Conditions: Cardiac Sarcoidosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 17
Healthy volunteers: no

Brief summary:
Sarcoidosis is a heterogeneous disorder of unknown etiology whose signature lesions are granulomatous inflammatory infiltrates in involved tissues. Tissue commonly affected are lungs, skin, eyes, lymph nodes and the heart. In this latter case, cardiac sarcoidosis (CS) can lead to atrioventricular (AV) blocks, ventricular arrhythmias, heart failure (HF) and sudden cardiac death. Similar to other involved organs, cardiac disease generally progresses from areas of focal inflammation to scar. However, the natural history of CS is not well characterized complicating an immediate and definitive diagnosis. The management of CS often requires multidisciplinary care teams and is challenged by data limited to small observational studies and from the high likelihood of side effects of most of the treatments currently used (eg: corticosteroids, methotrexate and TNF-alfa inhibitors).

Interleukin-1 (IL-1) is the prototypical pro-inflammatory cytokine, also referred to as master regulator of the inflammatory response, involved in virtually every acute process. There is evidence that IL-1 plays a role in mouse model of sarcoidosis and human pulmonary lesions as the presence of the inflammasome in granulomas of the heart of patients with cardiac sarcoidosis, providing additional support for a role of IL-1 in the pathogenesis of CS. However, IL-1 blockade has never been evaluated as a potential therapeutic agent for cardiac sarcoidosis.

In the current study, researchers aim to evaluate the safety and efficacy of IL-1 blockade with anakinra (IL-1 receptor antagonist) in patients with cardiac sarcoidosis.

Detailed description:
Researchers will perform an open label randomized clinical trial of anakinra (recombinant IL-1 receptor antagonist, Kineret, SOBI, Sweden) given for 4 weeks in 28 patients with cardiac sarcoidosis (defined using Heart Rhythm Society diagnostic criteria).

Arms:
arm 1: 100 mg/0.67 mL daily subcutaneous injection for 4 weeks arm 2: Continue standard of care treatment

Interventions: intervention 1: Anakinra
Intervention descriptions: intervention 1: Active Treatment

Protocol document:
Prot_SAP_000.pdf: 
Interleukin-1 Blockade for Treatment of Cardiac Sarcoidosis  
 
Jordana Kron, MD 
VCU IRB PROTOCOL NUMBER: HM20015843 
 
NCT04017936 
 
17 August 2021 
 


Interleukin-1 blockade in cardiac sarcoidosis 
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Interleukin-1 blockade in cardiac sarcoidosis 
Unique Protocol Identification Number: MAGiC ART 
National Clinical Trial (NCT) Identified Number: NCT04017936 
Principal Investigator: Jordana Kron 
IND/IDE Sponsor: IND exempt 
Funded by: NCATS 
Version Number: 2.002 
17 August 2021 
Summary of Changes from Previous Version: 10012020 v 2.001 
Affected Section(s) Summary of Revisions Made 
Rationale 
1.1 
Study duration increased to 36 
months. 
The duration of the study will continue 
for 36 months, in part due to COVID-19 
pandemic-related delays.  
5.1, 6.5 
Changed inclusion criteria, added 
4. to indicated need for ‘stable 
medical therapy for cardiac 
sarcoidosis for at least 30 days’. 
This is to clarify that it is important to 
avoid changes in background therapies 
would influence the findings of the 
study. 
5.2, 6.5, 8.2.2 
Changed exclusion criteria, added 
8. to include only Tumor Necrosis 
Factor- blockers as contra-
indicated medications. This is also 
clarified in Concomitant 
Medications and Risks Reduction 
Strategies for Anakinra treatment.
This is consistent with the Food & Drug 
Administration Prescribing Information 
for Anakinra (Kineret®) that allows the 
drug to be prescribed with other 
immunomodulating medications other 
than Tumor Necrosis Factor- blockers.
This will reduce the number of screen 
failures among the patients being 
considered.   
8.1.1 
Changes to biomarkers, added the 
use of additional exploratory 
cytokine bioassays available 
through LabCorp. We deleted the 
plan for storage of samples at VCU 
as part of this study. 
The additional cytokine bioassays may 
provide insight into the pathobiology of 
the disease.  
 
Summary of Changes from Previous Version: 070720 v 1.011 
Affected Section(s) Summary of Revisions Made 
Rationale 


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1.1, 1.2, 4.1, 6.1, 
6.2, 6.3, 7.1, 9.1, 
9.2, 9.3 
Change from double-blind to 
open-label study design 
Lack of availability placebo syringes. 
1.1 
Added in the Synopsis that Interval 
changes in CRP represents a 
secondary endpoint in this 
feasibility study but also the 
primary efficacy endpoint. 
Clarification needed for consistency 
between the different sections of the 
protocol. 
1.3 
Explanation of time window for 
baseline assessments; added 
comment on flexibility related to 
COVID-19 pandemic emergency. 
Provide explanation about planned 
timing for interventions. 
8.1.3 
Minor reformatting to indicate 
that ECG Holter monitoring will be 
performed both at VCU and 
UMich. Also added that operators 
interpreting the study will be 
blinded to treatment allocation. 
Clarification and adding blinded 
assessment piece. 
8.1.4 
Comment added that cardiac 
magnetic resonance operators 
interpreting the study will be 
blinded to treatment allocation. 
Clarification and adding blinded 
assessment piece. 
Additional minor changes throughout the text to maintain consistent in terminology used. 
Summary of Changes from Previous Version: 061020 v 1.010 
Affected Section(s) Summary of Revisions Made 
Rationale 
1.2, 6.2.4 
Eliminating the 14 day drug 
dispensing visit. 
We have now access to placebo 
syringes allowing to prepare a 28-day 
supply and not requiring re-dosing 
after 14 days. 
1.1, 1.2, 1.3, 3.0, 
8.1.5, 8.2.3, 9.1 
Eliminating cardiopulmonary 
exercise testing. 
Increased risk for aerosol transmission 
of viral particles, need for PCR testing 
before each test. Of note this is only a 
test done for a sub-study at VCU only. 
5.2 
Evidence of COVID-19 within the 
last 60 days or recent (21 days) 
exposure to close personal contact 
with COVID-19. 
Exclude patients with COVID-19 or at 
risk for COVID-19. 
10.1.6 
DSMB Liaison has been 
transitioned to Amy Ladd, PhD. 
Chris DeWilde has left VCU.  
 


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Summary of Changes from Previous Version: 020420 v 1.009 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
1.1  
Clarified that arrhythmia assessment will 
be done at both VCU and Michigan.  
Accurate representation of events. 
1.2 
Schema figure updated. Figure shows 
that Holter will be performed at both 
centers; the figure no longer specifies 
which diagnostic criteria since both HRS 
and Japanese criteria may be used. 
Accurate representation of events. 
1.2 
Protocol schematic revised to show that 
labs will not be drawn at 6 months. 
Accurate representation of events. 
5.1 
Clarification of inclusion criteria to 
include to include the Japanese 
Diagnostic criteria as an alternative to 
the Heart Rhythm diagnostic criteria. 
It is common clinical practice to use 
Japanese criteria specifically to 
diagnose isolated cardiac sarcoidosis. 
8.1.1 
Added that samples will be collected at 
baseline at VCU for a cardiac sarcoidosis 
repository and stored unidentified. 
Accurate representation of events.  
8.1.3 
Clarification of potential need for a chest 
radiograph in selected patients to 
determine the presence of fractured or 
retained device leads. 
It is common clinical practice to obtain 
chest radiograph prior to cardiac 
magnetic resonance when presence of 
fractured or retained device leads 
cannot be excluded. 
8.2.3 
Clarification of risk related to chest 
radiograph for selected patients. 
Description of risk. 
 
Summary of Changes from Previous Version: 010720 v 1.008 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
1.3 
Clarified that arrhythmia assessment 
will be done at both VCU and Michigan
Research plan includes arrhythmia 
assessment at both centers. 
1.3 
Clarified which safety labs and which 
inflammation labs will be drawn 
including pregnancy test (if applicable). 
Specific labs drawn at each time 
point had not been specified.  
5.2 
Clarified which other 
immunosuppression therapies patients 
may be on.  
Allowed and excluded concomitant 
therapies was not clear.  


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5.2 
Clarified that patients with severe 
kidney disease will be excluded.  
To optimize safety, patients with 
severe renal disease will be excluded.
6.5 
Clarified that stable doses of steroids is 
defined as > 1 month and allowed dose 
is <0.5 mg/kg/day.  
Allowed dose of concomitant 
steroids was not clear.  
 
 


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Table of Contents 
Statement of Compliance 7 
1 Protocol Summary 
8 
1.1 Synopsis ............................................................................................................................................................... 8 
1.2 Schema .............................................................................................................................................................. 10 
1.3 Schedule of Activities (SoA) ............................................................................................................................... 10 
2 Introduction 
12 
2.1 Study Rationale .................................................................................................................................................. 12 
2.2 Background ........................................................................................................................................................ 12 
2.3 Risk/Benefit Assessment.................................................................................................................................... 12 
2.3.1 Known Potential Risks ................................................................................................................................. 12 
2.3.2 Known Potential Benefits ........................................................................................................................... 13 
2.3.3 Assessment of Potential Risks and Benefits ............................................................................................... 14 
3 Objectives and Endpoints 
16 
4 Study Design 
17 
4.1 Overall Design .................................................................................................................................................... 17 
4.2 Scientific Rationale for Study Design ................................................................................................................. 17 
4.3 Justification for Dose ......................................................................................................................................... 17 
4.4 End of Study Definition ...................................................................................................................................... 18 
5 Study Population 
19 
5.1 Inclusion Criteria ................................................................................................................................................ 19 
5.2 Exclusion Criteria ............................................................................................................................................... 21 
5.3 Lifestyle Considerations ..................................................................................................................................... 22 
5.4 Screen Failures ................................................................................................................................................... 22 
5.5 Strategies for Recruitment and Retention ......................................................................................................... 22 
6 Study Intervention 
24 
6.1 Study Intervention(s) Administration ................................................................................................................ 24 
6.1.1 Study Intervention Description ................................................................................................................... 24 
6.1.2 Dosing and Administration ......................................................................................................................... 24 
6.2.1 Acquisition and accountability .................................................................................................................... 24 
6.2.2 Formulation, Appearance, Packaging, and Labeling ................................................................................... 24 
6.2.3 Product Storage and Stability ..................................................................................................................... 24 
6.2.4 Preparation ................................................................................................................................................. 24 
6.3 Measures to Minimize Bias: Randomization and Blinding ................................................................................. 25 
6.4 Study Intervention Compliance ......................................................................................................................... 25 
6.5 Concomitant Therapy ........................................................................................................................................ 25 
6.5.1 Rescue Medicine ......................................................................................................................................... 25 
7 Study Intervention Discontinuation and Participant Discontinuation/Withdrawal 
26 
7.1 Discontinuation of Study Intervention .............................................................................................................. 26 
7.2 Participant Discontinuation/Withdrawal from the Study .................................................................................. 26 
7.3 Lost to Follow-Up ............................................................................................................................................... 27 
8 Study Assessments and Procedures 
29 
8.1 Efficacy Assessments ......................................................................................................................................... 29 
8.2 Safety and Other Assessments .......................................................................................................................... 30 
8.3 Adverse Events and Serious Adverse Events ..................................................................................................... 35 


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8.3.1 Definition of Adverse Events (AE) ............................................................................................................... 35 
8.3.2 Definition of Serious Adverse Events (SAE) ................................................................................................ 35 
8.3.3 Classification of an Adverse Event .............................................................................................................. 35 
8.3.4 Time Period and Frequency for Event Assessment and Follow-Up ............................................................ 37 
8.3.5 Adverse Event Reporting ............................................................................................................................ 37 
8.3.6 Serious Adverse Event Reporting................................................................................................................ 37 
8.3.7 Reporting Events to Participants ................................................................................................................ 38 
8.3.8 Events of Special Interest ........................................................................................................................... 38 
8.3.9 Reporting of Pregnancy .............................................................................................................................. 38 
8.4 Unanticipated Problems .................................................................................................................................... 39 
8.4.1Definition of Unanticipated Problems (UP) ................................................................................................. 39 
8.4.2 Unanticipated Problem Reporting .............................................................................................................. 39 
8.4.3Reporting Unanticipated Problems to Participants ..................................................................................... 40 
9 Statistical Considerations 
41 
9.1 Statistical Hypotheses ........................................................................................................................................ 41 
9.2 Sample Size Determination................................................................................................................................ 42 
9.3 Populations for Analyses ................................................................................................................................... 42 
9.4 Statistical Analyses............................................................................................................................................. 43 
9.4.1 General Approach ....................................................................................................................................... 43 
9.4.2 Analysis of the Primary Efficacy Endpoint(s) .............................................................................................. 43 
9.4.3 Analysis of the Secondary Endpoint(s) ....................................................................................................... 43 
9.4.4 Safety Analyses ........................................................................................................................................... 43 
9.4.5 Baseline Descriptive Statistics .................................................................................................................... 44 
9.4.6 Planned Interim Analyses ........................................................................................................................... 44 
9.4.7 Sub-Group Analyses .................................................................................................................................... 44 
9.4.8 Tabulation of Individual Participant Data ................................................................................................... 44 
9.4.9 Exploratory Analyses .................................................................................................................................. 44 
10 Supporting Documentation and Operational Considerations 
45 
10.1 Regulatory, Ethical, and Study Oversight Considerations ................................................................................ 45 
10.1.1 Informed Consent Process ........................................................................................................................ 45 
10.1.2 Study Discontinuation and Closure ........................................................................................................... 46 
10.1.3 Confidentiality and Privacy ....................................................................................................................... 46 
10.1.4 Future Use of Stored Specimens and Data ............................................................................................... 47 
10.1.5 Key Roles and Study Governance ............................................................................................................. 47 
10.1.6 Safety Oversight ........................................................................................................................................ 47 
10.1.7 Clinical Monitoring .................................................................................................................................... 49 
10.1.8 Quality Assurance and Quality Control ..................................................................................................... 50 
10.1.9 Data Handling and Record Keeping .......................................................................................................... 51 
10.1.10 Protocol Deviations................................................................................................................................. 51 
10.1.11 Publication and Data Sharing Policy ....................................................................................................... 52 
10.1.12 Conflict of Interest Policy ........................................................................................................................ 52 
10.2 Additional Considerations ............................................................................................................................... 53 
10.3 Abbreviations ................................................................................................................................................... 53 
10.4 Protocol Amendment History ............................................................................. Error! Bookmark not defined. 
11 References 
55 
References ........................................................................................................................................................... 55 


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Statement of Compliance 
Provide a statement that the trial will be conducted in compliance with the protocol, International 
Council on Harmonisation Good Clinical Practice (ICH GCP) and applicable state, local and federal 
regulatory requirements. Each engaged institution must have a current Federal-Wide Assurance (FWA) 
issued by the Office for Human Research Protections (OHRP) and must provide this protocol and the 
associated informed consent documents and recruitment materials for review and approval by an 
appropriate Institutional Review Board (IRB) or Ethics Committee (EC) registered with OHRP. Any 
amendments to the protocol or consent materials must also be approved before implementation. Select 
one of the two statements below. If the study is an intramural NIH study, use the second statement 
below: 
1. The trial will be carried out in accordance with International Council on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
o 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812). 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
OR 
2. The trial will be conducted in accordance with International Council on Harmonisation Good 
Clinical Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), and 
the [specify NIH Institute or Center (IC) [ Terms and Conditions of Award. The Principal 
Investigator will assure that no deviation from, or changes to the protocol will take place 
without prior agreement from the funding agency and documented approval from the 
Institutional Review Board (IRB), and the Investigational New Drug (IND) or Investigational 
Device Exemption (IDE) sponsor, if applicable, except where necessary to eliminate an 
immediate hazard(s) to the trial participants. All personnel involved in the conduct of this study 
have completed Human Subjects Protection and ICH GCP Training. 
For either option above, the following paragraph would be included: 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form(s) must be obtained before any participant is consented. Any amendment to the protocol 
will require review and approval by the IRB before the changes are implemented to the study. 
All changes to the consent form(s) will be IRB approved; a determination will be made regarding 
whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 


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1 PROTOCOL SUMMARY 
1.1 SYNOPSIS 
Title:
Interleukin-1 blockade in cardiac sarcoidosis
Study Description: 
A Randomized Open-label Feasibility and Safety Pilot Study
Objectives: 
Primary Objective:
To 
determine 
feasibility 
of 
recruitment 
and 
tolerability of treatment with anakinra on top of 
standard anti-inflammatory therapy in patients with 
cardiac sarcoidosis 
Secondary 
Objectives: 
1) To determine the effects of anakinra on systemic 
inflammation 
measured 
by 
plasma-derived 
inflammatory biomarkers in patients with cardiac 
sarcoidosis (Primary Efficacy Endpoint). 
2) To longitudinally detect and monitor myocardial 
inflammation and fibrosis in cardiac sarcoidosis 
patients with cardiac magnetic resonance (CMR) and 
positron emission tomography (PET) imaging[Imaging 
Substudy @ VCU]. 
Endpoints: 
Primary Endpoint:
 
Number of subjects enrolled, stratified by 
race/ethnicity [Feasibility Endpoint] 
 
Interval changes in inflammatory biomarkers (CRP 
and IL-6) after 4 weeks of treatment with 
anakinra [Efficacy Endpoints]. 
Secondary 
Endpoints: 
 
Clinical outcomes:  
o 
incidence of death (cardiac and non-
cardiac) 
o 
hospitalization (for cardiac and non-
cardiac reasons) 
o 
change in medication use for sarcoidosis 
(number and doses) 
o 
change in medication use for heart disease 
(number and doses) 
o 
Adverse events at 28, 60, and 180 days 


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 
24 hour Holter arrhythmia assessment:  
o 
Number, duration, and rate of sustained 
VT 
o 
Number, duration, and rate of non-
sustained VT 
o 
absolute number and percentage of 
premature ventricular contractions 
o 
number and type of AV blocks 
o 
number and duration of sinus pauses 
o 
occurrence of atrial arrhythmias 
 
Quality of life assessment with Sarcoidosis 
Assessment Tool 
[For the Imaging Substudy @ VCU] 
 
Cardiac magnetic resonance imaging  
o 
change in left ventricular ejection fraction
o 
change in late gadolinium enhancement 
 
Cardiac FDG PET  
o 
change in intensity of tracer uptake 
Study Population: 
28 patients (age >21 years) with a clinical diagnosis of cardiac 
sarcoidosis, cardiac uptake on FDG-PET within 2 months, CRP high-
sensitivity assay ≥2 mg/L
Phase:
Phase II
Description of 
Sites/Facilities 
Enrolling 
Participants:
 
Virginia Commonwealth University, Richmond, VA 
University of Michigan, Ann Arbor, MI 
Description of Study 
Intervention: 
Two-center, randomized, open-label, clinical trial with allocation to Anakinra 
Anakinra 100 mg daily on top of standard of care or standard of care only in 
1:1 ratio for 28 days 
Study Duration:
36 months
Participant Duration: 180 days
  


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1.2 SCHEMA 
 
 
1.3 SCHEDULE OF ACTIVITIES (SOA) 
Screening visit 
(within 30 days)
Randomization / 
Treatment day 1 
283 
days 
607
days
1807
days
Inclusion/Exclusion criteria and 
Informed Consent 
X 
X 
 
 
 
Clinical Assessment (history 
and physical exam) 
X 
X 
X 
 
Safety laboratory tests (CBC 
with diff, CMP, [urine pregnancy
at randomization as applicable])
X 
 
 
X 
X 
Inflammatory biomarkers 
(hsCRP, IL-6) 
X 
 
X 
 
Quality of life (QoL) 
assessment 
X 
 
X 
 
Investigational drug dispensing 
(education on storage and self-
administration) 
 
X 
for anakinra group 
 
 
Assessment for adverse events 
(in-person or by telephone) 
 
 
X 
X 
X 
Anakinra 100 mg s.q. daily
on top of standard of care (n=14)
Baseline
Drug dispensing
28 days
Standard of care only
(n=14)
• Heart Rhythm or Japanese 
Ministry of Health Diagnostic 
Criteria
• Cardiac PET FDG w/in 2 mos
• CRP ≥ 2 mg/L
QoL
Holter
QoL
Labs
Holter
[PET]
Labs
180 days
60 days
Labs
Adverse Events
Adverse Events
Adverse Events
[CMR]
[CMR]
Randomization stratified by center
and by race/ethnicity


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Arrhythmia assessment with 
24-hour ECG Holter 
X 
 
X 
14 days
 
[Cardiac magnetic resonance] 
[X] 
 
[X] 
14 days
 
[Cardiac PET scan] 
[X] 
within 60 days
 
[X]
14 days
 
 
 
 
 
 
Procedures indicated in [brackets] denote additional testing done as part of the VCU Imaging Substudy.  
*_indicates complete blood cell count with differential and comprehensive metabolic profile at each time point, 
and pregnancy test at initial visit (if applicable) 
Considering the ongoing COVID-19 pandemic emergency, the PI will consider potential deviation to the 
protocol if needed to promote the safe conduct of the research. 


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2 INTRODUCTION 
2.1 STUDY RATIONALE 
The current study is designed to test the hypothesis that IL-1 activation represents a shared molecular 
mechanism common to different forms of cardiomyopathy, and that IL-1 blockade with anakinra can 
safely modulate systemic and cardiac inflammation in patients with a rare form of sarcoidosis affecting 
the heart. 
 
2.2 BACKGROUND 
Cardiac sarcoidosis is a rare presentation of sarcoidosis involving the heart that disproportionately affects 
young people, more commonly African-American women than other groups. Cardiac sarcoidosis can 
cause serious arrhythmic complications leading to death.  Corticosteroids are the standard treatment for 
sarcoidosis yet the evidence for efficacy is largely lacking and their use is associated with significant 
toxicities. There is no proof of survival benefit from corticosteroids and there have been no randomized 
clinical trials for patients with cardiac sarcoidosis.  
  
There is a dearth of safe, targeted anti-inflammatory therapies for patients with cardiac sarcoidosis. 
Interleukin-1 is the prototypical pro-inflammatory cytokine that is involved in virtually every acute 
process. Studies suggest IL-1 plays a role in the pathogenesis of sarcoidosis and we have demonstrated 
the presence of the inflammasome, a macromolecular structure that produces cytokines including IL-1, in 
the granulomas of heart tissue in patients with cardiac sarcoidosis.  While IL-1 plays a role in the 
pathogenesis of granuloma formation in sarcoidosis, the effects of IL-1 blockade have never been 
evaluated as a potential therapeutic agent for cardiac sarcoidosis. IL-1 blockers have been widely studied 
in patients with heart disease, showing a low rate of predictable complications, making it the preferred 
anti-inflammatory agent to be studied in cardiac sarcoidosis.  
 
2.3 RISK/BENEFIT ASSESSMENT 
2.3.1 KNOWN POTENTIAL RISKS 
  
Anakinra is a recombinant human IL-1 receptor antagonist that has been FDA-approved for the treatment 
of inflammatory disorders such as rheumatoid arthritis for many years. In pilot clinical trials, anakinra has 
led to improved cardiovascular function in patients with rheumatoid arthritis, ST-segment elevation acute 
myocardial infarction, and chronic systolic heart failure. The use of anakinra as an anti-inflammatory 
treatment for cardiac sarcoidosis is justified by anakinra’s relatively low risk/benefit ratio. Anakinra has 
been used in more than 150,000 patients with rheumatoid arthritis with a favorable risk profile.1 


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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%); 
 
Hypersensitivity reaction (rash, anaphylaxis, arthritis)(rare, 1-2%). 
 
Neutropenia (rare, <1%, reversible). 
  
The injection site reactions are by far the most common adverse reaction.2 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 rarely cause of discontinuation of therapy (<5%). 
  
Despite the increase in risk of serious infection with anakinra, such events are rather rare (<2% during 
chronic treatment in patients with rheumatoid arthritis already on other immunomodulating drugs 
[observational data]). Anakinra is indeed not associated with an increase in infection-related mortality, 
nor associated with opportunistic infection. In clinical trials with anakinra, the infection rates did not differ 
between active treatment and placebo. 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). 
  
2.3.2 KNOWN POTENTIAL BENEFITS 
  


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In a series of phase II studies led by the PI of this proposal, Dr. Abbate [VCU], treatment with anakinra was 
shown to be safe and associated with reduced incidence of heart failure in patients with ST-segment 
elevation MI (STEMI)3and with improved cardiorespiratory fitness and quality of life in patients with 
systolic heart failure.4, 5In the large CANTOS trial of 10,061 patients with previous myocardial infarction 
and elevated CRP (≥2 mg/L), canakinumab, a monoclonal antibody blocking interleukin- 1beta, led to a 
15% significantly lower rate of atherothrombotic events6, a 36% reduction in need for coronary 
revascularization6 and a dose-dependent reduction in hospitalization for heart failure.7 In a small CANTOS 
substudy completed here at VCU by Dr. Abbate’s team, patients with systolic heart failure treated with 
canakinumab experienced a significant improvement in cardiorespiratory fitness (peak VO2) and cardiac 
function (LVEF).8 In all instances, the clinical improvement correlated with reduction of the systemic 
inflammatory biomarkers, namely CRP, showing a dose-response relationship between CRP reduction and 
benefits observed. 
  
The hypothesis being tested is that Anakinra (Kineret) will inhibit the systemic inflammatory response in 
patients with cardiac sarcoidosis. As with all clinical trials, there is no guarantee that there is a benefit 
with anakinra. If anakinra treatment reduces inflammatory biomarkers, this could have a substantial 
potential benefit on the disease severity. 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
  
Importance of the Knowledge to be Gained 
Cardiac sarcoidosis is a condition of deregulated inflammatory response in the heart, causing a 
granulomatous response. A role for IL-1 in the local and systemic inflammatory response in cardiac 
sarcoidosis has been proposed. IL-1 targeted therapies are available to treat several chronic inflammatory 
diseases. Clinical trials have shown a benefit of IL-1 blockade in acute myocardial infarction and heart 
failure. No targeted anti-IL-1 therapies have been tested in patients with cardiac sarcoidosis. The 
unanswered question remains whether IL-1 is a key mediator (versus a manifestation) of systemic and 
cardiac inflammation in cardiac sarcoidosis. This proposal will investigate whether IL-1 blockade can 
reduce systemic inflammatory biomarkers. The findings will then form the basis for the subsequent design 
of a phase II-III clinical trials. 
  
Risks reduction strategies for Anakinra treatment 
The risks associated with Anakinra appear to be mostly related to risk of infection (1.8% vs 0.6% of serious 
infections in a rheumatoid arthritis study), and injection site reactions. To better estimate the risk, one 
needs to place the estimates in context: the estimated 2% risk of serious infection with anakinra quoted 
in the FDA approved package insert refers to the use of anakinra/Kineret as second line agent for the 
treatment of rheumatoid arthritis, in which anakinra was used in addition to corticosteroids or other 
disease-modifying agents further increasing infectious risk. The risk of infection of anakinra monotherapy 
is not known, but it does not appear to be high. In a study cohort of patients with Neonatal Onset 
Multisystem Inflammatory Disease, another autoinflammatory condition for which anakinra is indicated, 
no dose limiting toxicities were reported for anakinra over the 148.1 patient-year study period: there were 
only 3 serious infections reported (2 wound infections and 1 gastroenteritis) and in all 3 cases, treatment 


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with anakinra was considered possibly related to the event, however treatment was not discontinued and 
patients improved with antibiotics. Moreover, if one considers the ‘excess risk’ of serious infection with 
anakinra to evenly distributed through the year, a treatment of 1 month, would lead to an excess risk that 
is less than then 1.2% difference reported in the prescribing information. Nevertheless, the inherent anti-
inflammatory activity of anakinra may potentially mask some of the signs of infection such as fever and 
leukocytosis. In the CANTOS trial, canakinumab, another IL-1 blocker was associated with a 0.1% excess 
risk of life-threatening infection per year compared with placebo – canakinumab, at difference with 
anakinra, is long-acting and it cannot be stopped in case of infection, and therefore one would consider 
the risk of life-threatening infections with anakinra given for 1 month to be 10-fold lower than 
canakinumab for 1 year. 
  
To reduce the risk of infections with anakinra we plan to follow the following strategies: 
 
Exclude patients with acute or chronic infections at time of screening; 
 
Exclude patients with concomitant biologic immunomodulating medications, such as TNF-a blockers; 
 
Exclude patients who are neutropenic; 
 
Educate patients on the possibility that symptoms or signs of infections may be less evident with taking 
the investigational drug; 
 
Provide patient with 24/7 phone access to investigators to discuss potential symptoms or signs of 
infection; 
With this plan in place we have not seen any issues with severe infections since our first clinical trial with 
anakinra in acute STEMI in 2008 including now over 200 patients. 
 
 


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3 OBJECTIVES AND ENDPOINTS 
OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR ENDPOINTS
Primary
To determine the feasibility of 
recruitment and tolerability of 
treatment with anakinra on top 
of standard anti-inflammatory 
therapy in patients with cardiac 
sarcoidosis. 
Number of subjects screened, 
enrolled and treated, stratified 
according to race/ethnicity. 
  
We have established target 
enrollment for minority 
representation of >40%, of which 
>30% African-American. 
Secondary
To determine the effects of 
anakinra on systemic 
inflammation measured by 
plasma-derived inflammatory 
biomarkers in patients with 
cardiac sarcoidosis. 
Interval change in inflammatory 
biomarkers (CRP and IL-6) after 4 
weeks of treatment with 
anakinra. 
CRP and IL-6 are systemic 
inflammatory biomarkers that 
are surrogate for cardiovascular 
outcomes. 
Tertiary/Exploratory
To longitudinally detect and 
monitor myocardial 
inflammation and fibrosis in 
cardiac sarcoidosis patients with 
cardiac magnetic resonance 
(CMR) and positron emission 
tomography (PET) 
imaging[Imaging Substudy @ 
VCU]. 
We will measure changes in T1 
and T2 mapping at CMR and in 
signal intensity at PET over time in 
the cohort. 
T1 and T2 mapping at CMR are 
promising techniques for tissue 
level characterization of 
cardiomyopathies. 


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4 STUDY DESIGN 
4.1 OVERALL DESIGN 
We designed a randomized open-label study of anakinra 100 mg daily once daily for 28 days on top of 
standard of care in patients with cardiac sarcoidosis, cardiac FDG uptake on PET scan, and CRP ≥2 mg/L. 
  
The study is composed of 2 treatment arms: 
1. Anakinra 100 mg/0.67 mL daily subcutaneous injection on top of standard of care for 4 weeks [active 
treatment]; 
2. Standard of care only [control group]. 
 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
We chose to perform a pilot study a randomized, open label trial of 28 patients of anakinra 100 mg daily 
on top of standard of care versus standard of care only for 28 days to determine whether IL-1 blockade 
with anakinra is associated with a biological signal or not, based on surrogate endpoints of changes in 
systemic inflammatory biomarkers. 
  
We believe that this small pilot study is a necessary initial step to determine feasibility and estimate the 
effect size of anakinra in a phase II study, to be followed by an appropriately powered multicenter RCT if 
the results of this pilot study prove promising. 
  
This pilot study is structured to provide the necessary and sufficient information to make this 
determination.  
 
4.3 JUSTIFICATION FOR DOSE 
Anakinra is available for use with a label indication for rheumatoid arthritis and cryopyrin-associated 
periodic syndromes9 and it has a very favorable safety profile.10 The 100 mg daily subcutaneously is the 
currently approved dose on the FDA label, that has been shown to be efficacious across a wide range of 
clinical conditions, including heart failure,11,12 and also meets conditions for an IND exemption according 
to the criteria listed in § 312.2(b) of the federal regulation (see letter from FDA official). Treatment for 2-
4 weeks has been shown to be efficacious in reducing inflammatory plasma biomarkers and improving 
exercise capacity in patients with systolic heart failure with New York Heart Association class II-IV 
symptoms.4,5,13,14,15 We also recently completed a phase IB/II study in patients with pulmonary arterial 
hypertension and right ventricular failure treated with anakinra showing a significant reduction in 
inflammatory biomarkers after 2 weeks.8 Anakinra 100 mg daily for 14 days was also as effective as 100 


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mg twice daily for 14 days in quenching the acute inflammatory response associated with ST segment 
elevation MI (Abstract presented at the ESC 2019). 
 
4.4 END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed all phases of the study 
including the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA), Section 
1.3. 
  
The end of the study is defined as completion of the last visit or procedure shown in the SoA in the trial 
globally. 


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5 STUDY POPULATION 
5.1 INCLUSION CRITERIA 
Patients with sarcoidosis will be screened according to the following criteria (all 3 criteria need to be met): 
 
Clinical diagnosis of cardiac sarcoidosis according to either the  
Heart Rhythm Society Diagnostic Criteria based on one of the 2 diagnosis pathways (see below): 
1. Histological diagnosis from myocardial tissue – cardiac sarcoidosis is diagnosed in the presence of non-
caseating granuloma on histologic examination of myocardial tissue with no alternative cause identified 
(including negative stain for microorganisms – as applicable); 
2. Clinical diagnosis from invasive and/or non-invasive studies – it is probable that there is cardiac 
sarcoidosis if there is (a) histological diagnosis of extracardiac sarcoidosis and (b) one or more of the 
following: steroid +/- immunosuppressant responsive cardiomyopathy or heart block; unexplained 
reduction in LVEF (<40%); unexplained sustained (spontaneous or induced) ventricular tachycardia; 
Mobitz type II 2nd degree or 3rd degree AV block; patchy uptake on dedicated cardiac PET (in a pattern 
consistent with cardiac sarcoidosis); late gadolinium enhancement on cardiac magnetic resonance (in a 
pattern consistent with cardiac sarcoidosis); positive gallium uptake (in a pattern consistent with cardiac 
sarcoidosis) and (c) other causes for the cardiac manifestation(s) have been reasonable excluded. 
or the diagnostic guidelines for cardiac sarcoidosis based on New CS Guidelines in Japan (see below): 
1. Histological diagnosis group (those with positive myocardial biopsy findings) 
Cardiac sarcoidosis is diagnosed histologically when endomyocardial biopsy or surgical specimens 
demonstrate non-caseating epithelioid granulomas. 
2. Clinical diagnosis group (those with negative myocardial biopsy findings or those not undergoing 
myocardial biopsy) 
The patient is clinically diagnosed as having sarcoidosis: 
(1) When epithelioid granulomas are found in organs other than the heart and clinical findings 
strongly suggestive of the above-mentioned cardiac involvement are present (Table 1); or 
(2) When the patient shows clinical findings strongly suggestive of pulmonary or ophthalmic 
sarcoidosis; at least 2 of the 5 characteristic laboratory findings of a sarcoidosis (Table 2); and 
clinical findings strongly suggest the above-mentioned cardiac involvement (Table 1) 
 
TABLE 1.  Clinical findings defining cardiac involvement 
Cardiac findings should be assess based on the major criteria and the minor criteria.  Clinical findings that 
satisfy the following 1) or 2) strongly suggest the presence of cardiac involvement.  
(1) 2 or more of the 5 major criteria (a)-(e) are satisfied. 
(2) 1 of the 5 major criteria (a)-(e) and 2 or more of the 3 minor criteria (f)-(h) are satisfied.  
 
 
 


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1. Major criteria 
(a) High-grade AV block (including complete AV block) or fatal ventricular 
arrhythmia (e.g., sustained VT and VF) 
(b) Basal thinning of the ventricular septum or abnormal ventricular wall 
anatomy (ventricular aneurysm, thinning of the middle or upper 
ventricular septum, regional wall thickening 
(c) Left ventricular contractile dysfunction (LVEF < 50%)  
(d) 67Ga citrate scintigraphy or 18F-FDG PET reveals abnormally high tracer 
accumulation in the heart 
(e) Gadolinium-enhanced MRI revealed delayed contrast enhancement of 
the myocardium 
2. Minor criteria 
(f) Abnormal ECG findings: Ventricular arrhythmias (nonsustained VT, 
multifocal or frequent premature ventricular contractions, bundle 
branch block, axis deviation, or abnormal Q waves 
(g) Perfusion defects on myocardial perfusion scintigraphy (SPECT) 
(h) Endomyocardial biopsy: Monocyte infiltration and moderate or severe 
myocardial interstitial fibrosis 
Table 2. Characteristic laboratory findings of sarcoidosis 
1. Bilateral hilar lymphadenopathy 
2. High serum angiotensin-converting (ACE) activity or elevated serum lysozyme levels 
3. High serum soluble interleukin-2 receptor (sIL-2R) levels 
4. Significant tracer accumulation in 67Ga citrate scintigraphy or 18F-FDG PET 
5. A high percentage of lymphocytes with a CD4CD8 ration of >3.5 in BAL fluid. 
or the Diagnostic guidelines for isolated cardiac sarcoidosis based on New CS Guidelines in Japan 
Diagnostic guidelines for isolated cardiac sarcoidosis 
Prerequisite 
3. No clinical findings characteristic of sarcoidosis are observed in any organs other than the heart. 
(The patient should be examined in detail for respiratory, ophthalmic, and skin involvement of 
sarcoidosis.  When the patient is symptomatic, other etiologies that can affect the corresponding 
organs must be ruled out.) 
4. 
67Ga scintigraphy or 18F-FDG PET reveals no abnormal tracer accumulation in any organs other 
than the heart. 
5. A chest CT scan reveals no shadow along the lymphatic tracts in the lungs or no hilar and 
mediastinal lymphadenopathy (minor axis>10 mm).  
 
(1) Histological diagnosis group 
Isolated cardiac sarcoidosis is diagnosed histologically when endomyocardial biopsy or surgical 
specimens demonstrate non-caseating epithelioid granulomas. 
(2) Clinical diagnosis group 
Isolated cardiac sarcoidosis is diagnosed clinically when criterion (d) and at least 3 other major 
criteria (a)-(e) are satisfied. (Table 1) 
 
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3. CRP high-sensitivity assay ≥2 mg/l (performed within the prior 60 days) 
4. On stable medical therapy for cardiac sarcoidosis for at least 30 days prior to randomization 
 
5.2 EXCLUSION CRITERIA 
Subjects will not be eligible if they meet any one of the following exclusion criteria. 
1. Age<21 years; 
2. Pregnancy; 
3. Inability to obtain consent from patient or legally authorized representative; 
4. Contraindications to treatment with Anakinra (Kineret)(i.e. prior allergic reaction to the drug or to E. coli 
derived products or severe allergy to latex); 
5. Severe anemia (Hgb<8 g/dl - due to the need of more frequent blood sampling with this study). 
6. Acute or chronic active infections (not including treated/cured HCV with negative viral load). 
7. Acute or chronic inflammatory disease other than sarcoidosis.  
8. Treatment with Tumor Necrosis Factor- blockers. 
9. Active acute or chronic psychiatric illness that in the opinion of the investigator may prevent from 
complying with study instructions; 
10. Limited English Proficiency that in the opinion of the investigator may prevent from understanding the 
content of the informed consent form or safely completing the study procedures. 
11. Live vaccination within the prior month 
12. Neutropenia (defined as absolute neutrophil count < 1,500/ml or <1,000/ml if subject is African American) 
13. History of malignancy within the prior 5 years (with exception of basal cell skin cancer, carcinoma in-situ 
of the cervix or low risk prostate cancer after curative therapy) 
14. Participation in another concurrent intervention study within 30 day or treatment with an investigational 
drug within 5 half-lives prior to randomization 
15. Severe kidney disease (GFR <30 mL/min/1.73m2) 
16. Evidence of COVID-19 within the last 60 days or recent (21 days) exposure to close personal contact with 
COVID-19. 
17. [Chronic, moderate-to-severe kidney disease (GFR <60 mL/min/1.73m2) or acute kidney injury, or history of 
severe hypersensitivity reactions to gadolinium-based contrast agents] – For VCU Imaging Substudy 


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5.3 LIFESTYLE CONSIDERATIONS 
There are no specific lifestyle considerations of restrictions required of patients during this study.   
 
5.4 SCREEN FAILURES 
Screen failures will not be included in the trial.  Reasons for screening failure will be recorded.  Individuals 
who do not meet the criteria for participation in this trial (screen failure) because of may be rescreened if 
the subsequently meet all inclusion criteria and do not have any exclusion criteria.  Rescreened 
participants will be assigned a new participant number. 
 
5.5 STRATEGIES FOR RECRUITMENT AND RETENTION 
  
Virginia Commonwealth University 
 
The VCU Sarcoidosis Clinic is an interdisciplinary, collaborative clinic established in 2014. Dr. Kron is a 
founding member of this clinic, which provides sarcoidosis patients evaluation by cardiology, pulmonary, 
and rheumatology specialists. The VCU Sarcoidosis Clinic was recognized as a World Association for 
Sarcoidosis and Other Granulomatous Disorders (WASOG) Sarcoidosis Clinic in 2017. The multidisciplinary 
approach is unique in the region and one of only a few such clinics nationwide. The clinic provides care to 
a large volume of sarcoidosis patients in Richmond and Central Virginia and receives referrals from 
throughout the mid-Atlantic region. Since 2010, VCU has treated more than 1600 individual sarcoidosis 
patients in 12,160 patient encounters. 
 
Dr. Kron has a dedicated cardiac sarcoidosis clinic each week, to our knowledge the only such clinic in the 
country. Over the past 4 years, Dr. Kron has enrolled 80 patients from the Sarcoidosis Clinic to participate 
in the Cardiac Sarcoidosis Consortium prospective registry. Of the more than 20 international sarcoidosis 
centers, VCU is in the top 2 for patient enrollment to the registry. In 2016, Dr. Kron enrolled 25 CS patients 
to participate in a prospective study evaluating circulating fibrocytes. Based on clinic volume and track 
record of patient enrollment, we feel we can recruit 8-10 patients per year to participate in the current 
study. We will monitor recruitment and we will quickly intervene to add referrals from nearby providers 
if needed. Dr. Kenneth Bilchick, University of Virginia Cardiac Electrophysiologist, has committed to 
support the study with patient referrals from the Charlottesville region. 
  
University of Michigan 
The University of Michigan Sarcoidosis Clinic is also recognized as a WASOG Sarcoidosis Clinic. Our team 
of physicians, which includes UMich investigators, Drs. Crawford and Bogun, works in concert to provide 
expert care to patients with this multi organ disease. It is a collaboration of providers from cardiac 


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electrophysiology and heart failure, as well we pulmonology, rheumatology, dermatology, and others. 
Cardiac patients are discussed at monthly cardiac sarcoidosis conferences, during which 
electrophysiologists, heart failure specialists, pulmonologists, and radiologists review cases and develop 
diagnostic and treatment plans for the reviewed patients. Due to the relatively high volume of the patients 
diagnosed with this rare disorder through the concerted effort of the physicians in the Sarcoidosis Clinic, 
UMich has enrolled almost 100 patients in the prospective International Cardiac Sarcoidosis Registry. A 
significant number of patients, who are strongly suspected of having the disorder due to their clinical 
presentation and imaging studies, but who lack the pathognomonic tissue biopsy, are also followed. Based 
on the clinic volume of the cardiac sarcoidosis patients and the interest of a number of physicians from 
various specialties, we feel confident that we will be well suited to enroll at least 8-10 patients annually 
in the proposed pilot study. 
  
Retention Strategies 
The patients are regularly followed in clinic and will be chosen for their compliance. The proposed study 
is also designed to be short, only 4 weeks. All study participants will receive cards with 24-hour/7-day 
contact number for study team members. This approach has been sufficient to achieve a 90% retention 
on average in prior studies of IL-1 blockade in HF at VCU. We will also implement a patient reimbursement 
for each completed study visit up to $100 for the completion of all study visits. We believe this may 
overcome some financial barriers that our patients at VCU Health and Michigan Medicine (formerly 
University of Michigan Health System) may experience related to the time and cost of travel. We will 
collect data on enrollment and retention barriers to help enhance the success of a future 
 
 


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6 STUDY INTERVENTION 
6.1 STUDY INTERVENTION(S) ADMINISTRATION 
6.1.1 STUDY INTERVENTION DESCRIPTION 
  
We will select 28 patients and randomly assign them to treatment with anakinra 100 mg subcutaneously 
daily on top of standard of care or standard of care only for 4 weeks (1:1 ratio). 
6.1.2 DOSING AND ADMINISTRATION 
  
The study is composed of 2 treatment arms: 
1. Anakinra 100 mg/0.67 mL daily subcutaneous injection for 4 weeks on top of standard of care [active 
treatment]; 
2. Standard of care only  [control group]. 
 
6.2 Preparation/Handling/Storage/Accountability 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
  
Anakinra dispensed in small syringes (0.67 mL) will be provided to the patient for daily subcutaneous 
injection. 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
  
Anakinra will be provided as commercially available Kineret® product.  
6.2.3 PRODUCT STORAGE AND STABILITY 
  
Anakinra should be stored in the refrigerator at 2 degrees C to 8 degrees C (36 degrees F to 46 degrees F). 
Anakinra should not be frozen or shaken.  Anakinra should be protected from light.  
6.2.4 PREPARATION 
  
After completion of all baseline testing, patients randomized to anakinra will be given a 28-day supply of 
anakinra and will also receive instruction from the investigators regarding self-injection technique.  
  
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. 


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6.3 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDED ASSESSMENT 
Randomization will be handled by a member of the research team not involved in the consenting process 
using a dedicated randomization algorithm, stratified by center (VCU / UMich) and by race/ethnicity 
(Caucasian / Others). 
Assessment of ECG Holter and of imaging, for substudy, will be performed by operators who are blinded 
to treatment allocation. 
 
6.4 STUDY INTERVENTION COMPLIANCE 
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. 
 
6.5 CONCOMITANT THERAPY 
All concomitant medications and dosages will be recorded at each clinic visit.   
  
Patients may be on stable [at least 30 days] doses of steroids (< 0.5 mg/kg/day) or steroid-sparing 
agents including methotrexate but not tumor necrosis factor-alpha (TNF-alpha) blockers. 
  
6.5.1 RESCUE MEDICINE 
  
The investigational treatment in this study is viewed as treatment to be added on top of current treatment 
on patients considered to be stable. If at any time, the subject requires intensification of the treatment 
for sarcoidosis including a drug that would be render the patient no longer a candidate for the study, the 
subject may choose to discontinue to study treatment and initiate the new treatment without delay. The 
subject may however not be able to continue the investigational drug treatment if a new 
immunosuppressive or biologic agent is added. 
 
 


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7 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 DISCONTINUATION OF STUDY INTERVENTION 
Reasons for discontinuation of treatment 
Reasons for discontinuation of Anakinra: 
 
Systemic infection (sepsis)*; 
 
Surgery*; 
 
New diagnosis of cancer that requires local or systemic treatment; 
 
Hypersensitivity reaction (rash, anaphylaxis, arthritis); 
 
Severe injection site reactions*; 
 
Need for immunosuppressant therapy or treatment with a biologic agent (i.e. TNF-alpha blocker); 
 
Acute myocardial infarction or stroke*; 
 
Severe neutropenia (<1,000/mm3) if there is a perception of increased infectious risk by the provider*. 
In the cases labelled by * treatment may be restarted by investigators after the condition is resolved. 
 
7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Patient withdrawal 
Patients may withdraw from the study at any time. The investigators can withdraw any patient at any time 
from the study if medically necessary. Missing data will not be inputted. The decision regarding 
continuation or termination of the study will be solely based on safety data. Interim analyses will be 
performed by the DSMB as indicated below. 
  
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 early termination of the 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. 
  
Halting rules 
The study will be temporarily suspended if any of the following conditions are met: 
 
Any serious adverse event that probably or definitely related to the investigational product; 


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 
The number of subjects experiencing a serious adverse event considered unrelated or only possibly related 
to the investigational product exceeds 50% (after the first 3 or more subjects are enrolled); 
 
The number of subjects experiencing either a serious adverse event considered unrelated or only possibly 
related to the investigational product or a non-serious adverse event of at least moderate intensity that is 
probably or definitely related to the investigational product exceeds 75%. 
If any of these conditions are met, the enrollment is halted until the DSMB is given the opportunity to 
review the data. After the assessment of the DSMB, a discussion with the PI and the Sponsor (NCATS) 
should be held prior to the final decision to resume or permanently stop the study. 
  
Example of data provided to the DSMB: 
 
[____] of subjects with serious AE considered probably or definitely related, if >0,  halting rule 
 
[____] of subjects with serious AE considered unrelated or only possibly related, if >50%, halting rule 
 
[____] of subjects with serious AE unrelated or only possibly related + [_____] number of subjects with non-
serious AE of at least moderate intensity probably or definitely related, if >75%, halting rule 
  
7.3 LOST TO FOLLOW-UP 
  
The investigational treatment will be given for 28 days.  Participants will be followed for 180 days.  The 
patients are regularly followed in clinic and will be chosen for their compliance. The proposed study is also 
designed to be short, only 4 weeks. All study participants will receive cards with 24-hour/7-day contact 
number for study team members. This approach has been sufficient to achieve a 90% retention on average 
in prior studies of IL-1 blockade in HF at VCU. 
  
We will also implement a patient reimbursement of $100 for each of 3 compled study visits 
(Randomization Visit, 28-day Visit, and 60-day Visit) up to a total of $300 for completion of these study 
visits. 
  
We believe this may overcome some financial barriers that our patients at VCU Health and Michigan 
Medicine (formerly University of Michigan Health System) may experience related to the time and cost of 
travel. We will collect data on enrollment and retention barriers to help enhance the success of a future 
phase 3 trial. The power analysis has also taken into account a potential loss of data at follow up to 
20%.  Missing data will not be inputted.  
  
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled visits and is 
unable to be contacted by the study site staff. 
  
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 
The site will attempt to contact the participant and reschedule the missed visit within 2 weeks and counsel 
the participant on the importance of maintaining the assigned visit schedule and ascertain if the participant 
wishes to and/or should continue in the study. 
 
Before a participant is deemed lost to follow-up, the investigator or designee will make every effort to 
regain contact with the participant (where possible, 3 telephone calls and, if necessary, a certified letter to 
the participant's last known mailing address or local equivalent methods). These contact attempts should 
be documented in the participant's medical record or study file. 
 
Should the participant continue to be unreachable, he or she will be considered to have withdrawn from 
the study with a primary reason of lost to follow-up. 
  
  
 
 


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8 STUDY ASSESSMENTS AND PROCEDURES 
8.1 EFFICACY ASSESSMENTS 
8.1.1     Biomarkers 
  
Blood samples will be taken from a peripheral vein at time of screening, randomization visit and the 28-
day visit, and used for analysis of inflammatory markers - high-sensitivity C reactive protein (CRP) and 
Interleukin-6 (IL-6). 
  
Samples will be processed by the Department of Pathology at VCU or UMich, as standard of care tests are 
processed. 
  
We will compare interval changes in CRP and IL-6 between the 2 groups using an analysis of variance 
(ANOVA) for repeated measures and assessing for time_x_group interaction. 
 
Additional exploratory analyses will be conducted on cytokines from sera of patients with bioassays 
available through LabCorp.  
  
8.1.2      Quality of life questionnaires 
  
Quality of life (QoL) scores will be measured at randomization and 28-day visit with the disease-specific 
Sarcoidosis Assessment Tool (SAT), which has been shown to be reliable and consistent in sarcoidosis-
specific patient reported outcomes at baseline and at 28 days. The 51 question SAT requires about 5 to 
10 minutes to complete and is thus ideal for use in clinical settings. The SAT will be electronically 
administered as a REDCap survey on a printed format or a tablet during study visits with results directly 
built to a database. The scoring will be performed using a code provided by Dr. Marc Judson at University 
of Albany.  
  
We will compare interval changes in SAT QoL scores between the 2 groups using an analysis of variance 
(ANOVA) for repeated measures and assessing for time_x_group interaction. 
  
The following assessments of efficacy will be performed at VCU only as part of an imaging substudy. 
  
 
 8.1.3      ECG Holter Monitor  
  
Cardiac sarcoidosis is associated with a high arrhythmia burden and an increased risk of sudden 
death.  Even if asymptomatic, patients with cardiac sarcoidosis often have abnormal ECG Holter 
recordings. A 24-hour ECG Holter will be performed within 30 day of randomization and 2814 days 
follow-up to quantitate arrhythmias.  Arrhythmia data collected will include: (1) number, duration, and 
rate of sustained ventricular tachycardias;  (2) number, duration, and rate of non-sustained ventricular 


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tachycardias; (3) absolute number and percentage of premature ventricular contractions; (4) number and 
type of AV blocks; (5) number and duration of sinus pauses; and (6) occurrence of atrial 
arrhythmias.  Cardiac devices including defibrillators and pacemakers will be interrogated at baseline and 
at 28 days follow up to detect atrial and ventricular arrhythmia burdens, percentage of atrial and 
ventricular pacing, and any device malfunction. Operators blinded to treatment assignment will interpret 
the ECG Holter. 
 
8.1.4      [Cardiac Magnetic Resonance – part of Imaging Substudy @VCU] 
  
[Cardiac magnetic resonance will be performed within 30 days of randomization and after 2814 days of 
randomization visit. Cardiac function (left ventricular volumes, mass, and strain) will be assessed with a 
steady-state free precession (SSFP) cine stack in the short axis plane covering the heart from base to apex. 
Orthogonal long axis SSFP cines will be acquired to quantify long axis strain and 3D circumferential strain 
obtained with the short axis images. Tissue characterization of scar and inflammation will also be included 
in the cardiac magnetic resonance imaging protocol. Prior to contrast, short axis slices of the left ventricle 
(basal, mid-cavity, apical) will be acquired to produce native T1 and T2 maps. Following gadolinium 
contrast administration, post-contrast T1 maps will be repeated and late gadolinium enhancement (LGE) 
images will be acquired in short axis slices covering the heart. When necessary, a wideband LGE acquisition 
will be used to improve image quality and reduce artifacts associated with implanted cardiac devices. All 
images will be acquired on a 1.5T Siemens Aera scanner and images will be post-processed using Circle CVI 
42 software. In selected patients a chest radiograph may be necessary to determine the presence of 
fractured or retained device leads. Operators blinded to treatment assignment will interpret the ECG 
Holter.] 
   
 
8.2 SAFETY AND OTHER ASSESSMENTS 
This study involves greater than minimal risk related to treatment with an investigational drug, execution 
of non-invasive testing that are associated with a small, yet measurable risk, performance of multiple 
blood draws, risk of loss of privacy and confidentiality, and the possibility of incidental findings during the 
study investigations that may affect clinical care. The risk reduction strategies are presented herein. The 
risk/benefit ratio is discussed considering the potential beneficial effects of IL-1 blockade with anakinra in 
patients with recently decompensated systolic heart failure. 
 
8.2.1       Potential risks associated with anakinra 
  
Anakinra is a recombinant human IL-1 receptor antagonist that has been FDA-approved for the treatment 
of inflammatory disorders such as rheumatoid arthritis for many years. In pilot clinical trials, anakinra has 
led to improved cardiovascular function in patients with rheumatoid arthritis, ST-segment elevation acute 
myocardial infarction, and chronic systolic heart failure. The use of anakinra as an anti-inflammatory 


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treatment for cardiac sarcoidosis is justified by anakinra’s relatively low risk/benefit ratio. Anakinra has 
been used in more than 150,000 patients with rheumatoid arthritis with a favorable risk profile.16 
  
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%); 
 
Hypersensitivity reaction (rash, anaphylaxis, arthritis)(rare, 1-2%). 
 
Neutropenia (rare, <1%, reversible). 
  
The injection site reactions are by far the most common adverse reaction.17 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 rarely cause of discontinuation of therapy (<5%). 
  
Despite the increase in risk of serious infection with anakinra, such events are rather rare (<2% during 
chronic treatment in patients with rheumatoid arthritis already on other immunomodulating drugs 
[observational data]). Anakinra is indeed not associated with an increase in infection-related mortality, 
nor associated with opportunistic infection. In clinical trials with anakinra, the infection rates did not differ 
between active treatment and placebo. 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). 
  
  
8.2.2       Risks reduction strategies for Anakinra treatment 


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The risks associated with anakinra appear to be mostly related to risk of infection (1.8% vs 0.6% of serious 
infections in a rheumatoid arthritis study18), and injection site reactions. To better estimate the risk, one 
needs to place the estimates in context: the estimated 2% risk of serious infection with anakinra quoted 
in the FDA approved package insert refers to the use of anakinra/Kineret as second line agent for the 
treatment of rheumatoid arthritis, in which anakinra was used in addition to corticosteroids or other 
disease-modifying agents further increasing infectious risk. The risk of infection of anakinra monotherapy 
is not known, but it does not appear to be high. In a study cohort of patients with Neonatal Onset 
Multisystem Inflammatory Disease, another autoinflammatory condition for which anakinra is indicated, 
no dose limiting toxicities were reported for anakinra over the 148.1 patient-year study period: there were 
only 3 serious infections reported (2 wound infections and 1 gastroenteritis) and in all 3 cases, treatment 
with anakinra was considered possibly related to the event, however treatment was not discontinued and 
patients improved with antibiotics. Moreover, if one considers the ‘excess risk’ of serious infection with 
anakinra to evenly distributed through the year, a treatment of 1 month, would lead to an excess risk that 
is less than then 1.2% difference reported in the prescribing information. Nevertheless, the inherent anti-
inflammatory activity of anakinra may potentially mask some of the signs of infection such as fever and 
leukocytosis. In the CANTOS trial, canakinumab, another IL-1 blocker was associated with a 0.1% excess 
risk of life-threatening infection per year compared with placebo – canakinumab, at difference with 
anakinra, is long-acting and it cannot be stopped in case of infection, and therefore one would consider 
the risk of life-threatening infections with anakinra given for 1 month to be 10-fold lower than 
canakinumab for 1 year. 
  
To reduce the risk of infections with anakinra we plan to follow the following strategies: 
 
Exclude patients with acute or chronic infections at time of screening; 
 
Exclude patients on TNF-alpha blockers; 
 
Exclude patients who are neutropenic; 
 
Educate patients on the possibility that symptoms or signs of infections may be less evident with taking the 
investigational drug; 
 
Provide patient with 24/7 phone access to investigators to discuss potential symptoms or signs of infection. 
With this plan in place we have not seen any issues with severe infections since our first clinical trial with 
anakinra in acute STEMI in 2008 including now over 200 patients. 
  
8.2.3      Testing Risks and Risk Reduction Strategies 
  
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 will be further lowered 
by creating a secure database that does not link patient identity with clinical data. Loss of confidentiality 
is also a potential risk. However, except when required by law, patients will not be identified by name, 


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social security number, address, telephone number or any other personal identifier. The number of study 
visits could impact some aspects of the patients’ social lives. 
  
All study procedures will be performed in standard clinical settings with established protections for 
patient privacy. To protect patient confidentiality, all records will be stored in a locked office and/or 
password protected encrypted files. All patient identifiers will be removed in any presentations or 
publications. 
  
Vulnerable populations (i.e. prisoners, children) will not be eligible for participation. We will not include 
pregnant women. 
Considering the small size and the pilot nature of this study, the uncertainties of the benefit, and the 
potential challenges of communication regarding side effects, we plan to exclude subjects with limited 
English proficiency. 
  
The following risks pertain to the different tests that are being used for monitoring the treatment 
responses: 
  
 
Blood draw: minor bleeding (rare) and infection (extremely rare) at puncture site. 
 
Clinical assessment: no greater than minimal risk.  
 
Quality of life assessment: no greater than minimal risk. 
 
Adverse event assessment: no greater than minimal risk 
  
While the results of the FDG-PET are used to determine inclusion criteria, FDG-PET is considered standard 
of care and only one test will be necessary for the study and not be performed for study purposes alone. 
 
The ECG Holter monitoring has very little risk. The use of electrodes on the skin placed for 24 –or 48 hours 
can cause irritation to the skin. 
All the tests are either no greater than minimal risk or rather low risk. Only trained and skilled personnel 
will be performing study procedures thus reducing the risk of error. 
There is always the possibility of incidental findings of cardiac or non-cardiac abnormalities during the 
completion of the tests. The results will be reviewed by the PI and the other investigators, and when 
considered clinically significant the results will be communicated to the patient and documented in the 
electronic health record.  
 
The risks described below apply to the imaging substudy being completed at VCU alone: 
The risks associated with undergoing cardiac magnetic resonance include: 
During the CMR, the patient may feel mild vibrations throughout the body. The machine will produce a 
loud knocking noise.  The participant will be given earplugs to protect the ears. Some people, especially 
those who tend to feel uncomfortable in small or closed spaced, may feel “closed in” and become anxious 


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while in the scanner. The CMR will require a catheter to be inserted into one of the participant's veins in 
order to inject the CMR contrast agent. This may cause skin irritation, bleeding, and/or infection. The 
participant may have an allergic reaction to the contrast agent.  
 
Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF), a 
progressive fibrosis disease of the skin and internal organs, among patients with impaired elimination of 
the drugs. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease 
(GFR < 30 mL/min/1.73m2) as well as patients with acute kidney injury – patients with chronic moderate-
to-severe kidney disease or acute kidney injury will be excluded from this study.  
 
The magnetic field used in CMR scanning may harm people who have metal in their bodies 
(neurostimulators, certain clips, or staples from surgery). Gadolinium based contrast agents may remain 
in patients’ bodies, including the brain, for months to years after receiving these drugs. Gadolinium 
retention has not been directly linked to adverse health effects in patients with normal kidney function. 
The participant's defibrillator will be FDA approved to undergo CMR and the defibrillator will be turned to 
CMR mode for the CMR. The risks are rare (<1% chance that this will happen) and include: 
 
Abnormal fast or slow heart beats caused by the CMR.  
 
Discomfort due to slight movement or heating of the defibrillator.  
 
Fainting or passing out, worsening of heart failure.  
 
Mechanical damage to the defibrillator or leads caused by the CMR.  
 
Irregular defibrillator function caused by the CMR.  
 
Interruption of normal pacing or pacing too fast caused by the CMR.  
 
Device pacing irregularly or not continuously.  
 
Device not able to shock the heart.  
 
Increased pacing electricity needed to make the heart beat.  
 
Movement of the defibrillator or leads.  
 
Difficulty with the defibrillator being able to see your normal heart beat.  
 
Symptoms from the defibrillator making your heart beat at a slightly faster and fixed rate on purpose during 
the CMR.  
 
Death. 
 
For some devices, coming into contact with the strong magnetic field of a CMR scanner will likely damage 
the Beeper function on the defibrillator such that it may no longer be heard (Likely, > 50% chance that this 
will happen).  


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 
The heart doctor can explain the potential risks of loss of beeper function. For example: The device will no 
longer beep when the battery is low and it is time to replace. However, the heart doctor will be able to check 
the battery status with a programmer at every clinic visit to make sure the device is replaced before the 
battery runs out - or - The device will no longer beep for certain patient conditions or device malfunctions. 
However, the physician can use a programmer to identify and react to these situations. Home monitoring 
systems will also identify such conditions and alert the heart doctor. 
 
There is a risk that the CMR will detect an unrelated health problem that may need to be evaluated and 
treated. 
In selected patients, there may be a need for a chest radiograph to exclude the presence of retained or 
fractured device leads.  A chest radiograph exposes the patient to a very low dose of radiation, a negligible 
increased risk to health. 
 
8.3 Adverse Events and Serious Adverse Events 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
  
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
  
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the participant and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse. 
  
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
  
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines will 
be used to describe severity. 
  


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Grading: 
 
Mild: events require minimal or no treatment and do not interfere with the daily activities. 
 
Moderate: events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning and may require local or systemic drug 
therapy. 
 
Severe: events interrupt a patient’s usual daily activity and will likely require systemic drug therapy or 
other treatment. Severe events are often incapacitating. 
 
Serious or 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 (it does not include a reaction 
that had it occurred in a more severe form, might have caused death), or results in hospitalization (or 
prolongation of a hospitalization), disability or permanent damage, need of a surgical intervention or 
device implantation to prevent disability, or death. 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
  
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. The 
degree of certainty about causality will be graded using the categories below. In a clinical trial, the study 
product must always be suspect. 
  
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. 
  
8.3.3.3 EXPECTEDNESS 
  
Dr. Jordana Kron and/or Dr. Antonio Abbate will be responsible for the initial determination whether an 
adverse event (AE) is expected or unexpected.  An AE will be considered unexpected if the nature, 
severity, or frequency of the event is not consistent with the risk information previously described for the 
study intervention. 


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8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
  
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
  
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of onset, 
clinician's assessment of severity, relationship to study product (assessed only by those with the training 
and authority to make a diagnosis), 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 participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant's condition deteriorates at any time 
during the study, it will be recorded as an AE. 
  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
  
Dr. Jordana Kron and/or Dr. Antonio Abbate will record all reportable events with start dates occurring 
any time after informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the 
last day of study participation.  At each study visit, the investigator will inquire about the occurrence of 
AE/SAEs since the last visit.  Events will be followed for outcome information until resolution or 
stabilization. 
8.3.5 ADVERSE EVENT REPORTING 
  
 All suspected AEs must have their severity and relationship to study intervention assessed as soon as 
possible (possibly within 24 hours and always within 7 days). 
  
All AE reporting not meeting requirements for required immediate SAE reporting, as described below, will 
be reported in aggregate to the DSMB and NCATS every 6 months and to the IRB every 12 months. 
  
8.3.6 SERIOUS ADVERSE EVENT REPORTING 
  
The MAGiC ART is an investigator-initiated study in which, for the purpose of the FDA, the investigator is 
also the sponsor. 
The study is conducted under 21 CFR 312.2(b) regulation for IND exemption (as indicated by pre-IND 
inquiry 142352 of December 19, 2018 to Dr. Abbate) 


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All co-investigators will be instructed to immediately report to the PI (functioning as PI/Sponsor) of any 
serious adverse event, whether or not considered study intervention related, including those listed in the 
protocol or investigator brochure and must include an assessment of whether there is a reasonable 
possibility that the study intervention caused the event. 
  
The PI/Sponsor is responsible to determine if the criteria for reporting to the DSMB/NCATS/FDA are met. 
The PI/Sponsor is also responsible for following all serious adverse events (SAEs) until satisfactory 
resolution or until the site investigator deems the event to be chronic or the participant is stable.  
  
The PI/Sponsor will be responsible for notifying the DSMB, NCATS, IRB and the Food and Drug 
Administration (FDA) of any unexpected fatal or life-threatening suspected adverse reaction as soon as 
possible, but in no case later than 7 calendar days. 
  
The PI/Sponsor must report any suspected adverse reaction that is both serious and unexpected. 
The sponsor must report an adverse event as a suspected adverse reaction only if there is evidence to 
suggest a causal relationship between the drug and the adverse event, examples are: (A) A single 
occurrence of an event that is uncommon and known to be strongly associated with drug exposure (e.g., 
angioedema, hepatic injury, Stevens-Johnson Syndrome); (B) One or more occurrences of an event that is 
not commonly associated with drug exposure, but is otherwise uncommon in the population exposed to 
the drug (e.g., tendon rupture); (C) An aggregate analysis of specific events observed in a clinical trial (such 
as known consequences of the underlying disease or condition under investigation or other events that 
commonly occur in the study population independent of drug therapy) that indicates those events occur 
more frequently in the drug treatment group than in a concurrent or historical control group.” 
  
8.3.7 REPORTING EVENTS TO PARTICIPANTS 
  
Individuals affected by AEs will be debriefed on an individual levels and provided the opportunity to 
discuss additional diagnostic and therapeutic options, as applicable. These may include discontinuation of 
investigational therapy, targeted treatments, additional testing. When appropriate, and only if with the 
consent of the subjects, the primary care physician will also be debriefed and a note will be added to the 
electronic health record to document the findings. 
  
There will be no sharing of AEs in aggregate, other than what publicly disclosed in publications or 
presentations. 
8.3.8 EVENTS OF SPECIAL INTEREST 
Not applicable 
8.3.9 REPORTING OF PREGNANCY 
Not applicable 


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8.4 UNANTICIPATED PROBLEMS 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
  
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
  
 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are described 
in the protocol-related documents, such as the Institutional Review Board (IRB)-approved research protocol 
and informed consent document; and (b) the characteristics of the participant population being studied; 
 
Related or possibly related to participation in the research (“possibly related” means there is a reasonable 
possibility that the incident, experience, or outcome may have been caused by the procedures involved in 
the research); and 
 
Suggests that the research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
8.4.2  UNANTICIPATED PROBLEM REPORTING 
  
The investigator will report unanticipated problems (UPs) to the reviewing IRB and the DSMB. 
  
The UP report will include the following information: 
 
A detailed description of the event, incident, experience, or outcome; 
 
An explanation of the basis for determining that the event, incident, experience, or outcome represents an 
UP; 
 
A description of any changes to the protocol or other corrective actions that have been taken or are 
proposed in response to the UP. 
  
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:  
  
 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the DSMB within 5 days of the 
investigator becoming aware of the event. 
 
Any other UP will be reported to the IRB and to the DMSB  within 5 days of the investigator becoming aware 
of the problem. 


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8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS 
  
There will be no prespecified reporting procedure to participants regarding UAP. Any reporting procedure 
would be discussed with the IRB. 


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9 STATISTICAL CONSIDERATIONS 
9.1 STATISTICAL HYPOTHESES 
 
Primary Efficacy Endpoint(s): 
Interval change in CRP levels from baseline to 28 days  
  
We hypothesize that anakinra will reduce systemic inflammation as shown by CRP  levels. CRP will be 
measured with a widely available high-sensitivity assay able to detect values in the normal range (<2 mg/l). 
Hs-CRP will be measured at randomization visit and again at 28±3 days. We will use ANOVA for repeated 
measures and assess time_x_group interaction to determine differences between changes in the anakinra 
on top of standard of care group versus standard of care only group. 
  
 
Secondary Efficacy Endpoint(s): 
Interval change in IL-6 levels from baseline to 28 days  
  
We hypothesize that anakinra will reduce systemic inflammation as shown by IL-6 levels. IL-6 will be 
measured with a widely available ELISA assay . IL-6 will be measured at randomization visit and again at 
28±3 days. We will use ANOVA for repeated measures and assess time_x_group interaction to determine 
differences between changes in anakinra group versus control group. 
  
Interval change in QoL scores at SAT  
  
We hypothesize that anakinra will improve QoL scores on SAT questionnaires. QoL SAT will be measured 
at enrollment and again at 28±3 days. We will use ANOVA for repeated measures and assess time_x_group 
interaction to determine differences between changes in anakinra group versus control group 
 
Additional Efficacy Endpoints(s) for Imaging Substudy available at VCU 
 
[Interval change in T2 mapping at CMR] 
  
[We hypothesize that anakinra will reduce myocardial edema as measured by T2 mapping at CMR. T2 
mapping will be completed within 30 days of randomization and again at 28±14 days. We will use ANOVA 
for repeated measures and assess time_x_group interaction to determine differences between changes in 
anakinra versus control.] 
  
[Interval change in cardiac FDG-PET inflammation signal] 
  


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[We hypothesize that anakinra will reduce myocardial inflammation as measured by cardiac PET signaling. 
PET signaling will be completed within 60 days of randomization and again at 28±14 days. We will use 
ANOVA for repeated measures and assess time_x_group interaction to determine differences between 
changes in anakinra versus control.] 
  
9.2 SAMPLE SIZE DETERMINATION 
Using an informatics-based tool by TriNetX we ran a retrospective analysis of patients seen in the Cardiac 
Sarcoidosis Clinic at VCU in the past year: we identified 30 subjects with sarcoidosis who had CRP 3-20 
mg/L (we excluded patients with CRP>20 mg/L as they may have had concomitant bacterial infection, and 
therefore could be excluded upon screening). The mean age was 55 years (range 37-82), 55% were men, 
and 77% were African American. The CRP was 7.64 ±3.74 mg/L (mean±standard deviation). We predict a 
reduction of CRP by >60% in the anakinra group and no change in standard of care only group. The Table 
below shows estimated power for CRP reduction between 50% and 75% in the active treatment group (on 
top of standard of care changes, which are expected to be close to 0), and we evaluated 3 different 
standard deviation (SD) values starting with 3.74 mg/l which was obtained from our VCU cohort and 
exploring 0.9x and 1.1x SD. 
 
 
 
9.3 POPULATIONS FOR ANALYSES 
We plan to compare the 2 groups (anakinra and control) in an intention-to-treat analysis by which all 
patients who (1) met all inclusion/exclusion criteria and (2) were randomly assigned to one of the 2 groups 
were considered as ‘treated’ independent of whether the patients assigned to anakinra received all or 
some or any of the investigational treatment after randomization has been completed and treatment 
assigned. For exploratory purposes we will also perform a per-protocol analysis in which the individual 
subjects not only will need to meet conditions (1) and (2) but also (3) need to have reported compliance 
with >75% of investigational drug prescribed. 
 
 


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9.4 STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
  
We will compare the change using an ANOVA for repeated measures in which we assess for the 
significance of the interaction of treatment allocation and time interval (time_x_group interaction) using 
SPSS 25.0 (Chicago, IL).  Additional exploratory endpoints will include absolute CRP values at 28 days, and 
the percentage of patients with CRP <2 mg/L at each time point. The interval change in CRP levels from 
baseline to 28 days will be expressed as median and interquartile range. All reporting will be in conjunction 
with the CONSORT statement.19  
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
  
We therefore hypothesize that anakinra will reduce systemic inflammation as shown by CRP. CRP will be 
measured with a widely available high-sensitivity assay able to detect values in the normal range (<2 mg/l). 
CRP will be measured at enrollment and again at 28±3 days. 
  
Interval change in CRP levels from baseline to 28 days will represent the primary endpoint. 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
  
We will measure changes in IL-6, an additional inflammatory biomarker as a secondary endpoint. Changes 
in QoL scores will also be considered a secondary endpoint. 
  
Additional secondary endpoints to be completed as part of the imaging substudy at VCU includes 
assessment of myocardial edema with T2 mapping at CMR, and myocardial inflammation with cardiac 
FDG-PET. 
9.4.4 SAFETY ANALYSES 
  
The DSMB will monitor the progress of the present trial. The DSMB will meet regularly to review safety 
data every 6 months or sooner in case of a serious unexpected adverse event that is considered to be 
possibly, probably or definitely related to the research. All meetings, and specifically any action taken by 
the committee and the reasons for the actions, will be recorded. These documents will include any data 
summaries or analyses provided to the DSMB and will remain confidential until the study is concluded. 
No interim efficacy analyses are planned. 
  
Interim safety analyses will, however, be performed at each meeting. The DSMB will be provided with 
data related to adverse events. 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 
following pre-specified halting rules are provided to the DSMB as guidance. 


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Example of data provided to the DSMB: 
 
[____] of subjects with serious AE considered probably or definitely related, if >0, halting rule 
 
[____] of subjects with serious AE considered unrelated or only possibly related, if >50%, halting rule 
 
[____] of subjects with serious AE unrelated or only possibly related + [_____] number of subjects with non-
serious AE of at least moderate intensity probably or definitely related, if >75%, halting rule 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
  
The DSMB will be provided with the number of subjects enrolled, stratified by sex and race/ethnicity. 
Mean age and range will also be provided. 
9.4.6 PLANNED INTERIM ANALYSES 
  
There will be no planned efficacy interim analyses. 
9.4.7 SUB-GROUP ANALYSES 
  
Randomization will be stratified by site (VCU and UMich) and by race/ethnicity. Two pre-specified sub-
group analyses includes site and race/ethnicity. 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
  
Not applicable. 
9.4.9 EXPLORATORY ANALYSES 
  
Not applicable. 


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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Informed Consent forms describing in detail the study intervention, study procedures, and risks are 
given to the participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  The IRB-approved informed consent form is attached to 
this protocol as Appendix. 
  
Potential participants will be approached by the investigators during their standard-of-care visits in the 
VCUHealth or UMich Sarcoidosis Clinic in private patient rooms. The investigator will review the consent 
form with the patients and invite them ask any questions about the study. All potential participants will 
be allowed to take the consent form home to review with friends/family or other health care providers. 
Once the potential participants have had all of their questions answered, they will be invited to sign the 
consent form. 
  
Participants will not be coerced into participation. They will be advised that their refusal to participate 
will not affect their standard of care. All potential participants will be allowed to take the consent form 
home to review with friends/family or other health care providers. Participants will have as much time 
as needed to decide to participate or not. These are existing sarcoidosis patients that are regularly seen 
in the VCUHealth or UMich Sarcoidosis clinic. 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent is a process that is initiated prior to the individual's agreeing to participate in the 
study and continues throughout the individual's study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may arise. 
A verbal explanation will be provided in terms suited to the participant's comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research 
participants.  Participants will have the opportunity to carefully review the written consent form and ask 
questions prior to signing. The participants should have the opportunity to discuss the study with their 
family or surrogates or think about it prior to agreeing to participate. The participant will sign the 
informed consent document prior to any procedures being done specifically for the study. Participants 
must be informed that participation is voluntary and that they may withdraw from the study at any 
time, without prejudice. A copy of the informed consent document will be given to the participants for 
their records. The informed consent process will be conducted and documented in the source document 
(including the date), and the form signed, before the participant undergoes any study-specific 


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procedures. The rights and welfare of the participants will be protected by emphasizing to them that the 
quality of their medical care will not be adversely affected if they decline to participate in this study. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigators, and funding 
agency.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform study participants, the IRB, and sponsor and will provide the reason(s) for the 
termination or suspension.  Study participants will be contacted, as applicable, and be informed of 
changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
 
Determination of unexpected, significant, or unacceptable risk to participants 
 
Demonstration of efficacy that would warrant stopping   
 
Insufficient compliance to protocol requirements 
 
Data that are not sufficiently complete and/or evaluable 
 
Determination that the primary endpoint has been met 
 
Determination of futility 
  
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the IRB and/or DSMB. 
10.1.3 CONFIDENTIALITY AND PRIVACY 
  
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. Therefore, the study protocol, documentation, data, 
and all other information generated will be held in strict confidence. No information concerning the 
study or the data will be released to any unauthorized third party without prior written approval of the 
sponsor. 
  
All research activities will be conducted in as private a setting as possible. 
  
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) 


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and pharmacy records for the participants in this study. The clinical study site will permit access to such 
records. 
  
The study participant's contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
  
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at VCU. This will not include the participant's contact or identifying 
information if the subject was enrolled at UMich. Rather, individual participants and their research data 
will be identified by a unique study identification number. The study data entry and study management 
systems used by clinical sites and by VCU research staff will be secured and password protected. At the 
end of the study, all study databases will be de-identified and archived at VCU. 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA 
  
Data collected for this study will be analyzed and stored at the Virginia Commonwealth University and 
UMich. After the study is completed, the de-identified, archived data will be transmitted to and stored 
at the Virginia Commonwealth University. Permission to transmit data to the Virginia Commonwealth 
University will be included in the informed consent. 
  
With the participant's approval and as approved by local Institutional Review Boards (IRBs), de-identified 
biological samples will be stored at VCU. These samples could be used for research the causes 
of Sarcoidosis, its complications and other conditions for which individuals with Sarcoidosis are at 
increased risk, and to improve treatment.  
  
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for research. 
  
Access to study data and/or samples will be no longer allowed after study completion. 
  
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
SEE DELEGATION LOG ON FILE 
  
10.1.6 SAFETY OVERSIGHT 
  
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) composed of 
individuals with the appropriate expertise, included in the list below. The DSMB for this study is formed 
according to the Food and Drug Administration guidance document [OMB Control No. 0910-0581]. The 


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DSMB liaison and coordinator, Amy Ladd, PhD, will provide the board members with data regarding 
screening, enrollment, adverse events and withdrawals, and he/she will not participate in the voting. 
Members of the DSMB are independent from the study conduct and free of conflict of interest.  The 
DSMB will meet at least semiannually to assess safety and efficacy data on each arm of the study. The 
DMSB will operate under the rules of an approved charter that will be written and reviewed at the 
organizational meeting of the DSMB. At this time, each data element that the DSMB needs to assess will 
be clearly defined. The DSMB will provide its input to NCATS. 
  
The DSMB, whose members are independent from the study operations, is composed of 4 clinicians and 
a biostatistician not involved in the conduct of the study. The DSMB will include Dr. Lynda Rosenfeld 
(Professor of Medicine, Cardiac Electrophysiology, Yale University), serving as Chair of the board, Dr. 
Alpha Fowler (Director of VCU Johnson Center for Critical Care and Pulmonary Research), Dr. Melissa 
Smallfield (Associate Professor of Medicine, Advanced Heart Failure and Transplantation, VCU), and Dr. 
David Birnie (Deputy Chief and Directory of Research, University of Ottawa), and Le Kang, PhD (VCU 
Statistician). The DSMB will meet every 6 months or sooner in case of any unanticipated serious adverse 
events considered to be possibly, probably or definitely related to research. 
  
The DSMB may request an expert opinion by one or more non-members, however only the DSMB 
members will vote on any individual issue. The DSMB (following positive vote by 3 or more members) 
may request temporary or permanent halting of the study (see halting rules), or interruption of 
treatment of one or more patients. The minutes from each meeting will be distributed to the board 
members, 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 after every meeting which is to occur at least twice yearly. 
  
 
DSMB Voting Members 
  
Lynda Rosenfeld, MD  DSMB Chair 
Dr. Rosenfeld is a Professor of Medicine in Cardiology and Pediatrics at Yale University.  She is board 
certified in Internal Medicine and Cardiovascular Disease. She is the Director of the Clinical Cardiac 
Electrophysiology Fellowship Program.       
https://medicine.yale.edu/intmed/profile/lynda_rosenfeld/ 
  
Alpha Fowler, MD 
Dr. Fowler is a Professor of Medicine in Pulmonary and Critical Care Medicine at VCU.  He is board 
certified in Internal Medicine and Pulmonary Disease. He is the Director of the VCU Johnson Center for 
Critical Care and Pulmonary Research.  
https://www.vcuhealth.org/find-a-provider/find-a-provider/Alpha-Fowler 
  
Melissa Smallfield, MD 


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Dr. Smallfield is an Associate Professor of Medicine and serves as the Fellowship Program Director for 
Advanced Heart Failure and Transplantation. She is board certified in Internal Medicine, Cardiovascular 
Disease, and Advance Heart Failure and Transplant Cardiology. 
https://www.vcuhealth.org/find-a-provider/find-a-provider/melissa-smallfield  
  
David Birnie, MD 
Dr. Birnie is a Professor of Medicine in Cardiology at the University of Ottawa Health Institute.  He is the 
Deputy Division Head of Cardiology and the Director of Clinical Research for the Division of Cardiology.    
https://www.ottawaheart.ca/physician-researcher-profile/birnie-david 
  
Le Kang, PhD 
Dr. Kang is an Assistant Professor in the Department of Biostatistics at VCU. 
http://wp.vcu.edu/biostats/le-kang/ 
  
Non-voting Members 
DSMB Liaison 
  
Amy Ladd, PhD                       DMSB Liaison 
Amy Ladd, PhD, CCRP is a Research Regulatory Manager in the Division of Cardiology at VCU. 
  
NCATS Liaison 
  
Pablo Cure, MD, MPH                                   NCATS Liaison 
Dr. Cure is the Program Director of the Division of Clinical Innovation at the National Center for 
Advancing Translational Sciences, NIH.  He will be a non-voting member of the DSMB. 
  
  
10.1.7 CLINICAL MONITORING 
  
  
The DSMB will monitor the progress of the present trial. The DSMB will meet regularly to review safety 
data every 6 months or sooner in case of a serious unexpected adverse event that is considered to be 
possibly, probably or definitely related to the research. 
  
All meetings, and specifically any action taken by the committee and the reasons for the actions, will be 
recorded. These documents will include any data summaries or analyses provided to the DSMB and will 
remain confidential until the study is concluded. No interim efficacy analyses are planned. 
  
Interim safety analyses will, however, be performed at each meeting. The DSMB will be provided with 
data related to adverse events. 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. 


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If no safety concerns are found, enrollment will continue until the target sample size is reached. The 
following pre-specified halting rules are provided to the DSMB as guidance. 
  
Halting rules 
  
The study will be temporarily suspended if any of the following conditions are met: 
 
Any serious adverse event that probably or definitely related to the investigational product; 
 
The number of subjects experiencing a serious adverse event considered unrelated or only possibly related 
to the investigational product exceeds 50% (after the first 3 or more subjects are enrolled); 
 
The number of subjects experiencing either a serious adverse event considered unrelated or only possibly 
related to the investigational product or a non-serious adverse event of at least moderate intensity that is 
probably or definitely related to the investigational product exceeds 75%. 
  
If any of these conditions are met, the enrollment is halted until the DSMB is given the opportunity to 
review the data and consider the request for unblinding. After the assessment of the DSMB, a discussion 
with the PI and the Sponsor (NCATS) should be held prior to the final decision to resume or permanently 
stop the study. 
  
Example of data provided to the DSMB: 
 
[____] of subjects with serious AE considered probably or definitely related à if >0 --> halting rule 
 
[____] of subjects with serious AE considered unrelated or only possibly related à if >50% --> halting rule 
 
[____] of subjects with serious AE unrelated or only possibly related + [_____] number of subjects with 
non-serious AE of at least moderate intensity probably or definitely related à if >75% --> halting rule 
  
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
  
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.   
  
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated.  
  
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
  


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10.1.9 DATA HANDLING AND RECORD KEEPING 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
  
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.  
  
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report 
form (eCRF) derived from source documents should be consistent with the data recorded on the source 
documents. 
  
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and clinical 
laboratory data will be entered into OnCore, a 21 CFR Part 11-compliant data capture system provided 
by the [specify DCC]. The data system includes password protection and internal quality checks, such as 
automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical 
data will be entered directly from the source documents. 
10.1.9.2 STUDY RECORDS RETENTION 
  
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Conference on Harminosation (ICH) region and until there are no pending 
or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study intervention. These documents should be 
retained for a longer period, however, if required by local regulations. No records will be destroyed 
without the written consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform 
the investigator when these documents no longer need to be retained. 
10.1.10 PROTOCOL DEVIATIONS 
  
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or MOP requirements. The noncompliance may be either 
on the part of the participant, the investigator, or the study site staff. As a result of deviations, corrective 
actions are to be developed by the site and implemented promptly. 
  
These practices are consistent with ICH GCP: 
 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 


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 
5.1 Quality Assurance and Quality Control, section 5.1.1 
 
5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
  
It is the responsibility of the site investigator to use continuous vigilance to identify and report deviations 
within [specify number] working days of identification of the protocol deviation, or within [specify 
number] working days of the scheduled protocol-required activity.  All deviations must be addressed in 
study source documents, reported to NCATS Program Official and Virginia Commonwealth 
University.  Protocol deviations must be sent to the reviewing IRB per their policies. The site investigator 
is responsible for knowing and adhering to the reviewing IRB requirements. Further details about the 
handling of protocol deviations will be included in the MOP. 
  
10.1.11 PUBLICATION AND DATA SHARING POLICY 
  
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
  
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
  
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals.  Data from this study may be requested from other researchers x years after the 
completion of the primary endpoint by contacting [specify person or awardee institution or name of 
data repository]. 
  
In addition, this study will comply with the NIH Genomic Data Sharing Policy, which applies to all NIH-
funded research that generates large-scale human or non-human genomic data, as well as the use of 
these data for subsequent research. Large-scale data include genome-wide association studies (GWAS), 
single nucleotide polymorphisms (SNP) arrays, and genome sequence, transcriptomic, epigenomic, and 
gene expression data. 
  
10.1.12 CONFLICT OF INTEREST POLICY 
  
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore any actual conflict of interest of persons who have a role in the design, 


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conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study 
leadership in conjunction with the NCATS has established policies and procedures for all study group 
members to disclose all conflicts of interest and will establish a mechanism for the management of all 
reported dualities of interest. 
 
 
10.2 ADDITIONAL CONSIDERATIONS 
 
 
10.3 ABBREVIATIONS 
AE
Adverse Event
ANOVA
Analysis of Variance
CFR
Code of Federal Regulations
CLIA
Clinical Laboratory Improvement Amendments
CMP
Clinical Monitoring Plan
CMR
Cardiac Magnetic Resonance
COC
Certificate of Confidentiality
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form
CRP
C Reactive Protein
DHHS
Department of Health and Human Services
DSMB
Data Safety Monitoring Board
eCRF
Electronic Case Report Forms
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act of 2007
FDG PET
Fluoro-de-oxy-glucose positron emission tomography
FFR
Federal Financial Report
GCP
Good Clinical Practice
GLP
Good Laboratory Practices
GMP
Good Manufacturing Practices
HIPAA
Health Insurance Portability and Accountability Act
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IDE
Investigational Device Exemption


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IL-6
Interleukin-6
IND
Investigational New Drug Application
IRB
Institutional Review Board
ISM
Independent Safety Monitor
ISO
International Organization for Standardization
ITT
Intention-To-Treat
MedDRA
Medical Dictionary for Regulatory Activities
MOP
Manual of Procedures
MSDS
Material Safety Data Sheet
NCT
National Clinical Trial
NCATS
National Center for the Advancing Translational Sciences
NIH
National Institutes of Health
OHRP
Office for Human Research Protections
PI
Principal Investigator
QA
Quality Assurance
QC
Quality Control
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SMC
Safety Monitoring Committee
SOA
Schedule of Activities
SOC
System Organ Class
SOP
Standard Operating Procedure
UMich
University of Michigan
UP
Unanticipated Problem
US
United States
VCU
Virginia Commonwealth University
 
 


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11 REFERENCES 
REFERENCES 
1. Cavalli G, Dinarello CA. Anakinra therapy for non-cancer inflammatory diseases. Front Pharmacol 
2018;1157. 
2. Kaiser C, Knight A, Nordstrom D, Pettersson T, Fransson J, Florin-Robertsson E, Pilstrom B. Injection-site 
reactions upon Kineret (anakinra) administration: experiences and explanations. Rheumatol Int 
2012;32:295-9. 
3. Abbate A, Kontos MC, Abouzaki NA, Melchior RD, Thomas C, Van Tassell BW, Oddi C, Carbone S, Trankle 
CR, Roberts CS, Mueller GH, Gambill ML, Christopher S, Markley R, Vetrovec GW, Dinarello CA and Biondi-
Zoccai G. Comparative safety of interleukin-1 blockade with anakinra in patients with ST-segment 
elevation acute myocardial infarction (from the VCU-ART and VCU-ART2 pilot studies). Am J Cardiol. 
2015;115:288-92. 
4. Van Tassell BW, Arena RA, Toldo S, Mezzaroma E, Azam T, Seropian IM, Shah K, Canada J, Voelkel NF, 
Dinarello CA and Abbate A. Enhanced interleukin-1 activity contributes to exercise intolerance in patients 
with systolic heart failure. PLoS One. 2012;7:e33438. 
5. Van Tassell BW, Canada J, Carbone S, Trankle C, Buckley L, Oddi Erdle C, Abouzaki NA, Dixon D, Kadariya D, 
Christopher S, Schatz A, Regan J, Viscusi M, Del Buono M, Melchior R, Mankad P, Lu J, Sculthorpe R, 
Biondi-Zoccai G, Lesnefsky E, Arena R and Abbate A. Interleukin-1 blockade in recently decompensated 
systolic heart failure: Results From REDHART (Recently Decompensated Heart Failure Anakinra Response 
Trial). Circ Heart Fail. 2017;10. 
6. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, 
Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, 
Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ 
and Group CT. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 
2017;377:1119-1131. 
7. Everett BM, Cornel J, Lainscak M, Anker SD, Abbate A, Thuren T, Libby P, Glynn RJ and Ridker PM. Anti-
inflammatory therapy with canakinumab for the prevention of hospitalization for heart failure. 
Circulation. 2018. 
8. Trankle CR, Canada JM, Cei L, Abouzaki N, Oddi-Erdle C, Kadariya D, Christopher S, Viscusi M, Del Buono 
M, Kontos MC, Arena R, Van Tassell B and Abbate A. Usefulness of canakinumab to improve exercise 
capacity in patients with long-term systolic heart failure and elevated c-reactive protein. Am J Cardiol. 
2018;122:1366-1370. 
9. Kineret (Anakindra) Drug Approval Package. 2001;2018. 
10. Furst DE. Anakinra: Review of recombinant human interleukin-I receptor antagonist in the treatment 
ofrheumatoid arthritis. Clin Ther. 2004;26:1960-75. 


Interleukin-1 blockade in cardiac sarcoidosis 
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Protocol MAGiC ART 
31 AUG 2021
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
56
11. Buckley LF and Abbate A. Interleukin-1 blockade in cardiovascular diseases: A clinical update. Eur Heart J. 
2018;39:2063-2069. 
12. Buckley LF and Abbate A. Interleukin-1 blockade in cardiovascular diseases: From bench to bedside. 
BioDrugs. 2018;32:111-118. 
13. Van Tassell BW, Abouzaki NA, Oddi Erdle C, Carbone S, Trankle CR, Melchior RD, Turlington JS, Thurber CJ, 
Christopher S, Dixon DL, Fronk DT, Thomas CS, Rose SW, Buckley LF, Dinarello CA, Biondi- Zoccai G and 
Abbate A. Interleukin-1 blockade in acute decompensated heart failure: A randomized, doubleblinded, 
placebo-controlled pilot study. J Cardiovasc Pharmacol. 2016;67:544-51. 
14. Van Tassell BW, Arena R, Biondi-Zoccai G, Canada JM, Oddi C, Abouzaki NA, Jahangiri A, Falcao RA, Kontos 
MC, Shah KB, Voelkel NF, Dinarello CA and Abbate A. Effects of interleukin-1 blockade with anakinra on 
aerobic exercise capacity in patients with heart failure and preserved ejection fraction (from the D-HART 
pilot study). Am J Cardiol. 2014;113:321-327. 
15. Van Tassell BW, Trankle CR, Canada JM, Carbone S, Buckley L, Kadariya D, Del Buono MG, Billingsley H, 
Wohlford G, Viscusi M, Oddi-Erdle C, Abouzaki NA, Dixon D, Biondi-Zoccai G, Arena R and Abbate A. IL-1 
blockade in patients with heart failure with preserved ejection fraction. Circ Heart Fail. 2018;11:e005036. 
16. Cavalli G, Dinarello CA. Anakinra therapy for non-cancer inflammatory diseases. Front Pharmacol 
2018;1157. 
17. Kaiser C, Knight A, Nordstrom D, Pettersson T, Fransson J, Florin-Robertsson E, Pilstrom B. Injection-site 
reactions upon Kineret (anakinra) administration: experiences and explanations. Rheumatol Int 
2012;32:295-9. 
18. Mertens M, Singh JA. Anakinra for rheumatoid arthritis: a systematic review. J Rheumatol 2009;36:1118-
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19. Schulz KF, et al. CONSORT 2010 Statement: BMJ 2010;340:c332 - PMID:20335313. 

ICF_001.pdf: 
Interleukin-1 Blockade for Treatment of Cardiac Sarcoidosis  
 
Jordana Kron, MD 
VCU IRB PROTOCOL NUMBER: HM20015843 
 
NCT04017936 
 
Version 3-10-22, Approved 4/1/2022 


VCU IRB PROTOCOL NUMBER: HM20015843
RESEARCH PARTICIPANT INFORMATION AND CONSENT FORM
STUDY TITLE:
Interleukin-1 Blockade for Treatment of Cardiac Sarcoidosis 
VCU INVESTIGATOR: Jordana Kron, MD
Professor, Division of Cardiology
SPONSOR:
Virginia Commonwealth University 
FUNDING:
American Heart Association
Virginia Commonwealth University
National Center for the Advancing Translational Sciences
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.
AN OVERVIEW OF THE STUDY AND KEY INFORMATION
Why is this study being done?
The purpose of this research study is to test the safety, tolerability, and effectiveness of the 
medication Anakinra (Kineret®) when used to treat Cardiac Sarcoidosis. You are being asked to 
participate in this study because you have been diagnosed with Cardiac Sarcoidosis, 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 cardiac 
sarcoidosis.
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What will happen if I participate?
If you participate in this study, you will be randomly assigned (like the flip of a coin) to receive 
Anakinra (Kineret®) on top of standard of care or standard of care only. Anakinra (Kineret®) is 
administered as an injection under the skin, given once a day for 28 days in a row. You will be 
instructed how to give yourself the injections at home. If you are assigned to the standard of 
care only, you will not receive any additional treatment.
In this study, you will be asked to do the following things:
1. Visit Dr. Kron’s Clinic up to 4 times for study visits: a Screening visit (to make sure you meet 
the study entry requirements), a Randomization visit (where you will be randomly assigned 
to receive Anakinra on top of standard of care or standard of care only), at 28-days (after 
you’ve completed the study injections), and at 60 days for a blood draw.
2. If you are assigned to the Anakinra (Kineret®) arm, administer the study drug injections 
once a day for 28 days in a row. Anakinra (Kineret®) syringes will need to be stored in your 
refrigerator at home.
3. Have your blood drawn up to 3 times (Screening, 28-day, and 60-day study visits). You may 
have up to 3 tablespoons of blood drawn at each visit, which amounts to about 9 
tablespoons of blood that we may draw over the entire course of the study.
4. If you are a woman of child-bearing potential, a urine pregnancy test will be done at the 
Screening visit. Pregnant women and nursing mothers may not be in this study.
5. Have a Cardiac FDG-PET scan done 2 times (between the Screening and Randomization 
visits if you have not had one as part of your routine care within 2 months of enrollment 
and after the after 28-days of study injections or standard of care).
6. Have a Cardiac MRI scan done 2 times (between the Screening and Randomization visits and 
after 28 days of study injections or standard of care). You may need an additional X-ray of 
your chest or other part of your body to exclude loose fragments of metal before an MRI is 
performed.
7. Wear a 24-hour Holter monitor 2 times (between the Screening and Randomization visits 
and after 28 days of study injections or standard of care)
8. Complete a quality of life questionnaire about Cardiac Sarcoidosis 2 times (at the 
Randomization and the 28-day visits)
9. Give permission for the study staff to contact you at around 6 months after you enroll to ask 
how you are doing.
10. Give permission for the researchers to collect information from your medical records about 
your medical history, medications, and any side effects or hospital visits for up to 6 months 
after you start the study.
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Your participation in this study will last up to 6 months.
This is a multi-center study. This study will enroll 28 participants. Approximately 14 people will 
participate in this study at VCU.
This study will not use your samples to sequence all or part of your DNA.
What alternative treatments or procedures are available?
If you decide not to participate in this study, you can still receive the usual treatments for 
cardiac sarcoidosis.
What are the risks and benefits of participating?
There are both risks and benefits of participating in research studies. We want you to know 
about a few key risks right now. We will give you more information in the “WHAT RISKS AND 
DISCOMFORTS CAN I EXPECT FROM BEING IN THE STUDY?” section.
Risks and Discomforts
Benefits to You and
Others
1. There is a risk that adding Anakinra (Kineret®) may not be as 
good as the usual approach for cardiac sarcoidosis. Your 
condition may not get better (or could become worse) while 
you are in this study.
2. There is a risk that you could have side effects from taking 
study drug. Anakinra is generally well-tolerated but some side 
effects are possible, including:

Injection site reaction (> 10%) such as pain, redness or 
irritation at the site of the injections

Serious infection (< 5%)

Headache (1 – 10%)

Nausea (1 – 10%)

Diarrhea (1 – 10%)

Low white blood cell count (< 1%, but not associated with 
increased risk of infection)
3. There may be some risks that the study doctors do not know 
about yet, so we will let you know of any new findings.
4. Other risks to participation in this study include:

Blood draws may cause pain, bleeding, and/or bruising. 
You may faint and could develop an infection at the site 
where blood is drawn.
There is no guarantee 
that you will receive any 
medical benefits from 
being in this study.
The information from 
this research study may 
lead to a better 
treatment in the future 
for people with cardiac 
sarcoidosis.
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
For the FDG-PET scan, an IV will be inserted. This scan 
uses a small amount of radioactive tracer given through 
the IV. The amount of radiation you are exposed to is low 
and short-lived. There is a rare risk of allergic reaction to 
the tracer agent. There may be discomfort associated with 
being positioned in the scanner with your arms above 
your head.

For the Cardiac MRI, an IV will be inserted. The contrast 
agent given through the IV contains a metal called 
gadolinium. Gadolinium based contrast agents may stay in 
the body, including the brain for months to years after 
receiving these drugs. Gadolinium retention has not been 
directly linked to adverse health effects in patients with 
normal kidney function. There is a small risk of allergic 
reaction to the contrast agent. Some people may feel 
anxious while they are in the scanner. If you have an 
implanted defibrillator, coming in contact with the strong 
magnetic field of the MRI scanner might damage the 
beeper function on the defibrillator, or may cause other 
device malfunctions.

Select cases may require an X-ray before the MRI, which 
will expose you to a very small amount of radiation. This 
small amount will pose very little risk to you.

The study questionnaires ask questions about your health 
and symptoms and daily activities. Some people may feel 
uncomfortable answering some of the questions.
5. 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.
Please see the “WHAT RISKS AND DISCOMFORTS CAN I EXPECT
FROM BEING IN THE STUDY?” section for more information.
Now that you have a general overview of the study, we want to provide the details about 
what your participation involves. Please read, or have someone read to you, the rest of this 
document. If there is anything you don’t understand, be sure to ask the study staff.
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WHY IS THIS STUDY BEING DONE?
Sarcoidosis is an inflammatory disease that most commonly involves the lungs. Sarcoidosis can 
involve nearly any organ system, including the skin, liver, and eyes. Cardiac sarcoidosis occurs 
when sarcoidosis causes inflammation in the heart. Cardiac sarcoidosis is an uncommon 
disease that can lead to sudden cardiac death and/or heart failure.
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 cardiac 
sarcoidosis. 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 purpose of this research study is to test the safety, tolerability, and effectiveness of 
Anakinra in patients with cardiac sarcoidosis.
WHAT WILL HAPPEN IF I PARTICIPATE IN THE STUDY?
You will have your usual clinic visits with your doctor and some routine diagnostic tests for care 
related to your cardiac sarcoidosis. Some of the information for this study will be collected from 
your medical records and from your routine care (such as vital signs, lab work, ECGs , and other 
diagnostic tests), and some tests and assessments will be done specifically for the study.
If you decide to participate in this study, after you provide your consent, you will have a 
Screening visit at Dr. Kron’s Clinic located at the Stony Point campus, or at the downtown 
hospital campus. This visit will take approximately 30-60 minutes, and you will:

Be seen by the study doctor/study staff.

Have a blood sample (up to 3 tablespoons) taken. The blood will be used for chemistry and 
hematology tests and cardiac specific biomarkers.

Complete the Cardiac Sarcoidosis Quality of Life Questionnaire: You will be asked to 
complete the Sarcoidosis Assessment Tool (SAT) which asks you questions related to your 
sarcoidosis. The questionnaire will take about 10-15 minutes to complete.

If you are a woman of childbearing potential (meaning if you are not post-menopausal 
and/or have not had a hysterectomy) you will have a urine pregnancy test.

Schedule several baseline diagnostic tests. These tests include:
Cardiac F-18 Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) scan with 
Myocardial Perfusion Imaging (MPI): If you haven’t had one in the 2 months prior to 
enrolling in the study, a FDG-PET scan with MPI will be done. PET scans use a small 
amount of radioactive tracer to show the difference between healthy and unhealthy
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tissue. F-18 Fluorodeoxyglucose is the name of the tracer used in this type of PET scan. 
Myocardial Perfusion Imaging (MPI) shows how well blood flows through heart muscle 
and is done prior to the FDG-PET scan. These tests are done at the downtown location 
of VCU hospital and will take 1½ - 3 hours.
Testing Procedure: You will come in a day or two before your FDG-PET scan to have the 
MPI scan done. This will take 1½ to 2 hours.
The evening before the FDG-PET scan, you will eat a high-fat/high-protein, low- 
carbohydrate diet, and you will be given an instruction sheet about this. After the high- 
fat/high-protein, low-carb meal, you will need to fast (nothing to eat or drink except 
water) for 12 hours before the scan. You are allowed to take your usual pills with a sip of 
water. On the day of the scan, you will come in at 7:30 AM. An intravenous (IV) line will 
be started and your blood sugar will be checked. Before the scan is done, you will be 
given a dose of heparin (a blood thinner) and the tracer agent (F-18 
Fluorodeoxyglucose). When it is time to do the scan, you will be positioned in the 
scanner with your arms above your head. This allows for better images of your heart to 
be obtained. The prep time before the scan is about 45-60 minutes, and the scan itself 
will take about another 45-60 minutes. The total time on the day of the FDG-PET scan is 
about 3 hours.
Cardiac Magnetic Resonance Imaging (Cardiac MRI) scan: This scan uses magnetic fields, 
radio waves and a computer to produce detailed images of heart structures. This test 
will be done at the downtown campus of VCU hospital, and will take approximately 1½ - 
2 hours from the time you arrive to the time you leave. The scan itself takes about 30-45 
minutes; however, some cases may require an X-ray before the MRI can be conducted. 
Testing Procedure: You will have an IV started before the test which will be used to give 
the contrast agent (gadolinium) during the scan to make better images. You will need to 
lie very still while the scan is being done to minimize any distortion on the images. There 
may be some discomfort or anxiety associated with being in the scanner, especially for 
people who fear being in enclosed spaces (claustrophobia). The scanner produces some 
loud knocking noises, and earplugs can be provided to minimize the noise.
24-hour Holter Monitor: This test will be done at the downtown location of VCU 
hospital. It will take 15-30 minutes each on 2 consecutive days.
Testing Procedure: You will come in to have the monitor applied. This involves applying 
electrode patches to your chest which are attached to a small monitor box with wires, 
and takes about 15-30 minutes. You will come back 24 hours later to have the monitor 
and electrode patches removed, which takes about 15 minutes.
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After these tests are completed, you will come to Dr. Kron’s Clinic at the downtown campus for 
the Randomization Visit which will take about 30-60 minutes. At this visit you will:

Be seen by the study doctor/study staff.

Be randomized (like a flip of a coin) to receive either Anakinra on top of standard of care or 
standard of care only.

Be scheduled to return to the Cardiac Sarcoidosis Clinic in 28 days.

Patients randomized to Anakinra will also be instructed on how to give yourself the daily 
study injections and will receive 28 Anakinra (Kineret®) syringes.
On a case by case basis, the Screening and Randomization Visits may be combined in one visit.
At the 28-day Visit (which will take about 30-60 minutes at the downtown hospital campus ) 
you will:

Be seen by the study doctor/study staff. Have a blood sample (up to 3 tablespoons) will be 
taken. The blood will be used for chemistry and hematology tests and cardiac specific 
biomarkers.

Complete the Cardiac Sarcoidosis Quality of Life Questionnaire.
Within 2 weeks of the 28-day visit you will have the following tests:

FGD-PET scan with MPI

Cardiac MRI (and potential X-ray)

24-hour Holter Monitor
At the 60-day Visit (which will take about 30-60 minutes at the either the Stony Point campus 
or the downtown hospital campus) you will:

Be seen by the study doctor/study staff.

Have a blood sample (up to 3 tablespoons) taken. The blood will be used for chemistry and 
hematology tests.
Around 6 months after you enroll in the study, you will be seen in person at a regular office visit 
(if you have one scheduled) or you will be contacted by telephone by the study staff to check on 
how you are doing. Additionally, the study staff will review your medical records for medical 
history, medications, and any side effects or hospital visits for up to 6 months after you enrolled 
in the study.
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
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per standard protocol at VCU Health, which may include answering questions about your health 
and/or measuring your temperature.
WHAT ALTERNATIVE TREATMENTS OR PROCEDURES ARE AVAILABLE?
If you decide not to participate in this study, you can still receive the usual treatments for 
cardiac sarcoidosis.
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. 
The information from this research study may lead to a better treatment in the future for 
people with cardiac sarcoidosis.
WHAT RISKS AND DISCOMFORTS COULD I EXPERIENCE FROM BEING IN THE 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)
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.
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.
Possible Risks Associated with Study Tests:

Blood collection: Pain or bruising may occur. In rare cases, blood draws may result in 
skin/tissue infection. Blood draws will be completed by trained personnel.

IV insertion (for FDG-PET scan and Cardiac MRI scan): Pain/soreness, bruising, light- 
headedness, fainting, bleeding, or infection may occur. Multiple needle-sticks may be 
necessary. The IV will be inserted by trained personnel.
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FDG-PET scan: As a participant in this study, you will receive extra radiation exposure 
from one (1) PET scan that is for research purposes only (not for your direct clinical 
benefit). The radiation dose from this procedure is approximately 21% of the annual 
permissible occupational exposure level for radiation workers. The National Council on 
Radiation Protection and Measurements has set permissible occupational radiation 
exposure limits for many radiologists, technologists, and scientists who work with 
radiation and are exposed nearly every day. These limits are defined as the dose of 
radiation that, in light of present knowledge, is not expected to cause appreciable bodily 
injury to a person at any time during his/her lifetime. The risk of this amount of 
occupational exposure to radiation is, thus, considered to be very small and less than 
that associated with normal everyday activities. The radiation dose mentioned is what 
you will receive from the research component of this study only and does not include 
any exposure you may have received or will receive in the future from other tests.

There is a rare risk of allergic reaction to the tracer agent. You will also be given a dose of 
heparin (a blood thinner) for this test. There is a small risk of allergic reaction to the 
heparin. If you have a known allergy to heparin, you will still have the FDG-PET scan done, 
but no heparin will be given to you. There may be discomfort associated with being 
positioned in the scanner with your arms above your head. There will be a technician with 
you during the scan to assist with any discomfort you may have.

Cardiac MRI scan: The contrast dye used for MRI contains a metal called gadolinium. This is 
not the same type of dye that is sometimes used for CT scans. There is a small risk of allergic 
reaction to the gadolinium contrast dye used for the cardiac MRI, and the contrast could 
cause side effects of headache, nausea, dizziness, rash, itching, tingling feeling in the lips, 
arms, hands or feet. The majority of the gadolinium contrast dye is removed from the body 
through the urine within 24 hours, however gadolinium-based contrast agents may stay in 
the body, including the brain for months to years after receiving these drugs. Gadolinium 
retention has not been directly linked to adverse health effects in patients with normal 
kidney function. There may be some discomfort or anxiety associated with being in the 
scanner, especially for people who fear being in enclosed spaces (claustrophobia). The 
scanner produces some loud noises, and earplugs can be provided to minimize the noise. 
There will be a technician with you during the scan to assist you with any discomfort you 
may have. If you were to experience anxiety about the procedure or anxiety of being in 
small places (claustrophobia) you may be evaluated by a licensed clinician and you may be 
offered medication to help alleviate the anxiety. These medications are called 
benzodiazepines and are used to relieve anxiety. The licensed clinician will explain to you 
that the use of benzodiazepines can cause sleepiness (sedation) and difficulty breathing 
and, in rare cases this can even cause respiratory arrest. You will be assessed and monitored 
by the clinician before, during and after the procedure until you recover. You will not be 
required to take this medication if you wish not to and decide to undergo the procedure
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without the medication or to cancel. If you cannot participate in the MRI due to anxiety, you 
can continue to participate in the other portions of the study.

If you have an implanted defibrillator, it must be FDA approved to undergo the MRI scan 
and it will be turned to MRI mode during the scan. After the scan your device will be 
checked, MRI mode will be turned off and it will be returned to its original settings. For 
some devices, coming into contact with the strong magnetic field of the MRI scanner could 
likely damage the beeper function on the defibrillator such that it may no longer be heard 
(> 50% chance that this will happen). This means that the device will no longer beep when 
the battery is low or for certain patient conditions or device malfunction. However, your 
heart doctor will be able to check the device with a programmer at every clinic visit to make 
sure the battery is replaced before it runs out or identify and address any patient conditions 
or device malfunctions. Other risks associated with defibrillator devices and MRI are rare (< 
1 % chance of happening) and include discomfort due to slight movement or heating of the 
device, mechanical damage to the device or leads, and improper function/malfunction of 
the defibrillator. To minimize the risks of defibrillator malfunction during the MRI, the 
standard clinical protocols for MRI-conditional defibrillator devices will be followed, the 
device will be checked before and after the MRI, will be set to MRI mode during the scan, 
and returned to its original settings after the scan.

X-ray: X-rays produce small amounts of radiation. You are exposed to safe levels of 
radiation on a daily basis; the amount of radiation you will be exposed to should you require 
an X-ray prior to the MRI is the equivalent of a couple of days of normal radiation exposure. 
To minimize the risks associated with an X-ray, only a professionally trained technician will 
conduct it.

24-hour Holter Monitor: There may be some minor skin irritation from the electrode 
patches that are applied to the skin for 24 hours, or discomfort when the patches are 
removed.
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 
Cardiac Sarcoidosis Quality of Life questionnaire 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.
Reproductive Risks
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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 woman become pregnant there is a risk of injury to an 
unborn child. For similar reasons, women who are nursing an infant may not participate in this 
study.
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?
Anakinra (Kineret®) will be provided at no cost to you. You and your insurance plan will need to 
pay for the costs of medical care you get as part of the usual care for your condition, even if this 
information is collected for the study. This includes the Screening clinic visit, bloodwork, and 
FDG-PET scan (if done within 2 months of enrollment) which will be billed to you and/or your 
insurance provider as part of your routine care. If you have not had a FDG-PET scan done within 
2 months of study enrollment as part of your routine care, the baseline FDG-PET scan will be 
done for the study and will not be billed to you/your insurance provider.
You and your insurance plan will not have to pay for exams, tests, and procedures done for 
research purposes only or that are covered by the study. This includes:

Screening, Randomization, 28-day, and 60-day clinic visits.

Study bloodwork done at Randomization and 28-day visits.

FDG-PET scan and Cardiac MRI scan done between the Screening and Randomization visit 
and at the 28-day visit.

24-hour Holter Monitor done between the Screening and Randomization visit and at the 28- 
day visit.
WILL I BE PAID TO PARTICIPATE IN THE STUDY?
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You will receive $100 compensation (in the form of a gift card or check) at 3 of the study visits: 
the randomization visit, and the 28-day visit, and the 60-day visit. You will not receive 
compensation for the visits required to complete the study tests. The total compensation for 
completing the 3 study visits would be $300.  Transportation costs may also be reimbursed up 
to $100 per visit if the cost of transportation for your study visits is a financial barrier to your 
participation.
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 
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 THE 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?
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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

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.
In general, we will not give you any individual results from the study. If we find something of 
medical importance to you, we will inform you, although we expect that this will be a very rare 
occurrence.
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 any time.
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.
Certificate of Confidentiality
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To help us protect your privacy, we have obtained a Certificate of Confidentiality from the 
National Institutes of Health. A Certificate of Confidentiality helps the researchers keep your 
information private. For example, researchers can refuse to give out your information in a court 
case. Researchers may have to give your information if the study is audited, or if the 
information is required by the Food and Drug Administration (FDA).
The researchers cannot prevent you or others, for example a member of your family, from 
sharing information about you or your involvement in this research. If you give an insurer, 
employer, or other person permission 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 
 History and physical exam
Consultation reports
Progress notes
 Laboratory test results
 X-ray reports
 X-ray films / images 
Photographs, videotapes
Complete billing record
Itemized bill 
Information about drug or alcohol abuse
Information about Hepatitis B or C tests 
Information about mental health
Information about sexually transmitted
diseases
Who will use or share protected health information about me?
VCU and the VCU Health System 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
●
Health Care Providers at VCU Health
●
Data Coordinators
●
Institutional Review Boards
●
Research Collaborators
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●
Government/Health Agencies
●
Data Safety Monitoring Boards
●
Others as Required by Law
Once your health information has been disclosed to anyone outside of this study, the 
information may no longer be protected under this authorization.
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.
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:
Dr. Jordana Kron
 
Virginia Commonwealth University Medical Center 
WHOM SHOULD I CONTACT IF I HAVE QUESTIONS ABOUT THE STUDY?
The investigator and study staff named below are the best person(s) to contact if you have any 
questions, complaints, or concerns about your participation in this research:
Principal Investigator/Study Doctor: 
Dr. Jordana Kron
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
(804) 827-2157 
800 East Leigh Street, Suite 3000
Box 980568
Richmond, VA 23298 
https://research.vcu.edu/human_research/volunteers.htm
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Adult Participant Name (Printed)
Adult Participant’s Signature
Date
Name of Person Conducting Consent Discussion (Printed)
Signature of Person Conducting Consent Discussion
Date
Principal Investigator Signature (if different from above)
Date
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.
STATEMENT OF 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 for my records.
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