
 
 
5 
 
 
0 
0 
1 0  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 0 
3 0  
CRP (mg/L)  
 
 
R2  =  0.651 
P = 0.002 
 
 
 
 
 
 
 
 
 
 
 
4 0 
5 0  
therapeutic strategy to improve quality of life and 
reduce morbidity in HFpEF. 
Figure  4.  Preliminary  data  show  a  significant  inverse 
correlation between CRP levels and peak VO2. 
 
5)  
OBJECTIVES 
 
The current research  is designed  to investigate  the safety and efficacy  of Anakinra  in heart 
failure patients with preserved ejection fraction, evidence of impaired left ventricular relaxation, 
and elevated CRP levels (as a marker of inflammation) in a randomized double-blinded trial. We 
hypothesize that blockade of IL-1 will improve exercise capacity in these patients. 
 
5.1 
Primary Endpoint(s) 


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Absolute changes in aerobic exercise capacity (peak VO2) and ventilatory efficiency (VE/VCO2 
slope)  after 12 weeks  treatment  will be considered  co-primary  endpoints.  This will compare 
patients treated with anakinra (N=40) vs placebo (N=20), and provide a randomized, double- 
blinded assessment of the effects of IL-1 blockade on aerobic exercise performance. The data 
will be collected and electronically transferred to the core laboratory at the University of Illinois, 
Chicago, IL. 
 
5.2 
Secondary Exploratory Endpoints 
 
Additional endpoints will include parameters measured at CPET, echocardiography, as well as 
biomarkers, and clinical outcomes. 
 
Cardiopulmonary Exercise Test (CPX) parameters: in addition to the changes from baseline in 
VO2   and  VE/VCO2    at  12  weeks  (which  constitute  the  co-primary  endpoints),  secondary 
endpoints will compare changes in VO2 and VE/VCO2 at 4 and 24 weeks in patients treated with 
anakinra  versus  placebo.  This will help determine  when  the peak effect of IL-1 blockade  is 
achieved, the duration of effects after cessation of therapy, and the presence of any rebound 
effects. We will also analyze  changes  in heart rate and blood pressure  during exercise  and 
during recovery to assess chronotropic competency and heart rate recovery. The data will be 
collected  and  electronically  transferred  to  the  core  laboratory  at  the  University  of  Illinois, 
Chicago, IL. 
 
Echocardiography: structural and functional echocardiographic parameters include left and right 
ventricular  dimensions,  mass,  systolic  and  diastolic  function.  These  will provide  mechanistic 
insight as to whether the hypothesized changes in aerobic exercise performance are dependent 
upon changes in cardiac dimension/function. The data will be collected and electronically stored 
for further analysis at the conclusion of the study. 
 
Exercise  stress  echocardiography:  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. 
 
Questionnaires: Two independent questionnaires will be used to assess quality of life and HF 
symptoms.  The Minnesota  Living with Heart Failure questionnaire  (MLHFQ) is a 21-question 
graded questionnaire that has been extensively used to measure impairment in quality of life in 
patients  with  HF.[14]   The  Duke  Activity  Status  Index  (DASI)  questionnaire  is  a  12-question, 
yes/no, instrument that allows for the calculation of perceived functional capacity,[15]  in which 
each question describes a different physical activity and the questions are weighted according 
to their degree of physical exertion. Both questionnaires will be administered at 0, 4, 12 and 24 
weeks  in  accordance  with  CPET  and  echocardiography.   The  data  will  be  collected  and 
electronically stored for further analysis at the conclusion of the study. 
 
Biomarkers:  Blood will be collected at each timepoint throughout the study (0, 4, 12, and 24 
weeks) and analyzed for complete blood cell count, metabolic markers (including lipids and 
lipoproteins, glycemic control and insulin resistance, liver and renal panel, sterols), inflammatory 


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markers (i.e. high sensitivity CRP) and cardiac biomarkers (i.e. NT-proBNP and troponin I). The 
data will be collected and electronically stored for further analysis at the conclusion of the study. 
 
Clinical outcomes:  Incidence  of death (cardiac and non-cardiac),  hospitalizations  (for HF, for 
other cardiac causes not related to HF, or for non-cardiac reasons) will be recorded at 4,12, and 
24 weeks in every patient, and then every 12 weeks until study conclusion (max 108 weeks). 
The investigators and clinicians caring for the patients will remain blinded to treatment allocation 
and to the CRP data. Adjudication of events will be performed by an ad hoc committee blinded 
to treatment allocation and to CRP data. 
 
 
 
6)         ENROLLMENT IN THE STUDY 
 
6.1 
Screening 
 
Patients will be screened by the investigators in the VCU Pauley Heart Center Inpatient and 
Outpatient  services  during  the  course  of  their  regular  clinical  care.  A  waiver  to  obtain 
authorization  by the subjects to access personal health information during screening process 
has been obtained from the IRB. Those who meet entry criteria will be approached by the 
investigators for enrollment. Potential subjects will be provided with an Informed Consent Form 
in accordance with the local Institutional Review Board. Enrolled subjects will then undergo 
complete screening for entry criteria (listed below). Where possible, investigators will rely on 
clinically  available  laboratory  results;  the remaining  laboratory  analyses  will be ordered  and 
billed to the study account. The central laboratory at VCU Hospitals will be used for all clinically 
available  tests. Point-of-care  testing  may be used for the determination  of the plasma  CRP 
levels. Should enrollment fall behind this goal, we will pursue recruitment at other community- 
based centers in Central or Northern Virginia. 
 
 
 
6.2 
Subject Inclusion and Exclusion Criteria 
 
In order to be eligible for this study, patients must meet  ALL the 4 Inclusion criteria and  NONE 
of the Exclusion criteria. 
 
INCLUSION CRITERIA: 
 
1)  Symptoms and signs of heart failure (NYHA II-III) 
 
2)  Recent Imaging Study (<12 months) showing LVEF>50% and 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.   mPCW >12 
ii.   LVEDP>16mmHg 
b.   Tissue Doppler Echocardiogram 
i.   E/E’ >15 


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ii.   E/E’ 8-15 and one of the following 
o 
LVH 
o 
Afib 
o LAE 
o E/A<0.5+DT>280 
c.   Biomarkers 
i.   BNP>200pg/ml  (not  due  to a concomitant  disease  such  as  pulmonary 
arterial hypertension, pulmonary embolism, acute renal failure, or other) 
4)  hsCRP > 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: 
o physical inability to walk or run on a treadmill 
o angina or evidence of spontaneous or inducible ischemia 
o uncontrolled arterial hypertension 
o atrial fibrillation (or other arrhythmias) 
o moderate to severe valvular heart disease 
o chronic pulmonary disease 
o 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 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], TNF-α blockers, 
cyclosporine) not including 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 
 
 
7)  
STUDY DESIGN 
 
We designed a single center, placebo-controlled, double-blinded randomized study of Anakinra 
in patients  with heart failure  with preserved  ejection  fraction  (HFpEF).  Patients  will undergo 
baseline clinical assessment,  CPET, echocardiogram,  exercise stress echocardiography,  and 
blood tests for biomarkers. The CPET, the echocardiogram and blood tests will be repeated at 


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each visit (4, 12 and 24 weeks). The exercise stress echocardiogram will be repeated after 12 
weeks of treatment.  See Schematic of Study Design (3). 
 
7.1 
Treatment with Anakinra 
 
Anakinra and matching placebo syringes will be provided by the manufacturer, Swedish Orphan 
Biovitrum  (SOBI,  Stockholm,  Sweden)  to  the  Investigational  Pharmacy  at  the  coordinating 
center at VCU, where the syringes are stored until ready to be administered to the patient. SOBI 
has also guaranteed  a continuous supply of anakinra and placebo should the current supply 
expire prior to completion of the trial. 
 
After completion of all baseline testing patients will be given a 5-week supply of Anakinra or 
placebo, and will be instructed on how to store and self-administer the drug once daily 
(approximately at the same time every day). We added an extra 7-day supply in case of a need 
to delay Visit 2 of few days. An additional 7-week supply of Anakinra or placebo will be given on 
Visit 2 (4 weeks). The patient will also be educated on expected side effects and need to inform 
the investigators  about any foreseen  and unforeseen  events. A sharp container  sufficient  to 
contain all 60 syringes will be given to the patient to dispose the syringes in, and to bring back 
at the each visit. 
 
7.2 
Allocation concealment 
 
Anakinra  or  placebo  (vehicle)  will  be  supplied  by  the  manufacturer  of  Anakinra  (Kineret™, 
Swedish Orphan Biovitrum, Stockholm, Sweden), dispensed in small syringes (1 ml), provided 
to the patient for daily subcutaneous injection. The syringes for Anakinra or placebo will be 
undistinguishable.   The  randomization   log  will  be  prepared   by  a  consultant   outside  the 
institutions  involved  in the enrollment  (Giuseppe  Biondi-Zoccai,  MD, University  La Sapienza, 
Rome,  Italy)  and  sent  electronically  to the  director  of the  Investigational  Pharmacy  at VCU 
(Robin Sculthorpe, PharmD). Access to randomization log will be restricted and allowed only on 
an emergency basis, or as requested by the Data Safety and Monitoring Board, or at the end of 
the study including all data collection. In case of an emergency, a physician treating any patient 
enrolled  in  the  study  may  request  un-blinding  of  that  individual  patient  if  the  physician 
determines that un-blinding is necessary to make a treatment decision. The PI will contact the 
VCU Investigational Pharmacy to provide the treatment allocation to the PI, who will then relay 
the information to the treating physician. If requested by the DSMB, the PI will contact the VCU 
Investigational   Pharmacy  to  provide  the  randomization   log  directly  to  the  DSMB.  Upon 
completion of the study (including completion of all data collection and event adjudication), the 
PI will request the complete randomization log from the VCU Investigational Pharmacy. 
 
7.3 
Patient Compliance with Study Intervention 
 
One goal of the trial is to maximize adherence and retention throughout the study. Adherence 
will be addressed  by count of unused  syringes  and completion  of all study visits. Retention 
refers to the involvement of study patients throughout the intervention phase of the protocol. 
 
7.4 
Concomitant Medications 


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All concomitant medications will be recorded at each clinic visit. Administration of Anakinra with 
medications  that affect the immune  system  (i.e. immunosuppressant)  or increase  the risk of 
infection (i.e. cancer chemotherapy) is NOT permitted. If a patient requires treatment with such 
medications, he/she will not be eligible for inclusion in the study. If a patient already enrolled in 
the study requires such treatments, the investigational treatment (Anakinra or placebo) will need 
to be discontinued (see reason for discontinuation). 
 
7.5 
Standard Medical Management 
 
Patients  in  the  study  will  receive  guideline-based  medical  treatments  as  indicated.  Such 
treatments   may   include   β-adrenergic   receptor   blockers,   angiotensin   converting   enzyme 
inhibitors or receptor blockers, aldosterone blockers, isosorbide dinitrate, hydralazine, digoxin, 
aspirin, and statins. 
 
7.6 
Cardiopulmonary Test 
 
Upon completion of screening/enrollment, subjects will be scheduled for Visit 1 at the 
cardiopulmonary exercise suite. A physician-supervised maximal aerobic exercise test will be 
administered using a metabolic cart that is interfaced with a treadmill. A conservative ramping 
treadmill protocol will be used. Prior to each test, the oxygen and carbon dioxide sensors will be 
calibrated using gases of known oxygen, nitrogen, and carbon dioxide concentrations and the 
flow sensor will also be calibrated using a 3-liter syringe. Subjects will be briefed regarding the 
protocol and will be requested to exercise to fatigue. 12-lead ECG monitoring will be conducted 
at baseline, throughout the test and into recovery. Blood pressure will be measured every two 
minutes using an automated exercise-compatible device (Tango, SunTech Medical). In this 
technique, expired gases are sampled using a mouthpiece-mounted sensor, and analyzed to 
continuously measure oxygen (O2) uptake; the highest 10-second average value for O2 uptake 
defines  peak  oxygen  consumption  (VO2  peak  in  mL•kg-1•min-1).  The  ventilatory  equivalents 
method will be used to determine VO2 at ventilatory threshold. Ten second averaged VE and 
VCO2  data,  from  the  initiation  of  exercise  to  peak,  were  input  into  spreadsheet  software 
(Microsoft  Excel,  Microsoft  Corp.,  Bellevue,  WA)  to  calculate  the  VE/VCO2  slope  via  least 
squares linear regression (y = mx + b, m=slope).   American Heart Association guidelines for 
exercise testing contraindications and termination criteria will be followed. 
 
Upon completion of exercise testing, the results of the cardiopulmonary exercise test will be 
reviewed  and discussed  with the patients. Patients with angina, abnormal  blood pressure  or 
heart rate response, or ECG changes suggestive of coronary ischemia will be excluded from the 
study. 
 
Subjects  will  return  to  the  cardiopulmonary   exercise  suite  for  the  additional  visits  upon 
completion of 4 weeks (Visit 2, 28±7 days) or 12 weeks (Visit 3, 84±7 days) of treatment with 
Anakinra or placebo, or following 12 weeks of wash-out (Visit 4, 168±14 days). At each visit, 
subjects will undergo a brief physical exam and repeat exercise testing. 
 
7.7 
Echocardiogram 


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Prior  to  initiation  of  treatment,  the  patient  will  undergo  a  transthoracic  echocardiogram  to 
measure  left  and  right  ventricular  and  atrial  dimensions,  left  and  right  ventricular  systolic 
function, transmitral flow Doppler spectra, mitral and tricuspidal valve annulus tissue Doppler 
spectra,  ejection  time  and  stroke  volume,  inferior  vena  cava,  aorta  and  pulmonary  artery 
diameters and Doppler spectra, according to the recommendations of the American Society of 
Echocardiography.[16-18]  The echocardiogram will be repeated at each additional visit. 
 
 
7.8 
Blood pressure measurement through ccNexfin finger cuff 
 
 
A small cuff will be placed on the subject’s  finger to measure  blood flow. A standard  blood 
pressure  cuff  will  then  be  placed  on  the  arm  and  inflated  for  2-3  minutes.  The  finger  cuff 
[ccNexfin, Edwards Scientific] will measure changes in blood flow before and after cuff deflation 
to provide an estimate of flow mediated dilatation—a surrogate marker of endothelial function. 
The estimated duration of the study is less than 10 min. 
 
7.9 
Bioelectrical Impedance analysis (Bio-Impedance) 
 
 
Bioelectrical   Impedance   Analysis   or  Bio-Impendance   is  a  non-invasive,   quick  and  safe 
technique that allows estimating body composition. Impedance is briefly defined as the property 
of  the  electrical  ionic  conduction  of  soft  tissue  where  fat  and  bone  are  considered  poor 
conductors, however the microampere range developed during the test does not represent any 
hazard for the patient. The patient will be asked to stay still on the bed, with superior limbs 
abducted at 30° and the inferior ones at 45°. Four cutaneous electrodes (two on the foot and 
two on the homolateral hand) are applied. Between two electrodes, at least 5 cm distance is 
required.  A  small  electricity  current  is  applied  to  the  electrodes.  We  will  measure  how  the 
electricity is conducted through the body using a Quantum IV Body Composition Analyzer RJL 
Systems) and then, using a dedicated software, we will determine the body composition (water, 
lean mass and fat). The estimated duration of the study is less than 10 min. 
 
7.10 
Stress-Echocardiogram 
 
 
At visit 1 and visit 3, in correspondence of the CPET, the patient will undergo a limited 
echocardiogram acquisition prior to initiation of the exercise and after peak exercise. Two 
dimensional and Doppler images will be acquired to measure LV dimensions in diastolic and 
systole from the apical 4 chamber view, the pulsed wave and tissue Doppler spectra of the 
transmitral flow, the mitral annulus, the tricuspidal annulus. 
 
7.11 
Questionnaires 
 
Prior to each cardiopulmonary  exercise test, subjects will complete the Minnesota Living with 
Heart Failure and the Duke Activity Status Index (DASI) questionnaires. The Minnesota Living 
with Heart Failure questionnaire (MLHFQ) is a 21-question graded questionnaire that has been 
extensively used to measure impairment in quality of life in patients with HF.[14]  The questions 
are designed  to measure a wide rage of physical, emotional,  social, and mental factors that 


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contribute to overall quality of life. The DASI is a twelve-item “yes/no” questionnaire that allows 
for the calculation of perceived functional capacity. Each question describes a different physical 
activity and asks the subjects if they feel they can perform the task. The questions are weighted 
according to their degree of physical exertion. The weighted values from the “yes” responses 
are summed to produce a score in metabolic equivalents. 
 
7.12 
Biomarkers assessment 
 
Blood samples will be taken from a peripheral vein at 0, 4, 12 and 24 weeks. Samples will be 
centrifuged and then refrigerated, and shipped with cold packs within 24 hours to True Health 
Diagnostic Laboratories LLC., Richmond, VA. The results of the complete blood cell count and 
basic metabolic profile will be sent to the PI at VCU by email or fax. 
 
 
Blood samples will be used for analysis of for complete blood cell count, metabolic markers 
(including lipids and lipoproteins, glycemic control and insulin resistance, liver and renal panel, 
sterols),  inflammatory  markers  (i.e.  high  sensitivity  CRP)  and  cardiac  biomarkers  (i.e.  NT- 
proBNP and troponin I). 
 
One EDTA-containing tube, one SST containing tube, one Serum Separator Clot Activator tube 
and one PPT tube will be used for analysis of plasma levels of biomarkers by the True Health 
Diagnostics LLC, Richmond, VA. 


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7.13 
Study Schedule 
 
Enrollment 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Additional 
F/U 
(Baseline) 
(Week 4) 
(Week 12) 
(Week 24) 
Screening * 
X 
Consent 
X 
Clinical assessment ** 
X 
X 
X 
X 
X 
X 
Investigational therapy 
X 
X 
X 
CPET 
X 
X 
X 
X 
Echocardiogram 
X 
X 
X 
X 
ccNexFin monitoring 
X 
X 
X 
X 
Bio-Impedance 
X 
X 
X 
X 
Stress echocardiogram 
X 
X 
Biomarkers 
X 
X 
X 
X 
X 
*_Pregnancy test will be performed, if indicated 
**_Clinical assessment includes history and physical, medication reconciliation, and assessment 
of adverse events 
 
 
 
7.13 
Cost coverage analysis 
 
A cost coverage analysis was conducted prior to the initiation of the trial to determine what 
constitutes  standard  of care,  which  will  be  billed  to  the  patient  or the  insurer,  and  what  is 
considered ‘research’ which will be paid for with the study budget. 
 
 
8)         ASSESSMENT OF SAFETY 
 
8.1 
Specification of Safety Parameters 
 
Safety parameters will include data deriving from history and physical examination performed at 
each visit, laboratory data and results of functional and imaging tests. To enhance detection of 
adverse events between visits, all patients will be encouraged to contact the research team at 
any time with concerns or any perceived changes in their healthcare status. 


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Disease-related data (HF-related) will be assessed including changes in symptoms (or new 
symptoms), functional capacity, vital signs (including weight), renal function, or any significant 
changes in medications. 
 
Data specific to the treatment will also be assessed. The patient will be asked about symptoms 
and examined for signs of infection. Considering that Anakinra may mask signs of infection such 
as fever, a low threshold for further investigation will be advocated. A complete cell count will be 
measured   at  each  visit  to  exclude   the  unusual   cases   of  Anakinra-related   neutropenia 
(ANC<1000), for which suspension of active treatment will be encouraged until return to a value 
of ANC>1,800/mm3  (or >1,000/mm3  if patient is African-American). 
 
Changes  to  treatment  for  side-effects  or  unanticipated  problems  will  be  performed  without 
breaking the randomization code, unless deemed necessary for the treatment of the individual 
patient by the physician, in which case the physician will be made aware while the remainder of 
the team, especially the investigators performing and interpreting the tests, will be maintained 
blinded. 
 
The  risks  of the  tests  performed  have  been  described  above.  In  order  to  reduce  risk,  the 
procedures will be performed by skilled practitioners in the standard clinical fashion. 
 
Abnormal or incidental findings will be handled on a case by case basis as clinically indicated. 
 
8.2 
Data collection 
 
The principal investigator at the site will be provided with a data collection sheets or case report 
forms on which data about the individual subject will be collected. The subjects will be identified 
as a consecutive number (i.e. 01, 02, …08). The data collected on these forms will not contain 
any personal identifiable information. A database of de-identified data will be created. 
 
8.3 
Methods of Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
 
8.3.1 
Adverse Events 
 
All Adverse Effects (AEs) will be recorded on an AE form regardless of causality. 
 
An  AE  is defined  as  any  untoward  medical  occurrence  in a patient  or clinical  investigation 
subject administered a pharmaceutical product considered to be causally related to the study 
treatment or research conduct. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of medicinal (investigational) product. The occurrence of an AE may come to the attention 
of study personnel during study visits and interviews of a study recipient for medical care, or 
upon review by an investigator or study coordinator. An event that is considered by the 
investigator(s)  to  be  expected  and  related  to  the  natural  history  of  the  disease  is  NOT 
considered an AE. 
 
All events considered  AEs including local and systemic reactions not meeting the criteria for 
“serious  adverse  events”  should  be captured  on the appropriate  AE form. Information  to be 


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collected   includes   event   description,   time   of   onset,   clinician’s   assessment   of   severity, 
relationship to study intervention (assessed only by those with the training and authority to make 
a diagnosis, which would include a physician) and time of resolution/stabilization  of the event. 
All AEs occurring while on study must be documented appropriately regardless of relationship. 
All AEs will be followed to adequate resolution. 
 
Any  medical  condition  that  is  present  at  the  time  that  the  patient  is  screened  should  be 
considered as baseline and not reported as an AE. However, if it deteriorates at any time during 
the study, it should be recorded as an AE. 
 
All AEs must be graded for severity and relationship to study product. 
 
Severity  of  Event:  All  AEs  will  be  assessed  by  the  study  investigator  using  the  following 
guidelines: 
 
• 
Mild: events require minimal or no treatment and do not interfere with the patient’s daily 
activities. 
• 
Moderate: events result in a low level of inconvenience or concern with the therapeutic 
measures.  Moderate  events  may  cause  some  interference  with  functioning  and  may 
require systemic drug therapy or other treatment. 
• 
Severe: events interrupt a patient’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually incapacitating. 
• 
Life threatening: any adverse drug experience that places the patient or subject, in the 
view of the investigator, at immediate risk of death from the reaction as it occurred (i.e. 
does not include a reaction that might have caused death had it occurred  in a more 
severe form). 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the  event  at  each  level  of  intensity  to  be  performed.  Adverse  events  characterized  as 
intermittent require documentation of onset and duration of each episode. 
 
Relationship  to  the  intervention:  All  suspected  AEs  must  have  their  relationship  to  study 
intervention assessed using the terms: associated or not associated. In a clinical trial, the study 
intervention  must always be a suspect. To help assess, the following guidelines are used to 
assess causality: 
 
• 
Definitely  related:  The  event  is  temporally  related  to  the  administration  of  the  study 
intervention and, in the opinion of the investigator, no other etiology explains the event. 
• 
Probably  related:  The  event  is  temporally  related  to  the  administration  of  the  study 
intervention  and  represents,  in  the  opinion  of  the  investigator,  the  most  plausible 
explanation of the event. 
• 
Possibly  related:  The  event  is  temporally  related  to  the  administration  of  the  study 
intervention but, in the opinion of the investigator, it does not represent the most likely 
explanation of the event. 
• 
Definitely Unrelated: The event is temporally independent  of study intervention  and/or 
the event appears, in the opinion of the investigator, to be explained by another etiology. 


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8.3.2 
Serious Adverse Events 
 
An SAE  is any adverse  event/experience  occurring  between  baseline  assessments  and the 
patients final study visit that results in any of the following outcomes and is considered by the 
investigator(s) to be unexpected or not consistent with the natural history of the disease: 
 
• 
Death 
• 
Life threatening (subject at immediate risk of death) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in a persistent or significant disability or incapacity 
• 
Important  medical  events that may not result in death, be life threatening,  or require 
hospitalization   may  be  considered   SAEs  when,  based  upon  appropriate   medical 
judgment, may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
 
All the unexpected SAE will be promptly (within 24 hours) reported to the local IRB and DSMB 
(see  reporting  procedures).  The  DSMB  report  to  the  investigators  will  be  forwarded  to  the 
NHLBI Program Officer, including the discussion of the concerns, and the basis for any 
recommendations that the DSMB has made in response to the concerns (within 7 calendar days 
if fatal or life-threatening unexpected, suspected serious adverse reactions; or within 14 days for 
unanticipated problem that is not an SAE or within 15 calendar days for all non-fatal, non-life 
threatening unexpected, suspected serious adverse reactions, or within 30 days of receipt of the 
DSMB or IRB report for all other unanticipated problems or scheduled meetings). 
 
 
 
8.4 
Reporting Procedures 
 
8.4.1 
Serious Adverse Events 
 
All unexpected AEs that result in death or are otherwise reportable SAEs or AEs will be reported 
promptly to the Data Safety Monitoring Board (DSMB) and the IRB within 1 business day of 
knowledge of the event. 
 
AEs (serious or nonserious) that transpire secondary to an overdose must also be reported to 
the DSMB within 1 business day of knowledge of the event, using an AE form. 
 
The SAE form will always be completed as thoroughly as possible with all available details of 
the event, signed by the investigator (or designee), and, if a reportable adverse event as defined 
herein, forwarded to the DSMB within the designated time frames. If the investigator does not 
have all information  regarding  an SAE, he/she will not wait to receive additional  information 
before notifying the DSMB of the event and completing the SAE form. The form will be updated 
when additional information is received. 
 
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8.5 
AE/SAE Data Collection 
 
When an AE/SAE is suspected, it is the responsibility of the investigator(s) to review all 
documentation  (e.g. hospital progress notes, laboratory and diagnostic reports) relative to the 
event. The investigator will then record all relevant information regarding a suspected AE/SAE 
on the AE form. The investigator will attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE/SAE and not the individual signs/symptoms. 
 
8.6 
The Data and Safety Monitoring Board (DSMB) 
 
For this study, the DSMB is composed of a coordinator and 5 voting members, including a 
cardiologist  from  University  of  Florida  in  Jacksonville,  Florida,  a  heart  failure  specialist,  a 
general cardiologist, an infectious disease specialist, and a general internal medicine specialist. 
The composition of the DSMB has been approved by the VCU IRB. The DSMB will meet every 
6 months or sooner in case of unanticipated serious adverse events. The DSMB coordinator will 
provide the board members with data regarding screening, enrollment, adverse events and 
withdrawals, and he/she will not participate in the voting. The board members may request 
unblinding  at  any  time.  Upon  request  of  the  DSMB  (following  positive  vote  by  3  or  more 
members),  the  coordinator  will  retrieve  the  randomization  code  for  one  or  more  individual 
patients (as needed). If necessary the DSMB will inform the investigators of the unblinding of 
the  randomization  code,  if  not  necessary  the  investigators  (and  the  patients)  will  be  kept 
blinded. The DSMB may request an expert opinion by one or more non-members, however only 
the DSMB members will vote on any individual issue. The DSMB (following positive vote by 3 or 
more members) may request temporary or permanent halting of the study (see halting rules), or 
interruption  of  treatment  of  one  or  more  patients.  The  minutes  from  each  meeting  will  be 
distributed to the board members, NHLBI Program Officer, and to the IRB, and not to the 
investigators   unless   specifically   requested   by  the  DSMB.   A  brief  conclusive   statement 
addressing  whether  the  study  should  continue  as  planned  or  not  will  be  provided  to  the 
investigators and the IRB every 6 months. The investigators will provide the NHLBI staff with 
reports from the DSMB and the IRB in a timely fashion (within 7 calendar days if fatal or life- 
threatening unexpected, suspected serious adverse reactions; or within 15 calendar days for all 
non-fatal, non-life threatening  unexpected,  suspected  serious adverse reactions, or within 30 
days of receipt of the DSMB or IRB report for all other unanticipated problems or scheduled 
meetings). See Appendix – DSMB Chapter. 
 
8.7 
Regulatory Reporting 
 
This study is conducted in accordance to the NIH Good Clinical Practice guidelines. An 
Investigational  New Drug use waiver from the Division  of Cardiovascular  & Renal Products, 
Center for Drug Evaluation & Research, Food & Drug Administration was given to Dr. Abbate. 
The study protocol, consent, and Data and Safety Monitoring Plan has been approved by the 
VCU IRB. The investigators will provide the NHLBI staff with reports from the DSMB and the 
IRB in a timely fashion (within 7 calendar days if fatal or life-threatening unexpected, suspected 
serious  adverse  reactions;  or  within  15  calendar  days  for  all  non-fatal,  non-life  threatening 


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unexpected, suspected serious adverse reactions, or within 30 days of receipt of the DSMB or 
IRB report for all other unanticipated problems). 
 
8.8 
Type and Duration of Follow-up of Subjects after Adverse Events 
 
All AEs and SAEs will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, whichever occurs first. All AEs and SAEs documented at a previous 
visit/contact and designated as ongoing, will be reviewed at subsequent visits/contacts, where 
the designation may remain ongoing. The investigator will ensure that the follow-up includes any 
supplemental investigations as may be indicated to elucidate the nature and/or causality of the 
SAE. This may include  additional  laboratory  tests or investigations,  histopathological 
examinations, or consultation with other health care professionals. SAEs that are ongoing at the 
time of the subjects final study visit/contact will be documented as ongoing. 
 
8.9 
Halting Rules 
 
The  DSMB  will  monitor  the  progress  of  the  present  trial.  No  interim  efficacy  analyses  are 
planned; however an interim analysis could be performed at any time to assess efficacy and 
futility, if requested by the 3 or more members of the DSMB. The DSMB will meet regularly to 
review safety data every 6 months (or sooner in case of unanticipated serious adverse events). 
All meetings and actions taken by the committee will be recorded along with the reasons for the 
actions. These documents will include any data summaries or analyses provided to the DSMB 
and  will  remain  confidential  until  the  study  is  concluded.  The  DSMB  may  choose  to  stop 
enrollment on the basis of safety data observed. If safety concerns are found, further enrollment 
will not be allowed until issues are resolved. If no safety concerns are found, enrollment will 
continue until the target sample size is reached. 
 
 
 
9)         ADJUDICATION OF CLINICAL EVENTS 
 
9.1 
Event-adjudicating committee 
 
The event-adjudicating  committee  is composed  of a general  cardiologist,  a cardiologist  with 
training in heart failure, and a general internal medicine specialist. The committee will meet at 
the end of the study and adjudicate all the events. The committee will be blinded to treatment 
allocation. In order to favor allocation  concealment,  the committee  will also be blinded to C- 
reactive protein levels, which may be affected by treatment. 
 
9.2 
Definition of the events 
 
The events adjudicated will include: 
-    Death; 
-    Cardiac death (in which a direct cause attributable to cardiac disease is present); 
- 
Sudden cardiac death (in which cardiac death occurred out of the hospital and suddenly; or 
in  the  hospital  due  to  ventricular  arrhythmias  unrelated  to  other  concomitant  cardiac 
conditions); 


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- 
Non-cardiac death (in which the event of death is considered not to be a direct consequence 
of cardiac disease); 
-    Hospitalization for any cause; 
- 
Hospitalization   for  heart  failure  (in  which  the  primary  diagnosis  for  hospitalization   is 
decompensated  heart  failure  established  as  the  finding  at admission  of all  2 conditions 
listed: a. dyspnea or respiratory distress or tachypnea at rest or with minimal exertion; b. 
evidence of elevated cardiac filling pressure or pulmonary congestion (at least one of the 
conditions  must be met: pulmonary  congestion/edema  at physical exam OR chest X-ray; 
plasma BNP levels ≥200 pg/ml; or invasive measurement of left ventricular end-diastolic 
pressure >18 mmHg or of pulmonary artery occluding pressure (wedge) >16 mmHg) 
-    Acute myocardial infarction, as defined by the WHO consensus statement; 
-    Unstable angina, or need for coronary revascularization; 
- 
Cardiac tachy-or brady-arrhythmias  leading to a new hospitalization  or to prolongation  of 
hospital stay; 
-    Acute renal failure (defined as in increase in plasma creatinine levels of 50% or 0.5 mg/L); 
-    Acute respiratory failure (not due to heart failure); 
-    Sepsis or other serious infection requiring antibiotic therapy; 
-    Acute stroke. 
The analysis will consider time to first event and time to each event. It will also consider event 
rates at 1, 3 and 6 months, in order to favor comparisons with other studies. The number of 
days  free  of  hospitalization  during  the  first  1,  3  and  6  months  will  also  be  measured  and 
compared between groups. 
 
9.3 
Implications of the findings of the event-adjudicating committee 
 
The events will be adjudicated only after the completion of the study, and therefore the findings 
by the committee will have no implications on the conduct of the study. 
 
 
 
10)       DISCONTINUATION OF TREATMENT AND WITHDRAWAL 
 
10.1 
Reasons for Discontinuation of Treatment or Withdrawal from the Study 
 
Patients may withdraw from the study at any time. The investigators can withdraw any patient at 
any time from the study if medically necessary. It will be extremely important to obtain complete 
follow-up  data  on  each  patient,  except  on  those  who  withdraw  consent  to  release  such 
information. It will be documented whether or not each patient completed the study. If for any 
reason the study treatment or observations were discontinued, the reasons will be recorded and 
the IRB will be informed. 
 
Reasons for discontinuation of Anakinra (or placebo): 
1)  Neutropenia (ANC<1000)*; 
2)  Systemic infection (sepsis)*; 
3)  Surgery *; 
4)  Cancer; 


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5)  Hypersensitivity reaction (rash, anaphylaxis); 
6)  Severe injection site reactions *; 
7)  Need for immunosuppressant therapy; 
8)  Acute myocardial infarction or stroke. 
* treatment may be restarted after condition resolved 
 
 
 
 
10.2 
Handling of Withdrawals 
 
Loss to follow-up can occur due to patients’ withdrawal or unreported death. Patients that have 
withdrawn  from  treatment  will  still  be  offered  to complete  all the  functional  assessments  to 
analyze data in an intention-to-treat strategy. If patients are lost to follow up and their clinical 
condition cannot be established (alive vs dead, hospitalized vs not), they will be excluded from 
the  initial  analysis,  and  then  reintroduced  for  sensitivity  analysis  considering  all  potential 
outcomes. 
 
10.3 
Termination of Study 
 
The decision regarding continuation or termination of the study will be solely based on safety 
data, and will be made by the DSMB. Interim analyses will be performed by the DSMB upon 
request by the co-PIs. The co-PIs will meet every month (or sooner in case of unanticipated 
serious adverse events) to discuss enrollment, withdrawals, and adverse events. If protocol 
modifications  are warranted, close consultation with the DSMB and IRB will be required, and 
their approval will be needed. 
 
 
 
11)       RECRUITMENT STRATEGIES 
 
The investigators or coordinators in the study will screen and evaluate patients evaluated at the 
Virginia Commonwealth University Health System for heart failure. Such patients are likely to be 
found in the Department of Internal Medicine and the Department of Emergency Medicine. No 
advertisement strategies are planned at this time. 
 
 
 
12)       STATISTICAL CONSIDERATIONS 
 
12.1 
Study Hypothesis 
 
We hypothesize that IL-1 blockade with Anakinra will improve aerobic exercise performance and 
reduce hospital admission rates in patients with HF and preserved ejection fraction (HFpEF). As 
the first step in testing this hypothesis, we propose a randomized, double-blinded, pilot study to 
determine the effect of anakinra on aerobic exercise performance over the course of 6 months. 
Although this pilot study will not be powered to detect differences in the 3-month and 6-month 
hospital admission rates, we believe this study will provide an estimate of the potential effect. An 
improvement in aerobic exercise performance alone would represent a valuable achievement in 


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this HF population, and would provide the rationale—especially  if paired with a signal showing 
reduced readmission rates—for a subsequent Phase III clinical study to evaluate IL-1 blockade 
on the key outcomes of HF morbidity and mortality. 
 
12.2 
Sample Size Considerations 
 
The sample size for this pilot study is calculated according to the primary endpoint of difference 
in interval change in peak VO2 at 12 weeks between anakinra and placebo. Given an expected 
average peak VO2  of 15 ± 3.5 mL/kg/min for HF patients, 40 subjects randomized to anakinra 
and 20 subjects randomized to placebo (2:1 randomization) would provide approximately 95% 
power  to  detect  a  difference  of  3.5  mL•kg-1•min-1   (23%  improvement)  in  peak  VO2.  An 
improvement of 3.5 mL•kg-1•min-1  equals 1 metabolic equivalent and is typically associated with 
a 13–15% reduction in mortality. A conservative estimate of 20% loss to follow-up or withdrawal 
would retain >90% power. 
 
12.3 
Statistical Analysis 
 
12.3.1  Demographics and Baseline Characteristics 
 
Baseline measurement and demographic characteristics will be summarized for the patients into 
each of the treatment arms. Descriptive summaries of continuous measurements will consist of 
means, standard deviations and 95% confidence intervals; if the measurements have markedly 
non-normal  distributions,  then  medians  and  interquartile  ranges  will  be  provided  instead. 
Descriptive summaries of categorical measurements will consist of frequencies, proportions and 
95% confidence intervals on those proportions. The summaries for each measurement will be 
provided separately for each treatment group. 
 
12.3.2  Analysis of the Primary Endpoint 
 
The data will be collected and electronically transferred to the core laboratory at the University 
of Illinois, Chicago, IL, where Dr. Ross Arena, PhD, will analyze data at the end of the study. 
After locking the database, he will be provided a group allocation according to treatment A or B 
(blinded to real treatment). Dr. Arena and Dr. Lu (biostatistician) will analyze the data according 
to blinded group allocation and the description of the group allocation will be disclosed only after 
completion of the analysis. The differences in interval changes between the treatments will be 
compared  using  random-effect  analysis  of  variance  for  repeated  measures  to  analyze  the 
effects  of time  and  group  allocation.  Unadjusted  p values  will  be  reported  throughout,  with 
statistical significance set at the 2-tailed 0.05 level. All analyses will be based on a ‘complete 
case’ approach. 
 
12.3.3  Analysis of Secondary Endpoints 
 
The  data  will  be  collected  and  electronically  stored.  The  analysis  will  be  performed  at  the 
conclusion of the study as described above. For statistical analysis, all values will be reported 
as the median and interquartile range for potential deviation from Gaussian distribution. The 
differences between treatment groups will be computed using the Wilcoxon signed-rank test for 
continuous variables or Fisher’s exact test for discrete variables. 


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13) LITERATURE CITED 
 
1. 
Meta-analysis Global Group in Chronic Heart Failure (MAGGIC). The survival of patients 
with heart failure with preserved or reduced left ventricular ejection fraction: an individual 
patient data meta-analysis. Eur Heart J 2011 [Epub ahead of print]. 
2. 
Owan TE, Hodge DO, Herges RM, Jacobsen  SJ, Roger VL, Redfield  MM. Trends in 
prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 
2006;355:251-9. 
3. 
Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, Bravata DM, 
Dai S, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, 
Kissela BM, Kittner SJ, Lackland  DT, Lichtman  JH, Lisabeth LD, Makuc DM, Marcus 
GM, Marelli A, Matchar DB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter 
NP, Soliman EZ, Sorlie PD, Sotoodehnia  N, Turan TN, Virani SS, Wong ND, Woo D, 
Turner  MB.  Heart  Disease  and  Stroke  Statistics--2012  Update:  A  Report  From  the 
American Heart Association. Circulation 2012;125:e2-e220. 
4. 
Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. 
Blood 2011;117:3720-32. 
5. 
Luster  AD.  Chemokines--chemotactic  cytokines  that  mediate  inflammation.  N  Engl  J 
Med 1998;338:436-45. 
6. 
Van Tassell BW, Seropian IM, Toldo S, Goyal N, Robati R, Abbate A. Interleukin-1beta 
induces   a   reversible   non-ischemic   cardiomyopathy   in   the   mouse.   Eur   Heart   J 
2010;31:720-20. 
7. 
Van Tassell BW, Arena RA, Toldo S, Mezzaroma  E, Azam T, Seropian  IM, Shah K, 
Canada   J,  Voelkel   NF,  Dinarello   CA,  Abbate   A.  Enhanced   Interleukin-1   activity 
contributes  to  exercise  intolerance  in  patients  with  systolic  heart  failure.  PLoS  One 
2012;7:e33438. 
8. 
Thaik CM, Calderone  A, Takahashi  N, Colucci  WS. Interleukin-1  beta modulates  the 
growth and phenotype of neonatal rat cardiac myocytes. J Clin Invest 1995;96:1093-9. 
9. 
Wu CK, Lee JK, Chiang FT, Yang CH, Huang SW, Hwang JJ, Lin JL, Tseng CD, Chen 
JJ,  Tsai  CT.  Plasma  levels  of  tumor  necrosis  factor-alpha   and  interleukin-6   are 
associated with diastolic heart failure through downregulation of sarcoplasmic reticulum 
Ca2+ ATPase. Crit Care Med 2011;39:984-92. 
10. 
Liang KP, Myasoedova E, Crowson CS, Davis JM, Roger VL, Karon BL, Borgeson DD, 
Therneau TM, Rodeheffer RJ, Gabriel SE. Increased prevalence of diastolic dysfunction 
in rheumatoid arthritis. Ann Rheum Dis 2010;69:1665-70. 
11. 
Rudominer RL, Roman MJ, Devereux RB, Paget SA, Schwartz JE, Lockshin MD, Crow 
MK, Sammaritano  L, Levine  DM, Salmon  JE. Independent  association  of rheumatoid 
arthritis  with  increased  left  ventricular  mass  but  not  with  reduced  ejection  fraction. 
Arthritis Rheum 2009;60:22-9. 
12. 
Ikonomidis  I, Lekakis  JP, Nikolaou  M, Paraskevaidis  I, Andreadou  I, Kaplanoglou  T, 
Katsimbri P, Skarantavos G, Soucacos PN, Kremastinos DT. Inhibition of interleukin-1 
by anakinra improves vascular and left ventricular function in patients with rheumatoid 
arthritis. Circulation 2008;117:2662-69. 
13. 
Ikonomidis I, Nikolaou M, Dimopoulou I, Paraskevaidis I, Lekakis J, Mavrou I, Tzanela 
M,  Kopterides  P,  Tsangaris  I,  Armaganidis  A,  Kremastinos  DT.  Association  of  left 
ventricular diastolic dysfunction with elevated NT-pro-BNP in general intensive care unit 
patients  with  preserved  ejection  fraction:  a  complementary  role  of  tissue  Doppler 
imaging parameters and NT-pro-BNP levels for adverse outcome. Shock 2010;33:141-8. 
14. 
Garin  O, Ferrer  M, Pont  A, Rue  M, Kotzeva  A, Wiklund  I, Van  Ganse  E, Alonso  J. 
Disease-specific   health-related   quality   of   life   questionnaires   for   heart   failure:   a 
systematic review with meta-analyses. Qual Life Res 2009;18:71-85. 


VCU Clinical Study Protocol 
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15. 
Hlatky  MA, Boineau  RE, Higginbotham  MB, Lee KL, Mark  DB, Califf RM, Cobb  FR, 
Pryor DB. A brief self-administered  questionnaire to determine functional capacity (the 
Duke Activity Status Index). Am J Cardiol 1989;64:651-4. 
16. 
Gardin JM, Adams DB, Douglas PS, Feigenbaum H, Forst DH, Fraser AG, Grayburn PA, 
Katz  AS,  Keller  AM,  Kerber  RE,  Khandheria  BK,  Klein  AL,  Lang  RM,  Pierard  LA, 
Quinones MA, Schnittger I. Recommendations for a standardized report for adult 
transthoracic  echocardiography:   a  report  from  the  American  Society  of 
Echocardiography's Nomenclature and Standards Committee and Task Force for a 
Standardized Echocardiography Report. J Am Soc Echocardiogr 2002;15:275-90. 
17. 
Gottdiener JS, Bednarz J, Devereux R, Gardin J, Klein A, Manning WJ, Morehead A, 
Kitzman D, Oh J, Quinones M, Schiller NB, Stein JH, Weissman NJ. American Society of 
Echocardiography recommendations for use of echocardiography in clinical trials. J Am 
Soc Echocardiogr 2004;17:1086-119. 
18. 
Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, 
Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart 
WJ. Recommendations for chamber quantification: a report from the American Society of 
Echocardiography's  Guidelines  and  Standards  Committee  and  the  Chamber 
Quantification Writing Group, developed in conjunction with the European Association of 
Echocardiography,   a  branch  of  the  European   Society  of  Cardiology.   J  Am  Soc 
Echocardiogr 2005;18:1440-63. 


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DSMB CHARTER 
 
Charter, Data and Safety Monitoring Board for 
 
NHLBI 1R34HL118348-01A1 
 
Interleukin-1 blockade in heart failure with preserved ejection fraction: 
 
Diastolic Heart Failure Anakinra Response Trial -2 
(D-HART2) 
Updated on August 13, 2014 
 
Executive Secretary: Christine DeWilde, RN – dewildect@vcu.edu 
 
 
 
 
1 
Introduction 
 
This Charter is for the Data and Safety Monitoring Board (DSMB) for the study: Interleukin-1 
blockade in heart failure with preserved ejection fraction: Diastolic Heart Failure 
Anakinra Response Trial -2 (D-HART2) 
 
hereafter referred to as “D-HART2”. 
 
The Charter is intended to be a living document.  The DSMB may wish to review it at regular 
intervals to determine whether any changes in procedure are needed. 
 
2 
Responsibilities of the DSMB 
 
The DSMB is responsible for safeguarding the interests of study participants, assessing the 
safety and efficacy of study procedures, and for monitoring the overall conduct of D- 
HART2. 
 
The DSMB is an independent group advisory to the investigators, and is required to provide 
recommendations about starting, continuing, and stopping the study D-HART2. In 
addition, the DSMB is asked to make recommendations, as appropriate, to the 
investigators about: 
 
• 
Participant safety 
• 
Benefit/risk ratio of procedures and participant burden 
• 
Selection, recruitment, and retention of participants 
• 
Adherence to protocol requirements 
• 
Completeness, quality, and analysis of measurements 
• 
Amendments to the study protocol and consent forms 
• 
Notification of and referral for abnormal findings 
• 
Efficacy of the intervention at study termination (no interim analyses planned) 


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3 
Organization and Interactions 
 
Communication with DSMB members will be primarily through the DSMB executive secretary, 
Christine DeWilde, RN, Officer and the investigators at Virginia Commonwealth 
University (VCU).  It is expected that study D-HART2 investigators will not communicate 
with DSMB members about the study directly, except when making presentations or 
responding to questions at DSMB meetings or during conference calls. 
 
a.   DSMB Members and NHLBI Program Staff 
 
DSMB members and their expertise are listed in Appendix A. Consistent with NHLBI policy, the 
DSMB is assigned an Executive Secretary (ES) to provide an unbiased staff interface for 
the DSMB, especially during executive sessions. The ES is responsible for assuring the 
accuracy and timely transmission of the final recommendations and DSMB minutes. 
 
b. Scheduling, Timing, and Organization of Meetings 
 
DSMB meetings will be held at the Virginia Commonwealth University, Richmond, VA, unless 
otherwise specified. For DSMB members residing outside of Virginia, telephone 
participation will be allowed for all meetings. The purpose of the first meeting is to review 
and discuss this Charter, to provide an overview of study D-HART2 activities, to review 
and make recommendations about the protocol(s), and to determine the frequency of 
interim analyses and whether data will or will not be masked to identity of randomized 
groups. Enrollment in a study cannot begin until the DSMB’s recommendation for 
approval of the protocol has been made and IRB approval for the protocol including the 
DSMP has been obtained. 
 
Meetings are usually held approximately twice a year, every 6 months, with additional meetings 
or conference calls scheduled as needed.  Once the DSMB has established its working 
routine, consideration can be given to replacing one or both meeting per year with a 
conference call, if the agenda permits.  Meetings and conference calls will be scheduled 
and the agenda will be developed by the ES in close consultation with the Chair and the 
NHLBI Program Officer. 
 
• 
For this DSMB, meetings will be held twice per year. 
• 
The DSMB will monitor the progress of the present trial. 
• 
No interim efficacy analyses are planned; however an interim analysis could be 
performed at any time to assess efficacy and futility, if requested by the 3 or more 
members of the DSMB. 
• 
The DSMB may choose to stop enrollment on the basis of safety data observed. If safety 
concerns are found, further enrollment will not be allowed until issues are resolved. If no 
safety concerns are found, enrollment will continue until the target sample size is 
reached. 
 
The agenda for DSMB meetings and calls will be drafted by the ES in consultation with the 
Chair, investigators and the NHLBI Program Officer. The ES will finalize the agenda after 


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consultation with the DSMB Chair.  The agenda and meeting materials should be 
distributed by the ES 4 weeks before each meeting or call to the DSMB members, 
investigators, and the NHLBI Program Officer. 
 
The ES will collect and document all potential conflicts of interest from each member of the 
DSMB related to the design, conduct, interpretation, and publication of the study. Before 
each meeting, when the agenda is sent out, the ES will ask all DSMB members to state 
whether they have developed any new conflicts of interest since last meeting.  This 
review will be conducted in addition to the review for conflicts of interest conducted by 
the VCU IRB at the time of initial IRB approval. If a new conflict is reported, the Chair 
and staff will determine if the conflict limits the ability of the DSMB member to participate 
in the discussion. The DSMB also will review adverse event data, other safety data, 
quality and completeness of study data, and enrollment data at each meeting to ensure 
proper trial conduct. 
 
It is expected that all DSMB members will attend every meeting and call. However, it is 
recognized that this may not always be possible. Quorum for voting is considered to be 
half the number of standing members plus one. The Board may wish to decide if 
particular expertise is needed within the quorum for the meeting to be valid. All standing 
Monitoring Board members are voting members.  The Board may also wish to decide in 
advance whether ad hoc members can vote. 
 
A quorum of this DSMB is considered to be 3 members out of total 5. 
 
 
 
 
c. 
Discussion of Confidential Material 
 
DSMB meetings and calls will be organized into open, closed, and executive sessions. 
 
• 
During the open sessions, information will be presented to the DSMB by the Study 
Investigators and the NHLBI Program Staff as appropriate, with time for discussion. 
 
• 
During the closed sessions, the DSMB will discuss confidential data from the study D- 
HART2, including information on efficacy and safety by treatment arm, if available.  The 
DSMB will decide whether to remain masked to the treatment assignments at each 
meeting. If the closed session occurs on a conference call, steps will be taken to ensure 
that only the appropriate participants are on the call, and to invite others to re-join the call 
only at the conclusion of the closed session. NHLBI Program Officer would join the 
session only at the discretion of the Chair. 
 
The DSMB may elect to hold an executive session in which only the DSMB members, NHLBI 
Program Officer (at the discretion of the Chair) and the ES are present in order to 
discuss study issues independently. Voting on recommendations will follow Roberts’ 
Rules of Order (Robert's Rules of Order Newly Revised (10th Edition) RONR by 
Henry M. Robert III, William J. Evans (Editor), Daniel H. Honemann (Editor), Thomas J. 
Balch (Editor), Sarah Corbin Robert, Henry M. Robert III, General Henry M. Robert) 


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If the executive session occurs on a conference call, steps will be taken to ensure that only the 
appropriate participants are on the call, and to invite others to re-join the call only at the 
conclusion of the executive session. 
 
At the conclusion of the closed and executive sessions, the participants will be re-convened so 
that the DSMB Chair can provide a summary of the DSMB’s recommendations.  This 
provides an opportunity for study investigators and NHLBI Program Officer to ask 
questions to clarify the recommendations, if necessary.  The meeting is then adjourned. 
 
d.   Reports of DSMB Deliberations 
 
• 
Formal minutes:  The ES is responsible for the accuracy and transmission of the formal 
DSMB minutes, within 14 days of each meeting or call.  These minutes prepared to 
summarize the key points of the discussion and debate, requests for additional 
information, response of the investigators to previous recommendations, and the 
recommendations from the current meeting. Prior to submission to the investigators and 
the NHLBI Program Officer, minutes will be reviewed by the DSMB Chair for final review 
and approval. The DSMB Chair may sign the minutes or indicate approval electronically 
via email.  Then, the minutes are sent to the investigators and the NHLBI Program 
Officer. 
 
• 
Reports to IRBs: The investigators will prepare a memo documenting DSMB’s 
deliberations and recommendations and send the memo to VCU IRB and NHLBI 
Program Officer. 
 
• 
The DSMB report to the investigators will be forwarded to the NHLBI Program Officer, 
including the discussion of the concerns, and the basis for any recommendations that 
the DSMB has made in response to the concerns (within 7 calendar days if fatal or life- 
threatening unexpected, suspected serious adverse reactions; or within 14 days for 
unanticipated problem that is not an SAE or within 15 calendar days for all non-fatal, 
non-life threatening unexpected, suspected serious adverse reactions, or within 30 days 
of receipt of the DSMB or IRB report for all other unanticipated problems or scheduled 
meetings). 
 
e.   Reports to the DSMB 
 
For each meeting, the investigators will prepare summary reports and tables to facilitate the 
oversight role of the DSMB. The DSMB should discuss at the first or subsequent 
meetings what data they wish to review and how it should be presented. The regular 
reports to the DSMB will contain blinded data for all enrolled subjects. If necessary, the 
DSMB may request un-blinding of the data, in which case, the DSMB will request that 
the randomization log be sent to the study biostatistician (Juan Lu, PhD), who will then 
prepare an un-blinded report for the DSMB. 


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f. Statistical Monitoring Guidelines 
 
At the first meeting, review of the protocol will include review of the statistical analysis plan.  The 
DSMB should discuss the adequacy of that plan. The final plan, whether part of a 
research protocol or separate document, will be maintained as an appendix to this 
charter. The DSMB should discuss the statistical monitoring procedures they propose to 
follow to guide their recommendations about termination or continuation of the trial (if 
applicable). These procedures could include guidelines for early termination for benefit, 
termination for futility, and termination for safety reasons (if applicable). 


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Appendix A: DSMB members 
 
Dominick Angiolillo, MD, PhD 
DSMB Chair 
Dr. Angiolillo is an Associate Professor of Medicine in Cardiology at the University of Florida in 
Jacksonsville. He is board certified in Cardiology and Interventional Cardiology, and serves as 
Medical Director for the Cardiovascular Research Program in the division of Cardiology. 
http://www.hscj.ufl.edu/directory/bio.aspx?id=1318 
 
Richard Cooke, MD 
DSMB Member 
Dr. Cooke is an Associate Professor of Medicine in Cardiology at the Virginia Commonwealth 
University, and is the Chief of the Advanced Heart Failure Service in the VCU Pauley Heart 
Center. Dr. Cooke is board-certified in Internal Medicine, Cardiology, Heart Failure, and 
Interventional Cardiology.   http://www.pauleyheart.vcu.edu/staff/cooke.html 
 
Gonzalo Bearman, MD 
DSMB Member 
Dr. Bearman is a Professor of Medicine and serves as Chief of the Division of Infectious 
Disease as well as Hospital Epidemiologist. Dr. Bearman is Board Certified in Internal Medicine, 
Infectious Diseases, and General Preventive Medicine and Public Health. 
 
Ion Jovin, MD, PhD 
DSMB member 
Dr. Jovin is an Associate Professor of Medicine in Cardiology, and serves as Director of the 
Cardiac Catheterization Laboratories at the Hunter McGuire Veterans Administration Medical 
Center in Richmond, VA. Dr. Jovin is board certified in Cardiology and Interventional Cardiology. 
http://www.pauleyheart.vcu.edu/staff/jovin.html 
 
Jeffrey Kushinka, MD                       DSMB member 
Dr. Kushinka is an Associate Professor in the Division of General Internal Medicine, has served 
as Interim Chair for 2 years. He is also the clerkship director for 3rd Medical Students and an 
Associate Program Director for the Internal Medicine Residency Program. Dr. Kushinka is board 
certified in Internal Medicine. 


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Appendix B: Case Report Forms 
 
• 
Screening and Enrollment form (1 page) 
• 
Individual Patient Cover Sheets  (2 pages) 
• 
Individual Visit Assessment Form (5 pages) 
• 
Adverse Event reporting form (1 page) 


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D-HART2  
Screening and enrollment form 
Subject number: D-HART2   
_ 
Initials   
Date 
  
 
 
INCLUSION CRITERIA:  {A// 6 criteria need to be met) 
D Symptoms and signs of heart failure (NYHA 11-111) 
D Recent Imaging Study (<12 months) showing LVEF>50% and LVEDVI<97ml/m2 
D Evidence of abnormal LV relaxation, filling, diastolic distensibility, or diastolic stiffness as 
shown by one of the following: 
o   Invasive Hemodynamic measurements (mPCW >12 or LVEDP>16mmHg) 
o  Tissue Doppler Echocardiogram, EIE' >15 
o  Tissue Doppler Echocardiogram, EIE' 8-15 and one additional criterion (E/A<O.S and 
DT>280 ms, LVH, left atrial enlargement, prior atrial fibrillation) 
o   BNP>200pg/ml (not due to a concomitant disease such as pulmonary  arterial hypertension, 
pulmonary  embolism, acute renal failure, or other) 
D The patient is 2::21 years old, and willing and able to provide informed consent. 
D The  patient  is  willing  and  able  to  comply  with  the  protocol  (i.e. self  administration  of the 
treatment, and exercise protocol) 
 
EXCLUSION CRITERIA  (check only if applicable -7 patient excluded): 
o 
 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) 
o 
Persistent or chronic atrial fibrillation (prior history is not an exclusion if patient is in sinus rhythm) 
o    Active infection including chronic  infection 
o    Active cancer (or prior diagnosis of cancer  within the past 10 years) 
o    Anticipated need for surgery 
o 
 Recent  (<14 days) or active use of immunosuppressive drugs (including but not limited to high-dose 
corticosteroids [>1_mg/kg of prednisone equivalent],TNF-a blockers, cyclosporine) not including NSAIDs 
or corticosteroids used for IV dye allergy  only) 
o 
Chronic  auto-immune or auto-inflammatory disease (including but not limited to rheumatoid arthritis, 
systemic  lupus erythematosus) 
o    Active cancer (or prior diagnosis of cancer  within the past 10 years) 
o 
Neutropenia (absolute neutrophil count<1,800/mm 3 [or <1,000/mm  in African-American patients]) 
o 
Severe impairment in renal function (estimated glomerular filtration rate <30 mllkg*min) 
o 
Recent or planned use of vaccination with  live attenuated viruses 
o    Allergy to rubber or latex 
o    Allergy to products derived from Escherichia coli 
o 
Pregnancy or breastfeeding 
 
Eligibility  criteria verified and consenting completed by   
on   
(date) 
D Patient given a copy of the informed consent and sufficient time to read and have  questions, answered. 
D The original signed copy is stored for research, a signed copy is given to the patient,and an additional 
copy is placed in the chart. 
D Laboratory test for screening CRP sent 
Screening plasma C-reactive protein levels >2 mg/L -7 verified on _/_/_by   
_ 
 
 
 
 
Version  April 5, 2016 


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Participant Study ID: 
- Was the patient re-admitted between baseline and 4- 
week FU? NO  I  YES 
- Was the patient re-admitted between 4-week FU and 12- 
week FU? NO  I  YES 
- Was the patient re-admitted between 12-week FU and 
24-week FU? NO  I  YES 
151 Batch_o,f_
Dr,ug Dispensed to Participant 
Date: 
#of syringes dispensed:   
 
Date for 4-week follow-up: _/_/  
 
Date: _,_,   
Drug Returned by Participant at 4-week  FU 
#of syringes returned:   
 
251 Batch_o,f_
Dr,ug Dispensed to Participant 
Date: 
#of syringes dispensed:   
 
Date for 12-week follow-up: _/_/  
 
Drug Ret_
urn,_
ed,by Participant at 12-week FU 
Date: 
#of syringes returned:   
 
Eligibility Confirmed on _/_/__ 
Signed/Performed  by: 
If Re-Consented: 
Date ICF signed: _/_/  
 
Withdrew_
C,o_
ns,e nt: 
Date: 
Reason? 
Informed Consent: 
Version _!_!__ 
IRB approval _/_/  
; signed on _1_1  
 
Notes: 
Randomization: _/_/ 
Notes: 
Study Time Point 
Study Procedure 
Completed 
Notes 
Screening 
I   I 
Blood Draw (screening - VCU) 
Echocardiogram  (prior enrollment) 
_/_/ 
Note in CIS re: Clinical Triai/ICF 
Process 
Blood Draw (baseline- HDL) 
Echocardiogram 
FMD 
BIA 
Dietary Assessment 
Concomitant Rx 
Baseline History 
CPET 
Echo-stress 
Invest. Drug Dispensed (151 Batch) 
Drug Dose #1 administered 
Blood Draw (4-week  HDL) 
Echocardiogram 
FMD 
 
 
 
 
HM2000018 - lnterteukin-1Blockade in heart failure with preserved eiection fraction (0-HART2l 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline 


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_
4-w,_
ee,k FU
 
BIA 
CPET 
Concomitant Rx 
AE review/History 
Invest. Drug Dispensed (2nd Batch) 
Other: 
1_2,-w_e,ek FU 
Blood Draw (12-week HDL) 
Echocardiogram 
FMD 
BIA 
Dietary Assessment 
CPET 
Echo-stress 
Concomitant Rx 
AE review/History 
Other: 
2_
4-,w_e,ek FU 
Blood Draw (12-week HDL) 
Echocardiogram 
FMD 
BIA 
Dietary Assessment 
CPET 
Concomitant Rx 
AE review/History 
Other: 
Additional Notes: 
• SAEs  Reported? 
• Deviations? 
 
 
HM2000018 - lnterteukin-1Blockade in heart failure with reserved e·ection fraction ID-HART21 


VCU Clinical Study Protocol 
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D-HART2 Subject #  
Initials   
 Date on Enrollment   
_ 
 
 
Baseline 
 
 
[ ]lnclusion/exclus.ion criteria  reviewed; [  ] consent obtained 
 
[ ] Heart Failure symptoms - NYHA II [ ] or Ill [  ] 
 
 
Current symptoms  and signs: (check all that apply) 
[ ] shortness of breath; [ ] orthopnea;[  ] paroxysmal nocturnal dyspnea 
[ ] chest pain;[] tiredness/fatigue; [ ] edema (symptom); [  ] abdominal fullness 
On exam: [ ] pitting edema,[  ] 53 gallop, [ ] 54 gallop, [ ] JVD, [  ] rales 
 
Notes                                                                                                                               _ 
 
Medical History: (check all that apply) 
[ ]Ischemic heart disease;[  ] Prior PCI; [ ] Prior CABG;[  ] Prior CVA; [ ] Hypertension 
[ ] Diabetes;[  ] Hy[perlipidemia; [ ] Current Tobacco user;[  ] Peripheral Vase Disease 
[ ] Chronic Kidney Disease;[  ] Chronic Obstructive Lung Disease; [ ] DVT/PE; 
[ ] Obstructive sleep apnea;[  ] Morbid obesity, check [ ] if BMI >35 and [  ] if >40 
 
Body weight:  
kg/  
lb 
Height:   
m/  
ft 
BMI:   
kg/m2 
Blood Pressure:  
}  
mmHg 
HR:   
min 
Notes   
_ 
 
Planning: (check all completed) 
[ ] Baseline echoca rdiogram Doppler 
[ ] Nexfin and Bioel ectrical impedance analysis 
[ ] Dietary assessment 
[ ] Baseline cardiopulmonary exercise test 
[ ] Heart failure questionnaires 
[ ] Baseline stress echocardiogram Doppler 
[ ] Labs sent to HDL 
[ ] Recording of current medications 
[ ] Dispensing of investigational drug (for 35 days) by  
_ 
[ ] Patient education on drug handling,storage,and self-administration 
[ ] Outpatient Hospital Follow up on day 28 (24-32) on  
at   
_ 
Notes   
 
 _ 
 
 
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40 
 
 
 
 
D-HART2 Subject#  
Initials   
 Date on Enrollment   
_ 
 
 
Follow up visit: 4 weeks 
 
Date of  enrollment._---' Date of F/U visit   
_ 
 
 
Clinical conditions: (check all that apply) 
[ 1 heart failure symptoms, 
NYHA class (1-?IV},check [  1 if re-hospitalization 
[ 1 re-hospitalization for other cause (complete dedicated sheet) 
[ 1 death, check [ 1 if presumed cardiac death, check [  1 if sudden death 
[ 1 interruption of investigational treatment (complete dedicated sheet) 
 
Notes   
 
 
Current symptoms and signs: (check all that apply) 
[ 1 shortness of breath; [  1 orthopnea;[   1 paroxysmal nocturnal dyspnea 
[ 1 chest pain;[  1 tiredness/fatigue; [  1edema (symptom); [  1 abdominal fullness 
On exam: [ 1 pitting edema,[  1 53 gallop, [  154 gallop, [  1JVD,[  1 rales 
 
Notes   
 
 
Past MedicalHistory: (changes vs prior -new diagnoses) 
[1  
;[1 
;[ 1 
·[1--------- 
Notes   
 
 
Body weight:  
kg/  
lb 
Blood Pressure:  
}  
mmHg 
 
Planning: (check all completed) 
[ 1 F/u echocardiogram Doppler 
Height:   
m/  
ft 
HR:   
min 
BMI: _kg/m2 
[ 1 Nexfin and Bioelectrical impedance analysis 
[ 1 F/u cardiopulmonary exercise test 
[ 1 F/u stress echocardiogram Doppler (only at the 3 months visit) 
[ 1 Labs sent to HDL 
[ 1 Updating current medications 
[ 1 Assessment of compliance with investigational drug performed by   
_ 
(used syringes 
· returned syringes 
) 
[ 1 Assurance of compliance 
[ 1 Dispensing of investigational drug (for 49 days) by   
 
[ 1 Scheduling next appointment on  
at   
_ 
 
 
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VCU Clinical Study Protocol 
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[ 1 F/u stress echocardiogram Doppler (only at the 3 months visit) 
[ 1 Labs sent to HDL 
[ 1 Updating current medications 
[ 1 Assessment of compliance  with investigational drug performed by   
_ 
(used syringes
· returned syringes 
) 
[ 1 Assurance of compliance 
[ 1 Scheduling next appointment on 
at   
_ 
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D-HART2 Subject #  
Initials   
 Date on Enrollment   
_ 
 
 
Follow up visit: 12 weeks 
 
Date of  enrollment._---' Date of F/U visit   
_ 
 
 
Clinical conditions: (check all that apply) 
[ 1 heart failure symptoms, 
NYHA class (I IV},check [  1 if re-hospitalization 
[ 1 re-hospitalization for other cause (complete dedicated sheet) 
[ 1 death, check [ 1 if presumed cardiac death, check [  1 if sudden death 
[ 1 interruption of i11vestigational treatment (complete dedicated sheet) 
 
Notes   
_ 
 
 
Current symptoms and signs: (check all that apply) 
[ 1 shortness of breath; [  1 orthopnea;[   1 paroxysmal nocturnal dyspnea 
[ 1 chest pain;[  1 tir edness/fatigue; [  1edema (symptom); [  1 abdominal fullness 
On exam: [ 1 pitting edema,[  1 53 gallop, [  154 gallop, [  1JVD, [  1 rales 
 
Notes   
_ 
 
 
Past MedicalHistory: (changes vs prior - new diagnoses) 
[1  
;[1 
;[ 1 
·[1-------- 
Notes   
_ 
 
Body weight:  
kg/  
lb 
Blood Pressure:  
}  
mmHg 
 
Planning: (check all completed) 
[ 1 F/u echocardiogram Doppler 
Height:   
m/  
ft 
HR:  
min 
BMI:   
kgjm2 
[ 1 Nexfin and Bioelectrical impedance analysis 
[ 1 Dietary assessment 
[ 1 F/u cardiopulmonary  exercise test 


VCU Clinical Study Protocol 
Version 04052016 
[ 1 F/u stress echocardiogram Doppler (only at the 3 months visit) 
[ 1 Labs sent to HDL 
[ 1 Updating current medications 
[ 1 Assessment of compliance  with investigational drug performed by   
_ 
(used syringes
· returned syringes 
) 
[ 1 Assurance of compliance 
[ 1 Scheduling next appointment on 
at   
_ 
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42 
 
 
 
 
D-HART2 Subject#  
Initials   
 Date on Enrollment   
_ 
 
 
Follow up visit: 24 weeks 
 
Date of  enrollment_---' Date of F/U visit   
_ 
 
 
Clinical conditions: (check all that apply} 
[ 1 heart failure symptoms,  
NYHA class (1-?IV},check [  1 if re-hospitalization 
[ 1 re-hospitalization for other cause (complete dedicated sheet) 
[ 1 death, check [ 1 if presumed cardiac death, check [  1 if sudden death 
[ 1 interruption of investigational treatment (complete dedicated sheet) 
 
Notes   
 
 
 
Current symptoms and signs: (check all that apply) 
[ 1 shortness of breath; [  1 orthopnea;[   1 paroxysmal nocturnal dyspnea 
[ 1 chest pain;[  1 tiredness/fatigue; [  1edema (symptom);  [  1 abdominal fullness 
On exam: [ 1 pitting edema,[  1 53 gallop, [  154 gallop,[   1JVD, [  1 rales 
 
Notes   
 
 
 
Past MedicalHistory: (changes vs prior - new diagnoses) 
[1  
·[1  
;[ 1 
·[1-------- 
Notes   
 
 
Body weight:  
kg/  
lb 
Blood Pressure:  
}  
mmHg 
Height:   
m/  
ft 
HR:   
min 
BMI:   
kgjm2 
 
Planning: (check all completed) 
[ 1 F/u echocardiogram Doppler 
[ 1 Nexfin and Bioelectrical impedance analysis 
[ ] F/u cardiopulmonary exercise test 


VCU Clinical Study Protocol 
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43 
 
 
 
 
 
D-HART2 Subject#  
Initials   
 Date on Enrollment   
_ 
 
 
Unscheduled visit 
 
Date of enrollment  
,Date of F/U visit 
 
 
Clinicalconditions: (check all that apply) 
[ 1 heart failure symptoms, 
NYHA class (171V},check [  1 if re-hospitalization 
[ 1 re-hospitalization for other cause (complete dedicated sheet) 
[ 1 death, check [ 1 if presumed cardiac death, check [  1 if sudden death 
[ 1 interruption of investigational treatment (complete dedicated sheet) 
 
Notes   
_ 
 
 
Current symptoms and signs: (check all that apply) 
[ 1 shortness of breath; [  1 orthopnea;[   1 paroxysmal nocturnal dyspnea 
[ 1 chest pain;[] tiredness/fatigue; [ ] edema (symptom); [  ] abdominal fullness 
On exam: [ 1 pitting edema,[  1 53 gallop, [  154 gallop, [  1JVD, [ I rales 
 
Notes   
_ 
 
 
Past MedicalHistory: (changes vs prior - new diagnoses) 
[1  
;[1 
;[ 1 
·[1-------- 
Notes   
_ 
 
Body weight: 
kg/  
lb 
Blood Pressure:  }  
mmHg 
Height:   
m/  
ft 
HR:   
min 
BMI:   
kg/m2 
 
Planning: (check all completed) 
[ 1 Scheduling next appointment 
 
Notes  
_ 
 
 
 
 
 
 
 
 
 
 
 
 
 
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D-HART2 study 
Version April 7, 2015 
 
 
D·HART2 Study  EVENT FORM 
 
D-HART2 Subject   
 
 
Initials   
_ 
 
Hospitalization, date  
_ 
 
D  Acute Decompensated  Heart Failure as 
primary diagnosis  (see Protocol) 
D  Acute Coronary  Syndrome as primary 
diagnosis 
D  Arrhythmia  as primary diagnosis 
D  Acute Renal Failure 
D  Acute Respiratory Failure  (not due to 
heart failure) 
D  Sepsis, or Severe Infection 
D  TIA/Stroke 
D  Other (Specify   
_ 
 
Other events date  
_ 
(not leading to hospitalization) 
D  Injection site reaction 
D  Rash D Fever 
D Infection (requiring antibiotic tx D) 
D  NauseaNomiting/Diarrhea 
D  Others: (Specify  
) 
 
Interruption  of Treatment, 
date  
_ 
D  Mandated by protocol 
D  Decision made by patient 
Death, date  
_ 
 
D  Out of hospital and sudden 
D  In-hospital, associated with ventricular 
arrhythmia not secondary to other 
cardiac disease 
D  In-hospital, associated with acute 
cardiac issue 
D  In-hospital, associated with acute non 
cardiac issue (Specify  
) 
D  Other ( Specify   
_ 
D  Unknown 
 
 
 
ADVERSE EVENT: YES D NO  D 
 
 
ANTICIPATED D , NOT ANTICIPATED D 
 
 
SEVERITY: 
MILD 0; MODERATE 0; SERIOUS 0 
 
 
RELATED TO RESEARCH: 
UNRELATED 0; POSSIBLY 0; 
PROBABLY 0; DEFINITELY 0 
 
IF SERIOUS, UNANTICIPATED, and RELATED TO RESEARCH -7 
REPORT IMMEDIATELY TO THE PRINCIPAL INVESTIGATOR(s) 
 
 
 
Completed By, Name 
Signature  
Date 
 
Attach de-identified Notes from chart or notes (check  D if not available) 
 
 
Principal lnvestigator(s) 
Signature  
Date 
 
Prompt report to the IRB/DSMB needed D completed D by 
on   
_