Clinical trial NCT03797001
Conditions: Heart Failure, Systolic Inflammation
Keywords: heart failure inflammation anakinra exercise capacity
Sponsor: Virginia Commonwealth University
Start date: 2019-01-04; Completion date: 2024-07-22
Enrollment: 102 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
REDHART2 is a randomized, double-blinded, placebo-controlled trial to determine the effects of Anakinra on peak aerobic exercise capacity measured with a cardiopulmonary test after 24 weeks in patients with recently decompensated systolic heart failure and increased systemic inflammation.

Detailed description:
The REDHART2 (REcently Decompensated Heart failure Anakinra Response 2 Trial) study is a phase II clinical trial of anakinra or placebo to determine improvement in aerobic exercise capacity (by measuring maximal oxygen uptake (VO2)) in patients with recently decompensated systolic heart failure (HF). The recently completed pilot REDHART study showed anakinra treatment for 12 weeks led to a significant improvement in peak aerobic exercise capacity, whereas anakinra treatment for 2 weeks did not, and no significant changes were seen in placebo. The REDHART2 study is designed to expand and confirm the beneficial effect of sustained anakinra treatment (24 weeks) on peak VO2, and to explore the potential effect size on hospital readmissions for HF. The rationale of Interleukin-1 (IL-1) blockade with anakinra in heart failure stems from the evidence of a) reduced adverse cardiac remodeling and heart failure in animal models of acute myocardial infarction (AMI); b) reduced incidence of heart failure in patients with ST-segment elevation AMI; c) enhanced IL-1 activity in patients with heart failure, d) quenching of the acute inflammatory response in patients with acute decompensated heart failure, e) direct cardiodepressant effects of IL-1 in animal models, f) improved exercise capacity in pilot studies including patients with stable systolic heart failure, stable diastolic heart failure, and, recently decompensated systolic heart failure in the pilot REDHART study. Patients will be randomized 2:1 to active treatment, such that patients will be twice as likely to receive anakinra versus placebo.

Arms: arm 1: Anakinra subcutaneous injection, 100 mg daily for 24 weeks arm 2: Placebo subcutaneous injection, daily for 24 weeks
Interventions: intervention 1: Anakinra intervention 2: Placebo
Intervention descriptions: intervention 1: 100 mg subcutaneous injection, daily for 24 weeks intervention 2: subcutaneous injection, daily for 24 weeks

Protocol documents:
Prot_SAP_000.pdf: 
REDHART2 Clinical Protocol 
            
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Interleukin-1 Blockade in Recently 
Decompensated Heart Failure 
 
A Randomized Placebo-controlled Double-blinded Study 
 
 
The REDHART2 study 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigators: 
Antonio Abbate, MD, PhD; 
 Benjamin W. Van Tassell, PharmD  
 
 
 
Virginia Commonwealth University 
 
 
STUDY 
PROTOCOL 


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CHANGES TO PRIOR VERSION 
 
Prior version dated 10-25-2018 à new version 11-13-2018 
• 
Personnel updated in the DSMB Charter per NHLBI Liaison request (see also section 8.6, and 
DSMB charter); 
• 
Modified BNP criteria to include also NT-proBNP criteria – according to the European Society 
of Cardiology 2016 Heart Failure Guidelines (Ponikowski P et al. Eur Heart J 2016;37:2129-
2200. 
 
Prior version dated 11-13-2018 à new version 01-23-2019 
• 
Section 5.2:  Addition of the IPAQ questionnaire to the quality of life assessments. It will be 
administered at baseline, 6, 12 and 24 weeks to assess patient perception of changes 
• 
Section 6.3:  Changed exclusion criteria from “prior or current malignancy” to just “current 
malignancy receiving targeted therapy”. 
• 
Section 7.1: We clarify that the patient may need to come for additional visits between the 
pre-specified clinic visits for assessment and/or drug dispensing. 
• 
Section 7.7:  Addition of the IPAQ questionnaire to the list of study activities and clarification 
on when a physician will be alerted to review a participant’s chart based on questionnaire 
responses. 
• 
Section 11.3.2:  Clarification on when cases with missing CPX data will result in omission 
from efficacy analysis. 
DSMB Charter 3.f.:  Clarification of the Biostatistician as Voting Member of the DSMB. 
 
Prior version dated 01-23-2018 à new version 03-14-2019 
• 
Section 5.2:  Updated echocardiography description to include 6 and 12 week ECHO 
timepoints 
• 
Sections 7.5 and 7.9:  Updated echocardiography paragraph and procedure table to include 
ECHOs at weeks 6 and 12 
• 
Section 7.8: Removed “troponin I” from text as biomarker being tested 
 
Prior version dated 03-14-2019 à 08-27-2019 
• 
Section 6.3: Clarified exclusion criterion related to CRT and valve surgery (‘Cardiac 
resynchronization therapy (CRT) during index hospitalization, or planned CRT or valve 
surgeries within the following 6 months’). 
• 
Section 7.9: Corrected the time window for Visit 4 to 168±14 days (24±2 weeks). 
• 
Section 8.3.1: We have updated the AE section to list the most common risks related to 
anakinra or completion of the study procedures. 
• 
Section 10.1: We clarified that arthritis is a manifestation of hypersensitivity reaction that can 
demand discontinuation of the drug. 
 
Prior version dated 08-27-2019 -> 10-07-2019 
• 
Section 10.1: Specified the rules for restarting study drug after it has been suspended 
• 
Section 10.2: Distinction between withdrawing treatment and withdrawing from the study and 
clarification of how long each patient will be followed for safety reasons and how the data will 
be used after each type of withdrawal 
• 
Section 11.3.2: Clarification of primary method for handling missing data (LOCF) 
 
 


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Temporary Amendment in response to COVID19 Pandemic Emergency 03/27/2020 
• 
Enrollment has been halted on 03/17/2020. 
• 
All patients were instructed to interrupt treatment on that date. 
• 
Follow up provided to assess for any research-related adverse events up to 6 months. 
• 
Adjudication for events after 03/17/2020 will not be completed in consideration of the 
dynamic changes in the clinical care, challenges in diagnosis ascertainment, and possibility 
of COVID19 contributing to excess cardiovascular events.    
Resuming clinical research operations during COVID19 pandemic change in 
Protocol version dated 10-07-2019 à 04-24-2020 
• 
Resume screening and enrollment when Governor of Virginia and VCU / VCU Health 
authorize resumption of elective clinical procedures.  
• 
Change in exclusion criteria, adding a criterion related to COVID19: 
o Evidence of COVID19 within the last 60 days or recent (21 days) exposure to close 
personal contact. (Section 6.3, bullet 9). 
 
Changes to Key Personnel and DSMB Charter 
• 
Amy Ladd, PhD, has taken on a new position as Associate Director of the Pauley Heart Center 
and will no longer serve as Regulatory Coordinator for the REDHART2 study; Dr. Ladd will 
however serve as DSMB Liaison to the study instead of Dr. Christine DeWilde, who has left 
VCU as June 10, 2020. 
 
 


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1) 
Key Personnel 
2) 
Protocol summary 
3) 
Schematic of study design 
4) 
Description 
5) 
Objectives 
5.1  
Primary Endpoint(s) 
5.2 
Secondary Endpoints 
6) 
Enrollment in the study 
6.1   
Screening 
6.2 
 
Inclusion criteria 
6.3   
Exclusion criteria 
6.4 
 
Alternate consent 
7) 
Study design 
7.1   
Clinical assessment 
7.2 
 
Randomization and allocation concealment 
 
 
7.3   
Investigational treatment  
7.4 
 
Cardiopulmonary exercise test 
7.5 
 
Echocardiogram 
7.6 
 
Non-invasive hemodynamics and bio-impedance 
7.7 
 
Questionnaires 
7.8 
 
Biomarkers  
7.9 
 
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 
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-adjudication 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) 
Statistical considerations 
11.1   
Study hypothesis 


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11.2   
Sample size consideration 
12.3   
Statistical analysis 
 
 
 


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Appendix: DSMB Charter 
 
1)  
KEY PERSONNEL 
 
Please refer to the IRB Roster and Delegation Log for a complete personnel list  
 
Name  
 
 
 
Role  
 
 
Institution/ Division 
 
Antonio Abbate, MD/PhD  
Medical Responsible PI 
VCU, Cardiology  
Benjamin Van Tassell, PharmD   Study Operation PI   
VCU, School of Pharmacy  
 
Salvatore Carbone, PhD 
 
Clinical Trial Operations 
VCU, Cardiology 
Ross Arena, PhD 
 
 
CPX Core Lab 
 
University of Illinois, Chicago 
Robin Sculthorpe, PharmD  
Investigational Pharmacy VCU, School of Pharmacy 
Juan Lu, PhD 
 
 
Biostatistician 
 
VCU, Biostatistics 
 
Dominick Angiolillo, MD 
 
DSMB Chair  
     University of Florida, Cardiology 
Gonzalo Bearman, MD 
 
DMSB member 
 
VCU, Infectious disease 
Ramesh Kundur 
 
 
DSMB member 
   Virginia Cardiovascular Specialists 
Brant Ward, MD 
 
 
DSMB member 
      
VCU, Immunology 
Robert Perera, PhD  
 
DSMB member 
 
VCU, Biostatistics, CCTR  
Amy Ladd, PhD 
 
 
DSMB liaison 
 
VCU, Pauley Heart Center  
 
 
Abbreviations: DSMB=Data Safety Monitoring Board 
 
 
 


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2) 
 PROTOCOL SUMMARY 
 
Title: 
Interleukin-1 Blockade in Recently Decompensated Heart 
Failure  
 
Population: 
102 patients (age >21 years) with a clinical diagnosis of 
systolic heart failure, and recent (within 2 weeks of discharge) 
hospitalization for heart failure  
 
Site(s): 
Virginia Commonwealth University, Richmond, VA 
 
Study Duration: 
 
40 months 
 
Description:   
Phase II clinical trial of Anakinra (or Placebo) (2:1 allocation) 
for the treatment of patients with recently decompensated 
systolic (LVEF≤40%) heart failure and increased systemic 
inflammation (CRP>2 mg/L) 
 
 
 
 
 
Objectives: 
To determine the effects of Anakinra (or Placebo) on peak of 
aerobic exercise capacity (peak VO2) measured with a 
cardiopulmonary test after 24 weeks  
 
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 24 weeks 
 
 
 
 
Estimated Time to  
Complete Enrollment:   36 months 
 
Estimated Time to: 
 
First patient in: 
6-12 months from funding 
 
Last patient in: 
34 months from first patient enrolled 
 
Last patient out: 
40 months from first patient enrolled  
 
 


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3)  
SCHEMATIC OF STUDY DESIGN 
 
 
 
4)  
DESCRIPTION 
 
The REDHART2 (REcently Decompensated Heart failure Anakinra Response Trial 2) 
study is a phase II clinical trial of anakinra or placebo to improve aerobic exercise capacity 
in patients with recently decompensated systolic heart failure (HF).  
 
The recently completed pilot REDHART study, supported by a R34 NHLBI pilot clinical 
trial grant randomly assigned 60 patients with recently decompensated systolic heart 
failure to one of 3 strategies: 1) short-term treatment with anakinra for 14 days; 2) longer-
term treatment with anakinra for 12 weeks; 3) placebo for 12 weeks. An additional group 
of eligible patients who declined participation in the study was enrolled in an observational 
study to evaluate the rate of HF hospitalizations. Anakinra treatment for 12 weeks led to 
a significant improvement in peak aerobic exercise capacity (peak VO2), whereas 
anakinra treatment for 2 weeks did not. No significant changes were seen in placebo. The 
hospital readmission rate at 6 months was 5% in anakinra 12-week treatment group, 30% 
in the placebo group, 32% in the anakinra 2-week group, and 35% in the observational 
group of eligible patients who were not randomized to treatment.  
 
The REDHART2 study is designed to expand and confirm the beneficial effect of 
sustained anakinra treatment (24 weeks) on peak VO2, and to explore the potential effect 
size on hospital readmissions for HF. 
 
The rationale of Interleukin-1 (IL-1) blockade with anakinra in heart failure stems from the 
evidence of a) reduced adverse cardiac remodeling and heart failure in animal models of 


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acute myocardial infarction (AMI); b) reduced incidence of heart failure in patients with 
ST-segment elevation AMI; c) enhanced IL-1 activity in patients with heart failure, d) 
quenching of the acute inflammatory response in patients with acute decompensated 
heart failure, e) direct cardiodepressant effects of IL-1 in animal models, f) improved 
exercise capacity in pilot studies including patients with stable systolic heart failure, stable 
diastolic heart failure, and, recently decompensated systolic heart failure in the pilot 
REDHART study.  
 
5) 
OBJECTIVES 
 
The Objective of REDHART2 is to study the effects of IL-1 blockade with anakinra on 
parameters of aerobic exercise capacity (peak VO2) at cardiopulmonary exercise test 
(CPX) after 24 weeks of active treatment, as well as the effects of anakinra on 
inflammatory biomarkers, structural and functional echocardiographic data, and non-
invasive hemodynamics. 
 
5.1 
Primary Endpoint(s) 
 
Placebo-corrected changes in peak VO2 at CPX after 24 weeks of treatment will be 
considered the primary endpoint. This will compare patients treated with anakinra (N=68) 
vs placebo (N=34), 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 
(Ross Arena, PhD).  
 
 
 
5.2 
Secondary Exploratory Endpoints 
 
Secondary exploratory endpoints will include parameters measured at CPX, 
echocardiography, non-invasive hemodynamics, as well as biomarkers, and clinical 
outcomes. 
 
Additional CPX parameters: secondary endpoints include changes in peak VO2 at earlier 
endpoints (6 and 12 weeks), and changes in other CPX variables such as ventilatory 
efficiency (ventilation-carbon dioxide elimination slope [VE/VCO2 slope] and oxygen 
utilization efficiency slope [OUES]), anaerobic threshold, and peak oxygen pulse at 6, 12, 
and 24 weeks.  
 
Echocardiography: secondary endpoints include measuring left ventricular end-diastolic 
and end-systolic volumes, ejection fraction, stroke volume estimated by left ventricular 
outflow tract velocity-time integral, measures of myocardial relaxation at tissue Doppler 
E’, and estimate of left ventricular filling pressure using E/E’ ratio at baseline, 6, 12 and 
at 24 weeks. 
 
Non-invasive hemodynamics: secondary endpoints include estimates of arterial 
elastance (Ea), a measure of afterload, end-systolic elastance (Ees), a measure of load-
independent contractility also defined as end-systolic pressure-volume relationship, 


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ventriculo-arterial coupling is defined as the ratio of Ea to Ees, at 6, 12 and 24 weeks. The 
hemodynamic assessment will be conducted with echocardiography and non-invasive 
blood pressure measuring. 
 
Quality of life assessment: the Duke Activity Status Index (DASI), the Kansas City 
Cardiomyopathy Questionnaire (KCCQ), the International Physical Activity questionnaire 
(IPAQ-SF) and the Patient Health Questionnaire-9 (PHQ-9) will be administered at 
baseline, 6, 12 and 24 weeks to assess patient perception of changes.  
 
Biomarkers: Blood will be collected at each visit (baseline, 6, 12, and 24 weeks) and 
analyzed for a panel of complete blood cell count with differential, basic metabolic panel, 
high sensitivity C- reactive protein (CRP), and NT-proBNP. In addition, 5 – 10mL of blood 
will stored frozen for later batch analysis and phenotyping of the inflammatory response .   
 
Clinical outcomes: the incidence of death (cardiac and non-cardiac), hospitalizations (for 
HF, for other cardiac causes not related to HF, for non-cardiac reasons), medications use 
(number of HF medications, doses) will be recorded at each visit in every patient. 
Adjudication of events for research purposes will be performed by an ad hoc committee 
blinded to treatment allocation, based on all the data available in the chart including notes, 
pre-formatted sheets, laboratory and imaging modalities. 
 
6) 
ENROLLMENT IN THE STUDY  
 
6.1 
Screening 
 
Patients will be screened through one of the following routes: 
 
● Patients admitted to the main VCUHealth hospital in Richmond, VA  
Our hospital receives >1000 hospitalizations per year for acute decompensated 
systolic heart failure, of which, we anticipate approximately 30 per month (~36%) will 
be preliminary eligible for REDHART2 participation. These subjects may be identified 
by multiple means: direct patient contact by the co-PIs or one of the co-investigators 
during their regular clinical practice, referral to the research team by coworkers or by 
the HF Navigator Nurse (a program set to establish post-discharge follow up care for 
patients), manual screening of the new daily admission list on the electronic medical 
record by research team, and an automatic alert system generated by the electronic 
medical record that identifies all new cases that meet pre-specified criteria (i.e., 
receiving intravenous diuretics, BNP>200 ng/mL, edema on chest radiography). We 
have been using these strategies for clinical enrollment over the past 3 years. While 
the system may not be specific (many false positive alerts – screen failures) it is very 
sensitive with virtually no HF-patient being lost to evaluation. 
 
● Patients admitted to neighboring hospitals in Virginia  
Being the only academic medical center in Central Virginia we receive a large number 
of referrals for inpatient transfers or for outpatient evaluations, i.e., after acute 
decompensation, especially in underserved population such as the uninsured. In the 


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recent years, VCUHealth has partnered with the Community Memorial Hospital in 
South Hill, VA (a 200-bed hospital in the southern corridor of I-85) and with the Virginia 
Medical Group in Colonial Heights, VA (including a specialized cardiac center with 7 
specialists). 
 
● Post-hospital discharge clinics 
We have implemented a dedicated clinic for heart failure patients to be seen in clinic 
within 1 week of hospital discharge as part of the HF Navigator program. This clinic is 
staffed by a nurse practitioner and a nurse, and supervised by a HF specialist. The 
research team has access to the daily scheduling list and thus has access to those 
patients that may have been missed during hospitalization or that may be following up 
after hospitalization at a different hospital. 
 
6.2 
Inclusion Criteria 
 
All 6 criteria need to be met for enrollment of the patient in the study 
1. Primary diagnosis for hospitalization is decompensated heart failure established as 
the finding at admission of both conditions listed below: 
o dyspnea or respiratory distress or tachypnea at rest or with minimal 
exertion; 
o evidence of elevated cardiac filling pressure or pulmonary congestion (at 
least one of the conditions must be met): 
o pulmonary congestion/edema at physical exam OR chest X-Ray; 
o plasma BNP levels ≥200 pg/mL or proBNP ≥600 pg/ml; 
o invasive measurement of left ventricular end-diastolic pressure >18 mmHg or 
of pulmonary artery occluding pressure (wedge) >16 mmHg. 
2. The patient has a prior documentation of impaired left ventricular systolic function 
(ejection fraction ≤40%) at most recent assessment by any imaging modality (within 
12 months). 
3. The patient is now clinically stable, euvolemic, and meets standard criteria for 
hospital discharge as documented by all the 3 conditions listed below: 
o absence of dyspnea or pulmonary congestion/distress at rest; 
o absence of pitting edema in the lower extremities, or in any other region; 
o stable hemodynamic parameters (blood pressure, heart rate). 
4. The patient is of age ≥21 years old, and is willing and able to provide written 
informed consent. 
5. The patient is willing and able to comply with the protocol (i.e., self-administration, 
or exercise test). 
6. The patient has screening high sensitivity plasma C-reactive protein levels (hsCRP) 
>2 mg/L.  
 
6.3 
Exclusion Criteria 
 
Subjects will not be eligible if they meet any one of the following 15 exclusion 
criteria. 
1. The primary diagnosis for admission is NOT decompensated heart failure, including 


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diagnosis of acute coronary syndromes, hypertensive urgency/emergency, tachy- or brady-
arrhythmias. 
2. Concomitant clinically significant comorbidities that would interfere with the execution or 
interpretation of the study including but not limited to acute coronary syndromes, 
uncontrolled hypertension or orthostatic hypotension, tachy- or brady-arrhythmias, acute or 
chronic pulmonary disease or neuromuscular disorders affecting respiration. 
3. Cardiac resynchronization therapy (CRT) during index hospitalization, or planned CRT or 
valve surgeries within the following 6 months. 
4. Previous or planned implantation of left ventricular assist devices or heart transplant. 
5. Chronic use of intravenous inotropes. 
6. Recent (<14 days) use of immunosuppressive or anti-inflammatory drugs (including oral 
corticosteroids at a dose of prednisone equivalent of 0.5 mg/kg/day but not including inhaled 
or low dose oral corticosteroids or non-steroidal anti-inflammatory drugs). 
7. Chronic inflammatory disorder (including but not limited to rheumatoid arthritis, systemic 
lupus erythematosus). 
8. Active infection (of any type), including chronic/recurrent infectious disease (i.e. HBV, HCV, 
and HIV/AIDS) – but excluding HCV+ with undetectable plasma RNA. 
9. Evidence of COVID19 within the last 60 days or recent (21 days) exposure to close personal 
contact. 
10. Current malignancy (excluding carcinoma in situ [any location] or localized non-melanoma 
skin cancer) receiving targeted therapy 
11. Any comorbidity limiting survival or ability to complete the study. 
12. Stage V kidney disease or on renal-replacement therapy. 
13. Neutropenia (<1,500/mm3 or <1,000/mm3 in African-American patients). 
14. Pregnancy. 
15. Angina, hypertension, arrhythmias, electrocardiograph (ECG) changes, or other non-cardiac 
limitations (i.e., peak respiratory exchange ratio VCO2/VO2 [RER]<1.0, reflecting sub-
maximal test) that limit maximum exertion during CPX obtained during the baseline testing. 
16. Hypersensitivity to Kineret or to E. coli derived products. 
 
 
6.4 
Alternate Consent Group 
 
The subjects who are eligible to enroll in the study but decline to participate will be asked 
to sign an alternate consent that allows the research team to access the electronic health 
record for 6 months after the enrollment and make one follow up telephone call at the end 
of the 6 months period if needed to ascertain vital status and incidence of new event. This 
alternate consent group will provide an estimate of the event rate in a group free of other 
research interventions. 
 
7) 
STUDY DESIGN 
 
We designed a single center, placebo-controlled, double-blinded randomized study of 
Anakinra in patients with recently decompensated systolic heart failure. Patients will 
undergo 
baseline 
clinical 
assessment, 
CPX, 
echocardiogram, 
non-invasive 
hemodynamics, and blood tests for biomarkers. The CPX, the echocardiogram, non-
invasive hemodynamics and blood tests will be repeated at each visit (6, 12 and 24 
weeks). See Schematic of Study Design. 


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7.1 
Clinical Assessment 
 
A physician on the research team will conduct a thorough clinical assessment and review 
of the chart at time of enrollment to evaluate for all inclusion and exclusion criteria. Some 
of the information needed to determine eligibility may be missing, in which case additional 
testing would not be performed prior to consenting, and it would be completed only after 
the patient provided informed consent and it would be charged to the study charge 
account.  
 
A clinical evaluation will also be completed at Visit 1.5 (14±3 days) to determine tolerability 
of the treatment and side effects, medication reconciliation and completion of a complete 
blood cell count with differential and basic metabolic panel.  
 
Visits 2 (6±1 weeks), 3 (12±1 weeks) and 4 (24±2 weeks) will include a clinical safety 
evaluation as well as assessment of the endpoints. Additional visits may be scheduled as 
needed. 
 
 
 
7.2 
Randomization and Allocation Concealment 
 
Randomization will be handled by the investigational pharmacy using a dedicated 
randomization algorithm. Access to randomization log will be restricted and allowed only 
on an emergency basis, or as requested by the Data Safety and Monitoring Board 
(DSMB), or at the end of the study after event adjudication and the database has been 
locked.  


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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. The investigators will also be kept blinded on all inflammatory 
biomarkers by limiting access to results if obtained during the study (i.e., CRP) and by 
analyzing all other markers (i.e., cytokines) in a single-batch at the end of the study.  
 
7.3 
Investigational treatment 
 
Anakinra or placebo (vehicle) dispensed in small syringes (0.67 mL) will be provided to 
the patient for daily subcutaneous injection. The syringes for anakinra or placebo will be 
undistinguishable. This will be achieved by assuring that the syringes provided by the 
supplier (Swedish Orphan Biovitrum, Stockholm, Sweden) are labeled only by a number 
or other code. If the supplier is unable to provide placebo syringes that are 
indistinguishable, then the pharmacist will transfer the content of each syringe into an 
unlabeled syringe which will then be marked in a way that neither the patient nor the 
physician will be able to distinguish between anakinra or placebo.  
 
After completion of all baseline testing, patients will be given a 14-day supply of anakinra 
or placebo. Additional syringes from the initial batch may be given to assure that the 
patient has a sufficient number to last until the 14-day follow up visit, which will be 
scheduled within 14±3 days after baseline visit. Patients will also receive instruction from 
the investigators regarding self-injection technique. The next set of syringes (for another 
4±1 weeks of treatment) will be given to the patient at the time of 14-day follow-up visit. 
If needed, the first 2 sets of syringes (6±1 weeks) may be dispensed at the same time. A 
third set of syringes (for another 6±1 weeks of treatment) will be given at time of the 6 
weeks visit. A final set of syringes (for another 12±2 weeks) will be given at the 12-week 
visit.  
 
Adherence to the investigational treatment will be addressed by count of syringes and 
completion of all study visits. All concomitant medications will also be recorded at each 
clinic visit. Patients in the study will receive guidelines-based medical treatments as 
indicated. Such treatments may include diuretics, b-adrenergic receptor blockers, 
angiotensin converting enzyme inhibitors, angiotensin receptor blockers, neprilysin 
inhibitors, aldosterone blockers, isosorbide dinitrate, hydralazine, digoxin, ivabradine, 
aspirin, and statins. For such medications, we will record the start date and the daily dose, 
and any change in dose or suspension. 
 


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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 treatments, 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). 
 
7.4  
Cardiopulmonary Test  
 
Upon completion of screening/enrollment, all subjects will be scheduled for the CPX. A 
physician-supervised maximal exercise test will be administered using a metabolic cart 
(UltimaCardioO2, MGC Diagnostics, Saint Paul, MN) that is interfaced with a treadmill. A 
conservative ramping treadmill protocol will be used with workload increases of 0.3 
metabolic equivalents every 30-seconds. 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 then be briefed regarding the protocol and will be requested to exercise 
to volitional fatigue. Twelve-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 M2, SunTech Medical, 
Morrisville, NC). 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 during the final 30 seconds defines peak oxygen 
consumption (VO2 peak in mL•kg-1•min-1). The ventilatory equivalents method will be used 
to determine VO2 at the ventilatory anaerobic threshold. Ten second averaged VE and 
VCO2 data, from the initiation of exercise to peak, will be 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).  Peak Respiratory Exchange Ratio 
(VCO2/VO2) will be used for determining maximal to near maximal effort.  A peak 
RER≥1.10 is well accepted as a criterion for maximal effort and a peak RER≥1.0 is 
considered a minimal acceptable threshold. Subjects with RER<1.0, reflecting 
deconditioning as a non-cardiac cause of interruption of exercise, will be excluded. 
American Heart Association guidelines for exercise testing contraindications and 
termination criteria will be followed.  
 
Upon completion of exercise testing, the results of the CPX 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 6 weeks (Visit 3, 42±7 days) and 12 weeks (Visit 4, 84±7 days) and 24 
weeks (Visit 5, 168±14 days) of treatment with Anakinra or placebo. At each visit, subjects 
will undergo a brief physical exam and repeat exercise testing. Raw data from the 
cardiopulmonary test will be electronically transferred, free of patient identifiers, to the 
Core Lab at the University of Illinois, Chicago, IL. 


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7.5  
Doppler Echocardiogram 
 
Prior to initiation of treatment, all subjects will undergo a transthoracic Doppler 
echocardiogram to measure left ventricular diastolic and systolic volumes, transmitral flow 
Doppler spectra, mitral and tricuspidal valve annulus tissue Doppler spectra, and 
tricuspidal annulus plane systolic excursion, and global longitudinal strain analysis, 
according to the recommendations of the American Society of Echocardiography. The 
echocardiogram will be repeated at visits 2-4. All images and loops will be acquired in an 
electronic format and measurements will be performed at the end of the study by 2 
operators blinded to treatment allocations. The average of the two measurements will be 
used for measures differing ≤10%, whereas those with >10% were re-reviewed and 
discussed by the 2 operators resulting in a consensus. 
 
7.6  
Non-invasive hemodynamics and Bio-Impedance  
 
The non-invasive hemodynamic assessment will be performed using an automated blood 
pressure cuff measurement in the arm (V100 Dinamap, GE, Boston, MA, United States) 
and concomitant measurements from the echocardiography. Patients will be asked to 
seat, with both feet flat on the floor, knees bent at 90-degree angles and hands resting 
on the homolateral knee for 5 minutes. Arterial elastance (Ea) is a measure of LV 
afterload, including both pulsatile and non-pulsatile components. Ea is defined as the 
negative slope of left ventricular end-systolic pressure/end-diastolic volume relationship 
and was calculated as left ventricular end-systolic pressure/stroke volume. LV end-
systolic pressure is estimated as 0.9 x brachial artery systolic blood pressure measured 
with an arm cuff. End-systolic elastance (Ees) is a measure of load-independent LV 
contractility and is defined as the LV end-systolic pressure-volume relationship. Ees is 
calculated as LV end-systolic pressure / LV end-systolic volume. Ventriculo-arterial 
coupling is defined as the ratio of Ea to Ees.  
 


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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. 
 
7.7  
Questionnaires 
 
Prior to each CPX, subjects will complete the Kansas City Cardiomyopathy Questionnaire 
(KCCQ), the Duke Activity Status Index (DASI) questionnaires, and the Patient Health 
Questionnaire-9 (PHQ-9). The KCCQ is a 20-question graded questionnaire that has 
been extensively validated to measure impairment in quality of life in patients with HF. 
The questions are designed to measure a wide range of physical, emotional, social, and 
mental domains that contribute to overall quality of life. (Link to KCCQ  through FDA 
website 
and 
direct 
access 
to 
PDF;  
https://www.fda.gov/downloads/MedicalDevices/ScienceandResearch/MedicalDeviceDe
velopmentToolsMDDT/UCM581761.pdf 
/ 
http://columbiaheartvalve.org/sites/default/files/PDF-Kansas-City-Questionaire.pdf ). 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 (https://www.mdcalc.com/duke-
activity-status-index-dasi). The IPAQ-short form (IPAQ-SF) is a 7-question questionnaire 
that allows the estimation of daily physical activity by asking the subjects about duration 
and intensity of their daily physical activity. Lastly, subjects will also be asked to complete 
the 
Patient 
Health 
Questionnaire-9 
(PHQ-9) 
(https://www.phqscreeners.com/sites/g/files/g10049256/f/201412/PHQ-9_English.pdf), a 
nine question standardized test which has been validated in patients with heart failure. 
Patients who score question 9 on the PHQ-9 as one or higher or have a total score ≥ 20 
will prompt the team to alert a study team physician for patient evaluation. 
 
7.8  
Biomarkers assessment 
 
Blood samples will be taken from a peripheral vein at time of screening, baseline visit, 2, 
6, 12 and 24 weeks, and used for analysis of complete cell count with differential, 
comprehensive metabolic profile [including inflammatory markers] and cardiac specific 
biomarkers [NT-proBNP]. Testing will be performed at VCUHealth, with the exception of 
research-only inflammatory markers, for which the samples will be processed and stored 


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for single batch analysis at the end of the study. Research-only biomarkers will not be 
used for clinical care and will not be shared with the patient nor with the referring 
providers. 
 
7.9  
Study Schedule 
 
 
Screening (
≤14 days 
from 
discharge) 
Visit 1 
(Baseline) 
Visit 1.5 
(14±3 
days) 
Visit 2 
(42±7 
days) 
Visit 3 
(84±7 
days) 
Visit 4 
(128±14 
days) 
Visit location 
Hospital 
or CRSU 
CRSU 
CRSU*** 
CRSU 
CRSU 
CRSU 
Screening * 
X 
 
 
 
 
 
Consent 
X 
 
 
 
 
 
Clinical assessment ** 
X 
X 
X 
X 
X 
X 
Medication reconciliation 
X 
X 
 
X 
X 
X 
Investigational therapy 
dispensing 
 
X 
 
X 
X 
 
CPX 
 
X 
 
X 
X 
X 
Echocardiogram 
 
X 
 
X 
X 
X 
Non-invasive 
hemodynamics/  
Bio-Impedance 
 
X 
 
X 
X 
X 
Safety labs  
    (CBC, renal function) 
 
X 
X 
X 
X 
X 
Biomarkers  
    (hsCRP, NTproBNP) 
 
X 
 
X 
X 
X 
*Includes hsCRP - Pregnancy test will be performed, if indicated 
**Clinical assessment includes history and physical, medication reconciliation, and 
assessment of adverse events 
***Visit 1.5 may happen in the CRSU or in other clinics with the patient’s own provider. 
 
7.10  Cost coverage analysis  
 
A cost coverage analysis has been conducted by the team: all tests listed in the Schedule 
of Events will be considered ‘research’ and paid for with the study funds. Any additional 
tests (not listed above) that is necessary for patient care will be considered standard of 
care and will be billed to the patient or the insurer. 
 
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 


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contact the research team at any time with concerns or any perceived changes in their 
healthcare status. 
 
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 considered until return to a value of ANC>1,800/mm3 (or >1,000/mm3 if patient is 
African-American). Cessation of Anakinra will not be mandatory. 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 


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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 AE” should be captured on the appropriate AE form. Information to be 
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. 
 
Most common AEs expected with Anakinra are: 
 
Anakinra, recombinant human IL-1 receptor antagonist, has been FDA-approved for the 
treatment of inflammatory disorders such as rheumatoid arthritis for many years. It has 
been used in more than 150,000 patients with rheumatoid arthritis with a favorable risk 
profile. 
 
Anakinra is given as a subcutaneous injection of 100 mg (0.67 mL) daily or every other 
day in patients with severe impairment in renal function. There is no loading dose and no 
dose-adjustments needed with age, weight, or liver failure. Drug-to-drug interactions have 
not been reported. There are no known toxic effects of anakinra in pregnancy (category 
B), however pregnant women will be excluded from this research study.  
 
In a study following patients with rheumatoid arthritis for up to 3 years, anakinra was 
generally well-tolerated with few side effects.  
 
The most likely side effects associated with the use of anakinra include: 
- Injection site reaction (>10%, up to 50%, but infrequently leading to interruption of 
treatment <5%) 
- Serious Infection (1.8% in anakinra vs 0.6% in placebo in clinical trial of rheumatoid 
arthritis);  
- Headache, generally mild and self-limiting (1-10%); 
- Diarrhea, generally mild and self-limiting (1-10%); 
- Nausea, generally mild and self-limiting (1-10%) 
- Neutropenia (rare, <1%, reversible). 
- Hypersensitivity reaction (rash, anaphylaxis, arthritis)(rare, 1-2%). 
 
The injection site reactions are by far the most common adverse reaction. The reactions 
present as painful irritation/redness at the site of injection usually occurring 1-2 weeks 
after start of treatment. They are responsive to topical steroids and/or antihistamine 
therapy. The reactions are common (up to 50%) but are rarely cause of discontinuation 
of therapy (<5%). 


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Despite the increase in risk of serious infection with anakinra, such events are rather rare 
(<2% during chronic treatment). Anakinra is indeed not associated with an increase in 
infection-related mortality, nor associated with opportunistic infection. Anakinra may, 
however, mask some of the signs of infection such as fever and leukocytosis, and 
therefore education on the need to be aware of risk of infection is warranted. Nevertheless 
when given to patients with sepsis in the setting of a clinical trial anakinra had no negative 
effect on survival. While anakinra is postulated to prevent inflammatory-based 
hypercoagulability, anakinra has not been associated with any appreciable bleeding risk 
in pre-clinical, clinical, or post-marketing surveillance (including animal studies at >100X 
the clinically relevant dose). 
 
There is a social/psychological risk in this study of breaching confidentiality and having a 
patient’s diagnosis discovered. The likelihood of this occurring, however, is very low, and 
not different from the patient receiving clinical care at the same time. The number of study 
visits could impact some aspects of the patients’ social lives. Loss of confidentiality is a 
potential risk. However, except when required by law patients will not be identified by 
name, social security number, address, telephone number or any other personal 
identifier. Study related tests may be reported to the NHLBI but patients will not be 
identified. 
 
The following risks pertain to the different tests that are being used for monitoring the 
treatment responses: 
 
• ECG: no greater than minimal risk. 
• Blood draw: minor bleeding (rare) and infection (extremely rare) at puncture site 
• Cardio pulmonary exercise test (CPX): very low risk of rhythm disturbance of the heart 
and syncope. With adequate medical supervision extremely low risk of serious 
complication. A physician will be present during the CPX. 
• Bioimpedance analysis: no greater than minimal risk 
• Echocardiogram: no greater than minimal risk. 
• Questionnaires: the PHQ-9 is a depression screening tool that includes questions that 
may be upsetting to some patients 
 
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 that require minimal or no treatment and do not interfere with the 
patient’s daily activities. 
● Moderate: events that 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 


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(i.e. does not include a reaction that might have caused death had it occurred in a 
more severe form). 
 
A dedicated AE form will be used to capture of pertinent information about the event. 
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. 
 
 
8.3.2 Serious Adverse Events 
 
A serious adverse event (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 


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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 investigators becoming aware of the event. AEs (serious or non-serious) 
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. The investigator will always provide an 
assessment of causality at the time of the initial report. 
 
 
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, 5 voting members (see DSMB 
Chapter in the Appendix), chaired by a cardiologist from University of Florida in 
Jacksonville, Florida, who has extensive clinical trial experience, and including an 
infectious disease specialist. an immunologist, a heart failure specialist, and a 
biostatistician. The composition of the DSMB will have been reviewed and 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 


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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 will have 
been approved by the VCU IRB prior to study initiation. 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). 
 
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 


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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-adjudication committee 
 
The event-adjudicating committee will be composed of professionals from different 
backgrounds including general cardiologists, cardiologists with training in heart failure, 
general internal medicine specialists, emergency medicine specialists, and infectious 
disease specialists. Each event will be reviewed by at least 3 members. Agreement will 
be necessary for all 3 members, disagreement will be resolved with discussion of the 
case, followed by voting of at least 5 members if disagreement remains. The committee 
will meet at the end of the study and review all adjudicated 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); 
- 
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); 
- 
Outpatient worsening of heart failure (defined as the need for intravenous diuretic 
treatment or need for increase in oral diuretic dose, or new prescription for first or add-
on diuretic);  
- 
Acute myocardial infarction, as defined by the WHO consensus statement 4th edition; 
- 
Unstable angina, or need for coronary revascularization; 


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- 
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 may temporarily 
suspend treatment at any time in patients experiencing an adverse event considered 
possibly, probably, or definitely to related to the study drug. The study drug may then be 
restarted upon resolution of the adverse event unless the adverse event is considered 
likely to reoccur or the patient is unwilling to restart treatment. 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) Systemic infection (sepsis)*; 
2) Surgery*; 
3) New diagnosis of cancer that requires local or systemic treatment; 
4) Hypersensitivity reaction (rash, anaphylaxis, arthritis); 
5) Severe injection site reactions*; 
6) Need for immunosuppressant therapy; 
7) Acute myocardial infarction or stroke*; 
8) Severe neutropenia (<1,000/mm3) if there is a perception of increased infectious risk 
by the provider*. 
* treatment may be restarted by investigators after the condition is resolved 
 


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10.2 Handling of Withdrawals 
 
Patients who permanently stop study injection (whether due to adverse event, investigator 
decision, or patient decision) will be considered withdrawn from treatment. 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. Patients who have 
withdrawn from treatment will also be followed for the complete duration of 6 months 
follow-up to monitor for safety. Loss to follow-up can occur due to patients’ withdrawal or 
unreported death. 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.  
 
Patients will be considered withdrawn from study if they express a desire to stop active 
participation. However, the investigators will continue to record adverse events, 
hospitalizations, and survival in these patients from the electronic medical record in an 
observational manner unless these patients withdraw consent. Upon withdrawal of 
consent, no further information will be collected from those patients. 
 
 
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 SAE) 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) 
STATISTICAL CONSIDERATIONS 
 
 
11.1 Study Hypothesis  
 
We hypothesize that IL-1 blockade with Anakinra will improve aerobic exercise 
performance and reduce hospital admission rates in patients with recently 
decompensated systolic HF. 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 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 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.  
 
11.2 Sample Size Considerations  
 
The sample size for this pilot study is calculated according to the primary endpoint of 


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difference in interval change in peak VO2 at 24 weeks between anakinra and placebo. 
Given an expected average peak VO2 of 15 mL/kg/min for HF patients, 68 subjects 
randomized to anakinra and 34 subjects randomized to placebo (2:1 randomization) 
would provide approximately >95% power to detect a difference of 1.6 mL∙kg-1∙min-1 
(standard deviation of 1.7-2.0 mL∙kg-1∙min-1) in peak VO2 on top of placebo. A 
conservative estimate of 20% loss to follow-up or withdrawal would retain >90% power.  
 
 
 
Effect size of treatment on top of placebo 
 
mL!kg-1! 
min-1 
+1.2 
+1.4 
+1.6 
+2.4 
+3.2 
Standard 
Deviation 
2.3 
0.70 
0.83 
0.91 
>0.99 
>0.99 
2.0 
0.82 
0.92 
0.97! 
>0.99 
>0.99 
1.7 
0.92 
0.98 
0.99 
>0.99 
>0.99 
1.4 
0.98 
0.99 
>0.99 
>0.99 
>0.99* 
 
 
 
11.3 Statistical Analysis 
 
 
11.3.1 Demographics and Baseline Characteristics 
 
Descriptive summaries of continuous measurements will be reported as median and 
interquartile ranges due to potential deviation from Gaussian distribution. Descriptive 
summaries of categorical measurements consist of frequencies, proportions and 95% 
confidence intervals, when applicable. All analyses will be conducted after database 
locking once all data has been gathered and electronically captured. All analyses will be 
based on the intention-to-treat principle (i.e., analyzing groups as randomized and 
including all patients with outcome data available). The difference in interval changes in 
peak VO2 at 24 weeks between the anakinra vs. placebo groups will be compared using 
random-effect analysis of variance for repeated measures to analyze the effects of 
treatment within each group and the effect of time_x_group allocation. Unadjusted p-
values will be reported throughout, with statistical significance for the primary endpoint 
set at the 2-tailed 0.050 level. To evaluate the group differences in the secondary 
endpoints, data will be compared across all groups using the random-effect analysis of 
variance for repeated measures as indicated above for paired analyses, or Kaplan-Meier 
curves with Log-rank testing for event rates.  
 
 
11.3.2 Handling of Missing Data 
 
Cases with missing data for all follow-up CPX at 6, 12  and 24 weeks will be omitted from 
the efficacy analysis due to inability to calculate the primary endpoint (change in peak 
VO2). Considering that the main variable of interest (peak VO2) is expected not to improve 
over time with placebo in patients with systolic HF and exclusion of patient with missing 


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data would inevitably lead to a survivorship bias, we will use the last observation carried 
forward (LOCF) method to impute the missing data at 12 and 24 weeks for the primary 
analysis. We will also perform the Little’s Missing Completely At Random (MCAR) test to 
determine whether the appropriateness of imputing missing values and perform a 
Multivariate Imputation by Chained Equation (MICE) to validate the finding of peak VO2 
using a different method for data inference.  
 
11.3.3 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). The data will be analyzed 
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.  
 
 
 


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30 
 
 
DSMB CHARTER 
Charter, Data and Safety Monitoring Board for  
NHLBI 1R34HL118348-01A1 
Interleukin-1 blockade in heart failure with preserved ejection fraction: 
REcently Decompensate Heart failure Anakinra Response Trial -2  
(REDHART2) 
Updated on October 25, 2018 
DSMB Liaison: Amy Ladd, PhD – amy.ladd@vcuhealth.org 
 
1 Introduction 
 
This Charter is for the Data and Safety Monitoring Board (DSMB) for the study: 
Interleukin-1 blockade in recently decompensated heart failure: the REcently 
Decompensated Heart failure Anakinra Response Trial-2 (REDHART2), 
hereafter referred to as “REDHART2”. 
 
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 REDHART2. 
 
The DSMB is an independent group advisory to the investigators, and is required to 
provide recommendations about starting, continuing, and stopping the study 
REDHART2. 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) 
 
 
3 Organization and Interactions 
 
Communication with DSMB members will be primarily through the DSMB executive 
liaison, Amy Ladd, PhD, NIH Officer and the investigators at Virginia Commonwealth 
University (VCU).  It is expected that study REDHART2 investigators will not 
communicate with DSMB members about the study directly, except when making 


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31 
 
 
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 
REDHART2 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 held 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 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 


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32 
 
 
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. Alternate 
members will be added to fill in cases in which the quorum of 3 cannot be achieved. 
All alternate members will receive equal vetting from the local IRB and from the 
Sponsor, NHLBI. 
 
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 REDHART2, 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) 
 
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-


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33 
 
 
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. 
 
f. Statistical Monitoring Guidelines  
A biostatistician will serve as a voting member of the DSMB. 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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34 
 
 
Appendix A:  
 
DSMB voting members  
 
Dominick Angiolillo, MD, PhD DSMB Chair 
Dr. Angiolillo is a 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  
 
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. 
https://intmed.vcu.edu/divisions/infectious/chair.html  
 
Ramesh Kundur, MD 
 
DSMB Member 
 
 
 
Dr. Kundur is a practicing cardiologist with Virginia Cardiovascular Specialist. He is board-
certified in Internal Medicine, Cardiovascular Medicine, and Heart Failure and 
Transplantation. www.vacardio.com/vcs-physicians/dr-ramesh-n-kundur/  
 
Brant Ward, MD 
 
DSMB member 
 
 
Dr. Ward is an Assistant Professor in the Division of Allergy, Immunology and 
Rheumatology. 
He 
has 
extensive 
experience 
in 
chronic 
autoimmune 
and 
autoinflammatory diseases as well as with immunodeficiency states. Dr. Ward is board 
certified in Internal Medicine and in Allergy/ Immunology. https://www.vcuhealth.org/find-
a-provider/find-a-provider/brant-ward  
 
 
Robert Perera, PhD 
 
DSMB Biostatistician (voting member) 
Dr. Perera is an Assistant Professor of Biostatistics, and a Biostatistician on staff for the 
Wright 
Center 
for 
Clinical 
and 
Translational 
Research 
at 
VCU. 
www.biostatistics.vcu.edu/robert-perera  
 
 
DMSB Liaison 
 
Amy Ladd, PhD 
 
DMSB Liaison 
Dr. Ladd, PhD, is the Associate Director of the Pauley Heart Center. 
 
 
NHLBI Liaison 
 
Emily Tinsley, PhD 
 
NHLBI Program Officer 
 
Alternate Members 
 


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35 
 
 
Ion Jovin, MD, PhD 
 
 
Alternate 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. 
https://health.usnews.com/doctors/ion-jovin-633298 
 
Patricia Uber, PharmD 
 
Alternate DSMB Member 
Dr. Uber is a pharmacist in the Division of Cardiology, Section of Heart Failure and 
Transplantation, at VCU. She is an expert in the field of pharmacology of heart failure and 
transplantation, including immunosuppressive therapies. She is also the Executive Editor 
of the Journal of Heart-Lung Transplantation. https://vcuphc-thebeat.org/2018/01/dr-
patricia-uber-assists-heart-patients/  
 
 

ICF_001.pdf: 
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RESEARCH PARTICIPANT INFORMATION AND CONSENT FORM
TITLE: The Effects of Interleukin-1 Blockade On Exercise Capacity In Patients With 
Recently Decompensated Systolic Heart Failure (REDHART2)
VCU IRB PROTOCOL NUMBER: HM20014686
INVESTIGATORS: Benjamin Van Tassell, PharmD, Antonio Abbate, MD, PhD
SPONSOR: National Heart, Lung, and Blood Institute, National Institutes of Health 
ABOUT THIS CONSENT FORM
You are being invited to participate in a research study. It is important that you carefully think 
about whether being in this study is right for you and your situation.
This consent form is meant to assist you in thinking about whether or not you want to be in this 
study. Please ask the study doctor or the study staff to explain any information in this 
consent document that is not clear to you. You may take home an unsigned copy of this 
consent form to think about or discuss with family or friends before making your decision.
Your participation is voluntary. You may decide not to participate in this study. If you do 
participate, you may withdraw from the study at any time. Your decision not to take part or to 
withdraw will involve no penalty or loss of benefits to which you are otherwise entitled. 
KEY INFORMATION ABOUT THIS STUDY
Heart failure is a condition in which the heart struggles to pump blood effectively. Inflammation 
in the body may affect heart function and contribute to heart failure. This study will test the 
safety, tolerability, and effectiveness of an anti-inflammatory medicine (anakinra) in patients 
with heart failure. You are being asked to participate in this study because you have recently 
been hospitalized for heart failure and may meet the study entry requirements.
Anakinra (Kineret®) is a naturally occurring protein that blocks inflammatory signaling in the 
body. The Food and Drug Administration (FDA) has approved Anakinra for the treatment of 
rheumatoid arthritis, but Anakinra is not currently approved for the treatment of heart disease. 
Anakinra is generally well-tolerated, but can cause pain or redness at the injection site and 
may affect your risk of infections. The study team will work with you to help you avoid (or 
manage) any side effects throughout the study.
The study is designed to measure the effect of Anakinra on heart function. Your participation 
in this study will last approximately 24 weeks. During this time, you will give yourself daily 
injections with Anakinra or placebo (a liquid that looks like Anakinra but contains no active 
medicine) for 24 weeks. Your assignment to treatment with Anakinra or placebo will be 
determined by randomization (like the “flip of a coin”). Approximately 102 people will 
participate in this study over the course of 4 years.
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Your participation in this study will consist of cardiac ultrasounds (to measure your heart 
function), exercise tests, and questionnaires about your heart failure symptoms. We will also 
draw blood for safety assessments and record any side effects or hospitalizations during 
study participation. 
WHAT WILL HAPPEN IF I PARTICIPATE?
After you sign this consent form, the investigators will perform a screening evaluation to 
determine your eligibility for the study. This screening will consist of a brief interview about your 
medical history, followed by a brief physical assessment (including height, weight, pulse, blood 
pressure, and temperature), and blood draw to measure basic laboratory and inflammatory 
biomarkers (approximately 1 to 2 tablespoons of blood). This screening may include a pregnancy 
test (if indicated). 
If you meet all the requirements to participate in this study, you will be asked to schedule five 
study visits at VCU Health over the next 24 weeks. 
Visit 1
Upon arrival to the Clinical Research Services Unit (North Hospital, 8th floor), you will have your 
vital signs measured (height, weight, blood pressure, temperature, breathing rate) and undergo 
a blood draw (1 to 2 tablespoons of blood). The blood draw will measure inflammatory 
biomarkers and routine safety tests. You will then complete a bioimpedance analysis, 
transthoracic echocardiogram, patient surveys, and cardiopulmonary test.
A bioimpedance analysis measures the water, lean mass, fat content of your body. A 
technician will place small patches (electrodes) on your skin and deliver a very small amount of 
electricity while you lie down on a bed. You will not be able to feel the electricity running 
through the body. This procedure will last approximately 10 minutes.
A transthoracic echocardiogram is an ultrasound of your heart. To perform this procedure, 
you will lie down in a bed while a technician applies a small amount of gel to your chest and uses 
a probe to take pictures of your heart. This procedure will last approximately 10 minutes.
You will complete four surveys to evaluate your heart failure symptoms, physical activity, and 
symptoms of depression. The Duke Activity Status Index (DASI) questionnaire contains 12 
questions to which you will answer “yes” or “no”. Each question asks you to describe your ability 
to perform different activities. The Kansas City Cardiomyopathy Questionnaire contains 15 
questions that ask you to mark how often you experience various symptoms of heart failure (i.e. 
swelling in your legs, shortness of breath, etc). The Patient Health Questionnaire-9 (PHQ-9) 
contains 9 questions about your mood and potential symptoms of depression. The International 
Physical Activity Questionnaire (IPAQ) contains 7 questions about the kinds of physical activities 
that you do as part of your everyday life. Please talk to the study team if you are uncomfortable 
answering any of these questions.
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The cardiopulmonary test will evaluate your aerobic exercise capacity as you walk on a 
treadmill. The test will begin at a slow walking speed. The speed (or incline) of the treadmill will 
then gradually increase every 30 seconds. Small electrodes will be placed on your chest 
(electrocardiogram [ECG]) to measure your heart rhythm at the beginning of testing, during the 
test, and at the end of the test. Blood pressure will be measured throughout the exercise test 
using a standard blood pressure cuff on your arm. American Heart Association (AHA) guidelines 
for exercise testing will be followed. A trained physician will supervise all exercise tests. If you 
experience significant chest pain or signs of poor blood flow to the heart (“ischemia”) that limit 
your ability to complete the exercise test, you will not be permitted to continue the study. This 
procedure will take approximately 30-40 minutes.
After the exercise test, you will receive your first supply of study medication. The investigators 
will teach you how to self-administer subcutaneous (under the skin) injections of the study 
medication. You will administer the medication daily throughout the course of the 24-week study 
while you are at home. The syringes should be stored in the refrigerator.
The entire visit will take approximately 2 hours.
Visit 2
Approximately 2 weeks after Visit 1, you will return the Clinical Research Services Unit (North 
Hospital, 8th floor), to undergo a blood draw (1 to 2 tablespoons of blood) and brief physical 
assessment. This visit will take approximately 30 minutes. If needed, this visit may also be 
performed by your own cardiologist or clinical provider.
Visits 3, 4, and 5
You will return to the Clinical Research Services Unit (North Hospital, 8th floor) after 6 weeks, 12 
weeks, and 24 weeks to repeat all of the procedures from Visit 1. These procedures include a 
brief physical assessment, blood draw, bioimpedance analysis, questionnaires, cardiac 
ultrasound, and exercise test. These visits will take approximately 2 hours each.
Upon completion of Visit 5, your active participation in the study will be over. However, 
investigators may contact you at the conclusion of the entire study (after all 102 patients have 
finished their participation) to verify whether you have been re-hospitalized since the beginning 
of the study.
Visit
1
2
3
4
5
Week
0
2
6
12
24
Physical assessment
X
X
X
X
X
Blood draw
X
X
X
X
X
Bioimpedance analysis
X
X
X
X
Echocardiogram
X
X
X
X
Questionnaires
X
X
X
X
Exercise test
X
X
X
X
Receive new study medicine
X
(X)
X
X
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Throughout the study, any test results that may affect your heart failure treatment will be provided 
and explained to you. All of your individual results from the study will be made available to you 
upon your request. No genetic testing or sequencing will be conducted as part of this research.
Additional study visits may be requested for things such as additional blood draws for safety 
reasons or to pick up additional medication.
You will not be able to participate if you have been recently affected by COVID-19 in the prior 
60 days or you have been in close contact with a person affected by COVID-19 in the prior 21 
days.  At each visit, you may be asked to undergo screening questions and tests for COVID-19 
as per standard protocol at VCU Health, which may include answering questions about your 
health, measuring your temperature, or having a nasopharyngeal test performed to detect the 
presence of SARS-CoV2 virus.
WHAT ALTERNATIVE TREATMENTS OR PROCEDURES ARE AVAILABLE?
If you decide not to enter this study, you can still receive the usual medical treatments for heart 
failure. You do not have to participate in this study to be treated for heart failure.
WHAT ARE THE BENEFITS OF BEING IN THE STUDY?
There is no guarantee that you will receive any medical benefits from being in this study. 
However, possible benefits include improved exercise capacity and reduced heart failure 
symptoms during your participation. You may also benefit from the information obtained through 
the physical exams, lab tests, and other study procedures. We hope that the information from 
this research study may lead to a better treatment in the future for people with heart failure. 
WHAT RISKS AND DISCOMFORTS COULD I EXPERIENCE FROM BEING IN THE STUDY?
Your condition may not get better (or may become worse) while you are in this study. 
Possible Risks Associated with Anakinra 
Anakinra is generally well-tolerated, but some side effects are possible. 

Injection site reaction (>10%) such as pain, redness, or irritation at the site of injection.

Serious infection (<5%)

Headache (1 –10%)

Nausea (1 – 10%)

Diarrhea (1 – 10%)

Low white blood cell count (rare, but not associated with increased risk of infection)

Hypersensitivity reaction (rash, anaphylaxis, arthritis)(rare 1-2%)
Anakinra may block your body’s ability to have a fever. This means that you may not have a 
fever if you become sick or ill. If you are feeling sick during the study, please contact your study 
doctor immediately. Allergic reaction to Anakinra is possible. Severe allergic reactions can be 
life threatening. Please contact your study doctor or seek immediate medical attention if you 
experience skin rash, swelling, or difficulty breathing as these may be signs of allergic reaction.
Other risks to participation in this study include the following:

Pain or bruising during blood draws. In rare cases, blood draws may result in skin/tissue 
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infection.

Shortness of breath, chest pain, fatigue, or an abnormal cardiovascular response during 
exercise testing (i.e. markedly elevated blood pressure or heart rate).

Minor skin irritation (rare) from the adhesives or gels used in bioimpendance analysis, 
electrocardiograms, or cardiac ultrasound.

Minor discomfort of your arm during blood pressure measurement.
Only the study participant can take the study drug.  It must be kept out of the reach of children 
and persons who may not be able to read or understand the label.
Non-Physical Risks
Participation in research might involve some loss of privacy. There is a small risk that someone 
outside the research study could see and misuse information about you. The questions in the 
depression surveys may be upsetting to some patients.
Unknown or Unforeseeable Risks
During the course of the research, we will inform you of any significant new findings that may 
affect your willingness to continue participation.
As the study procedures might injure an unborn child, pregnant women may not participate. 
Women who might become pregnant should use a medically accepted form of birth control such 
as total abstinence, birth control pills, an IUD, diaphragm, progesterone injections or implants, 
or condoms plus a spermicide. Methods of birth control other than total abstinence are not 100% 
effective, and should a women become pregnant there is a risk of injury to an unborn child. For 
similar reasons, women who are nursing an infant may not participate.
For men, the study procedures might increase the risks for birth defects of any child conceived 
during treatment and several months after treatment is stopped. Men in this study who have the 
potential of fathering children should be aware of this possibility and consider using a medically 
accepted form of birth control. For men this would include total abstinence and condoms plus a 
spermicide, or for the female partner, birth control pills, an IUD, diaphragm, progesterone 
injections or implants. Methods of birth control other than total abstinence are not 100% effective, 
and should a woman become pregnant there is a risk of injury to an unborn child.
WHAT ARE THE COSTS?
Study drug will be provided at no cost to you. You will not be charged for the study visits or any 
study-related procedures. 
WILL I BE PAID TO PARTICIPATE IN THE STUDY?
You will receive $100 compensation for each study visit to account for the time and expense of 
study participation. You will receive an additional $50 compensation if you are asked to return 
for an unscheduled visit.
Total payments within one calendar year that exceed $600 will require the University to report 
these payments annually to the IRS and you. This may require you to claim the compensation 
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you receive for participation in this study as taxable income. VCU is required by federal law to 
collect your social security number. Your social security number will be kept confidential and will 
only be used to process payment.
Please be aware that the investigative team and the University may receive money for the 
conduct of this study.
WHAT HAPPENS IF I AM INJURED OR BECOME SICK BECAUSE I TOOK PART IN THE 
STUDY?
If you are injured by, or become ill, from participating in this study, please contact your study 
doctor immediately.  Medical treatment is available at the Virginia Commonwealth University 
Health System (VCU Health System).  Your study doctor will arrange for short-term emergency 
care at the VCU Health System or for a referral if it is needed.  Fees for such treatment may be 
billed to you or to appropriate third party insurance.  Your health insurance company may or may 
not pay for treatment of injuries or illness as a result of your participation in this study.  To help 
avoid research-related injury or illness it is very important to follow all study directions.
CAN I STOP BEING IN THIS STUDY?
You can stop being in this research study at any time. Leaving the study will not affect your 
medical care, employment status, or academic standing at VCU or VCU Health. Tell the study 
staff if you are thinking about stopping or decide to stop.
Your participation in this study may be stopped at any time by the study doctor or the sponsor 
without your consent. The reasons might include:

the study doctor thinks it necessary for your health or safety;

you have not followed study instructions;

the sponsor has stopped the study; or

administrative reasons require your withdrawal.
HOW WILL INFORMATION ABOUT ME BE PROTECTED?
VCU and the VCU Health System have established secure research databases and computer 
systems to store information and to help with monitoring and oversight of research. Your 
information may be kept in these databases but are only accessible to individuals working on 
this study or authorized individuals who have access for specific research related tasks. 
Identifiable information in these databases are not released outside VCU unless stated in this 
consent or required by law. Although results of this research may be presented at meetings or 
in publications, identifiable personal information about participants will not be disclosed. 
Personal information about you might be shared with or copied by authorized representatives 
from the following organizations for the purposes of managing, monitoring and overseeing this 
study:

The study Sponsor, representatives of the sponsor and other collaborating organizations 

Representatives of VCU and the VCU Health System
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
Officials of the Department of Health and Human Services or the Federal Food and Drug 
Administration 
It will be noted in your protected electronic health record at VCU Health that you are in this study. 
Information about the study (including any medications you may receive) will be included in the 
record. This information is protected just as any of your other health records are protected. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you.  At most, the Website 
will include a summary of the results. You can search this Web site at anytime.
There are no plans to share any money or profits with you if the use of your sample(s) results in 
inventions or discoveries that have commercial value. In the future, identifiers might be removed 
from the information and samples you provide in this study, and after that removal, the 
information/samples could be used for other research studies by this study team or another 
researcher without asking you for additional consent.
To help us protect your privacy, we have obtained a Certificate of Confidentiality from the 
National Institutes of Health. The researchers can use this Certificate to legally refuse to disclose 
information that may identify you in any federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings, for example, if there is a court subpoena. The researchers will 
use the Certificate to resist any demands for information that would identify you, except as 
explained below.
The Certificate cannot be used to resist a demand for information from personnel of the United 
States Government that is used for auditing or evaluation of federally funded projects or for 
information that must be disclosed in order to meet the requirements of the federal Food and 
Drug Administration (FDA).
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, employer, or other person obtains your written consent to receive 
research information, then the researchers may not use the Certificate to withhold that 
information.
HOW WILL MY HEALTH INFORMATION BE USED AND SHARED DURING THIS STUDY?
As part of this research study, we will ask you to share identifiable health information with us 
and/or permit us to access existing information from your healthcare records. New health 
information may also be created from study-related tests, procedures, visits, and/or 
questionnaires. This type of information is considered “Protected Health Information” that is 
protected by federal law. 
What type of health information will be used or shared with others during this research?
The following types of information may be used for the conduct of this research:
 Complete health record
 Diagnosis & treatment codes
 Discharge summary
 Complete billing record 
 Consultation reports
 Progress notes
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 History and physical exam
 X-ray reports
 X-ray films / images
 Photographs, videotapes
 Laboratory test results
 Itemized bill
 Information about drug or alcohol abuse
 Information about Hepatitis B or C tests
 Information about psychiatric care
 Information about sexually transmitted diseases
Who will use or share protected health information about me?
VCU and VCU Health are required by law to protect your identifiable health information. By 
consenting to this study, you authorize VCU/VCU Health to use and/or share your health 
information for this research. The health information listed above may be used by and/or shared 
with the following people and groups to conduct, monitor, and oversee the research:

Principal Investigator and Research Staff    
Study Sponsor    

Research Collaborators    

Institutional Review Boards   

Data Safety Monitoring Boards   

Government/Health Agencies  

Others as Required by Law
When will this authorization (permission) to use my protected health information expire?
This authorization will expire when the research study is closed, or there is no need to review, 
analyze and consider the data generated by the research project, whichever is later.
Right to Revoke Authorization and Re-disclosure
You may change your mind and revoke (take back) the right to use your protected health 
information at any time.  Even if you revoke this Authorization, the researchers may still use or 
disclose health information they have already collected about you for this study. If you revoke 
this Authorization you may no longer be allowed to participate in the research study.  To revoke 
this Authorization, you must write to the Principal Investigator.
Statement of Privacy Rights
You may change your mind and revoke (take back) the right to use your protected health 
information at any time. However, even if you revoke this authorization, the researchers may still 
use or disclose health information they have already collected about you for this study. If you 
revoke this Authorization, you may no longer be allowed to participate in the research study. To 
revoke this Authorization, you must write to the Principal Investigator at Benjamin Van Tassell, 
410 North 12th Street, Richmond VA, 23298-0533.
QUESTIONS
If you have any questions, complaints, or concerns about this research, contact:
Benjamin Van Tassell, PharmD
Virginia Commonwealth University
410 North 12th Street, Rm 660A
Richmond, VA 23298
(804) 828-4583
Roshanak Markley, MD
Virginia Commonwealth University
West Hospital, 5th Floor, Rm 528B
Richmond, VA 23298
(804) 628-3981 (pager 3440)
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If you have general questions about your rights as a participant in this or any other research, or 
if you wish to discuss problems, concerns or questions, to obtain information, or to offer input 
about research, you may contact:
Virginia Commonwealth University Office of Research
800 East Leigh Street, Suite 3000, Box 980568, Richmond, VA 23298
(804) 827-2157; https://research.vcu.edu/human_research/volunteers.htm 
Do not sign this consent form unless you have had a chance to ask questions and have received 
satisfactory answers to all of your questions. 
CONSENT 
I have been provided with an opportunity to read this consent form carefully.  All of the questions 
that I wish to raise concerning this study have been answered. By signing this consent form, I 
have not waived any of the legal rights or benefits, to which I otherwise would be entitled. My 
signature indicates that I freely consent to participate in this research study. I will receive a copy 
of the consent form once I have agreed to participate.
___________________________________________________
Participant Name (Printed)
___________________________________________________ ________________
Participant Signature 
      Date
___________________________________________________
Name of Person Conducting Informed Consent Discussion (Printed)
___________________________________________________ ________________
Signature of Person Conducting Informed Consent Discussion
      Date
___________________________________________________ ________________
Principal Investigator Signature (if different from above) 
      Date
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