Clinical trial NCT04025554
Conditions: Multiple Sclerosis
Keywords: Chronic Active Lesions Ultra-high-field (7T) MRI Interleukin-1 (IL-1) White Matter Paramagnetic Rim
Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)
Start date: 2019-10-25; Completion date: 2023-10-24
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

Multiple sclerosis (MS) is a disease of the central nervous system (CNS). People who have MS may have lesions that form on parts of the CNS, such as the brain. Some of these lesions may be inflamed for a long time. This causes MS to progress. There is no treatment for these lesions. Researchers believe that a drug that decreases inflammation can help.

Objective:

To see if a drug called anakinra can help clear inflammation in MS brain lesions.

Eligibility:

People 18 and older with MS and at least one white matter lesion.

Design:

Participants will be screened with one or more Neuroimmunology Clinic protocols.

Participants will have a medical history and physical exam. They will have blood and urine tests. They will have a lumbar puncture. For this, a needle is inserted between the bones in the back, and cerebrospinal fluid is removed. They will also have an MRI of the brain. The MRI scanner is a cylinder surrounded by a strong magnetic field. Participants will lie on a table that slides in and out of the scanner.

Participants will repeat the above procedures throughout the study.

Participants will get their first dose of anakinra at the clinic. They will administer the rest of the doses themselves, by injection under the skin.

Participants will track their daily dosage electronically or in a written drug diary.

Participants will have 4 visits while taking the drug. At each visit, sharps boxes and empty vials will be collected.

Participants will have 2 follow-up visits after completing treatment.

The study will last 28 weeks.

Detailed description:
Objective:

The overall goal of this study is to determine the safety, tolerability, and radiological efficacy of up to 12 weeks of subcutaneous injection of anakinra in people with multiple sclerosis and evidence, by magnetic resonance imaging (MRI), of chronic active (also known as smoldering ) lesions in the white matter.

Study population:

5 people with progressive or stable MS, at least one paramagnetic rim lesion on 7-tesla MRI, and no new white matter lesion formation for at least 3 months or clinical relapse for at least 12 months, will complete the study.

Design:

In this open label, dose escalation study, participants will receive up to 12 weeks of

subcutaneous anakinra with initial dose of 100 mg daily up to a target dose of 300 mg daily. Study visits will occur every 4 weeks while on treatment, with 2 follow-up visits at 4 and 12 weeks after treatment discontinuation.

Outcome measures:

The primary outcome measure is disappearance of one or more paramagnetic rims from white matter lesions identified at baseline. Secondary outcomes include safety and tolerability, clinical and radiological outcomes. Exploratory serological and CSF measures will also be obtained to investigate mechanism of action of anakinra and for biomarker development.

Arms: arm 1: Patients with MS will be assigned to the same intervention
Interventions: intervention 1: Anakinra
Intervention descriptions: intervention 1: 100 mg daily weeks 1-4, 200 mg daily weeks 5-8, 300 mg daily weeks 9-12.

Protocol documents:
Prot_SAP_000.pdf: 
 
CNS IRB Protocol Template (5.4.17) 
 
 
Title: Anakinra for the Treatment of Chronically Inflamed White Matter Lesions 
in Multiple Sclerosis 
ClinicalTrials.gov ID: NCT04025554 
Date: March 19, 2024 
 
 
 


 
 
 
 
 
 
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Protocol Title: Anakinra for the treatment of chronically inflamed white matter lesions in multiple 
sclerosis 
Abbreviated Title: ATaC-MS 
Protocol Number: 19-N-0124 
Date of This Submission/Version: 10/24/2022 
 
NIH Principal Investigator: 
 
  
 
 
 
Daniel Reich, MD, PhD 
Translational Neuroradiology Section/NINDS 
  
 
 
 
Building 10, Rm 5C-103 
9000 Rockville Pike 
Bethesda, MD 20892 
Phone: 301-496-1801 
Fax: 301-402-0373 
E-mail: daniel.reich@nih.gov 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
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Précis: 
• 
Objective. The overall goal of this study is to determine the safety, tolerability, and radiological 
efficacy of up to 12 weeks of subcutaneous injection of anakinra in people with multiple sclerosis 
and evidence, by magnetic resonance imaging (MRI), of chronic active (also known as “smoldering”) 
lesions in the white matter. 
• 
Study population. 5 people with progressive or stable MS, at least one paramagnetic rim lesion on 7-
tesla MRI, and no new white matter lesion formation for at least 3 months or clinical relapse for at 
least 12 months, will complete the study. 
• 
Design. In this open label, dose escalation study, participants will receive up to 12 weeks of 
subcutaneous anakinra with initial dose of 100 mg daily up to a target dose of 300 mg daily. Study 
visits will occur every 4 weeks while on treatment, with 2 follow-up visits at 4 and 12 weeks after 
treatment discontinuation.  
• 
Outcome measures. The primary outcome measure is disappearance of one or more paramagnetic 
rims from white matter lesions identified at baseline. Secondary outcomes include safety and 
tolerability, clinical and radiological outcomes. Exploratory serological and CSF measures will also be 
obtained to investigate mechanism of action of anakinra and for biomarker development. 


 
 
 
 
 
 
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Table of Contents 
 
1. Contents 
Précis: 2 
Table of Contents ...............................................................................................................................3 
List of Abbreviations ..........................................................................................................................6 
1. 
Introduction and Background .................................................................................................8 
Rationale for studying chronic active MS lesions .............................................................................................................. 8 
Role of IL-1 in chronic active lesions in MS .......................................................................................................................... 9 
Anakinra .......................................................................................................................................................................................... 10 
Study rationale ............................................................................................................................................................................. 11 
Dosing Considerations ............................................................................................................................................................... 12 
Rationale for outcome measures .......................................................................................................................................... 12 
2. 
Study Objectives .................................................................................................................. 13 
Primary objectives ....................................................................................................................................................................... 13 
Secondary objectives .................................................................................................................................................................. 13 
3. 
Subjects ............................................................................................................................... 13 
Description of study populations .......................................................................................................................................... 13 
Inclusion criteria ........................................................................................................................................................................... 14 
Exclusion criteria .......................................................................................................................................................................... 14 
4. 
Study Design and Methods ................................................................................................... 15 
Study overview ............................................................................................................................................................................. 15 
Recruitment ................................................................................................................................................................................... 16 
Screening ......................................................................................................................................................................................... 17 
Study procedures ......................................................................................................................................................................... 17 
Criteria for Early Discontinuation of Dose Escalation .................................................................................................. 19 
End of participation .................................................................................................................................................................... 20 
5. 
Management of Data and Samples ....................................................................................... 20 
Storage ............................................................................................................................................................................................. 20 
Data and sample sharing plan ............................................................................................................................................... 20 
6. 
Additional Considerations .................................................................................................... 21 
Research with investigational drugs or devices .............................................................................................................. 21 
Gene therapy ................................................................................................................................................................................. 22 
7. 
Risks and Discomforts .......................................................................................................... 22 
Risks of study drug ...................................................................................................................................................................... 22 
Risks of study procedures ......................................................................................................................................................... 23 


 
 
 
 
 
 
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8. 
Subject Safety Monitoring .................................................................................................... 26 
Monitors for individual subjects during participation in study procedures ........................................................ 26 
Parameters to be monitored .................................................................................................................................................. 26 
Toxicity tables/criteria to be used ........................................................................................................................................ 26 
Criteria for individual subject withdrawal ......................................................................................................................... 26 
9. 
Outcome Measures .............................................................................................................. 27 
Primary outcome measures .................................................................................................................................................... 27 
Secondary outcome measures ............................................................................................................................................... 28 
Exploratory outcome measures ............................................................................................................................................. 28 
10. 
Statistical Analysis ............................................................................................................... 28 
Analysis of data/study outcomes ......................................................................................................................................... 28 
Power analysis .............................................................................................................................................................................. 29 
11. 
Human Subjects Protection .................................................................................................. 29 
Subject selection .......................................................................................................................................................................... 29 
Justification for exclusion of children .................................................................................................................................. 29 
Justification for exclusion of other vulnerable subjects ............................................................................................... 29 
Justification for inclusion of employees ............................................................................................................................. 30 
Justification for sensitive procedures .................................................................................................................................. 30 
Safeguards for vulnerable populations and sensitive procedures .......................................................................... 30 
12. 
Anticipated Benefit .............................................................................................................. 31 
13. 
Consent Documents and Process .......................................................................................... 31 
Designation of those obtaining consent ............................................................................................................................ 31 
Consent procedures .................................................................................................................................................................... 31 
Consent documents .................................................................................................................................................................... 33 
14. 
Data and Safety Monitoring ................................................................................................. 33 
Data and safety monitor and monitoring plan ............................................................................................................... 33 
Criteria for stopping the study or suspending enrollment or procedures ............................................................ 33 
15. 
Quality Assurance (QA) ........................................................................................................ 34 
Quality assurance monitor ...................................................................................................................................................... 34 
Quality assurance plan .............................................................................................................................................................. 34 
16. 
Reporting of Unanticipated Problems, Adverse Events and Protocol Deviations..................... 34 
17. 
Alternative Therapies ........................................................................................................... 34 
18. 
Privacy ................................................................................................................................. 34 
19. 
Confidentiality ..................................................................................................................... 34 
For research data and investigator medical records .................................................................................................... 34 
For stored samples ...................................................................................................................................................................... 35 
Special precautions ..................................................................................................................................................................... 35 


 
 
 
 
 
 
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20. 
Conflict of Interest ............................................................................................................... 35 
Distribution of NIH guidelines ................................................................................................................................................ 35 
Conflict of interest ....................................................................................................................................................................... 35 
Role of a commercial company or sponsor....................................................................................................................... 35 
21. 
Technology Transfer ............................................................................................................. 35 
22. 
Research and Travel Compensation ...................................................................................... 36 
23. 
Attachments/ Appendices .................................................................................................... 36 
Appendix 1. Eligibility checklist ...................................................................................................................................... 36 
Appendix 2. Expanded Disability Status Scale (EDSS) ...................................................................................... 37 
Appendix 3. Drug diary ........................................................................................................................................................ 39 
Appendix 4. Instructions for preparing the correct dose of Anakinra ................................................... 40 
24. 
Consent Forms ..................................................................................................................... 41 
25. 
References ........................................................................................................................... 41 
 
 
 
 


 
 
 
 
 
 
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List of Abbreviations 
AE ……………………………………………………………………………………………………………………………………….adverse event 
ANC ………………………………………………………………………………………………………………….absolute neutrophil count 
ALT  ......................................................................................................................... alanine aminotransferase 
AST  .................................................................................................................... aspartate aminotransferase 
BBB  .................................................................................................................................. blood-brain barrier 
CBC ………………………………………………………………………………………………………………………..complete blood count 
CDC ………………………………………………………………………………………..centers for disease control and prevention 
CNS  ............................................................................................................................ central nervous system 
CSF  .................................................................................................................................... cerebrospinal fluid 
DLT ………………………………………………………………………………………………………………………....dose-limiting toxicity 
EAE …………………………………………………………………………………………….experimental allergic encephalomyelitis 
E.coli ………………………………………………………………………………………………………………………………..Escherichia coli 
EDSS ……………………………………………………………………………………………………….Expanded Disability Status Scale 
EGFR …………………………………………………………………………………………………estimated glomerular filtration rate 
 
GVHD …………………………………………………………………………………………………………………graft versus host disease  
HDS …………………………………………………………………………………………………………………………..human data sharing  
IL ……………………………………………………………………………………………………………………………………………..interleukin 
IL-1 ……………………………………………………………………………………………………………………………………….interleukin-1 
IL-1α- ………………………………………………………………………………………………………………………..interleukin-1 α (alfa) 
IL-1β- ……………………………………………………………………………………………………………………….interleukin-1 β (beta) 
IL-1Ra ……………………………………………………………………………………………………interleukin-1 receptor antagonist 
rhIL-1ra ………………………………………………………………..recombinant human interleukin-1 receptor antagonist 
sIL-1R …………………………………………………………………………soluble mouse recombinant interleukin-1 receptor 
IP-10/CXCL10 ………………………………………interferon-gamma-induced protein 10/C-X-C motif chemokine 10 
IND .......................................................................................................................... investigational new drug 
IFNγ…………………………………………………………………………………………………………………………….. interferon gamma 
IRB ……………………………………………………………………………………………………………………institutional review board 
IRIS ……………………………………………………………………………………………Integrated Research Information System 
ISM  .................................................................................................................... independent safety monitor 
IV  ................................................................................................................................................. intravenous 
KDa…………………………………………………………………………………………………………………………………………. kilo Dalton 
LP ……………………………………………………………………………………………………………………………………lumbar puncture 
MRI  ................................................................................................................... magnetic resonance imaging 
MS  ...................................................................................................................................... multiple sclerosis 
MSFC ………………………………………………………………………………………………………………..MS Functional Composite  
NOMID …………………………………………………………………….Neonatal-Onset Multisystem Inflammatory Disease 
NMR ……………………………………………………………………………………………………………..nuclear magnetic resonance 
OCT  ................................................................................................................ ocular coherence tomography 
PET  ................................................................................................................. positron emission tomography 


 
 
 
 
 
 
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PMN ……………………………………………………………………………………………………….polymorphonuclear neutrophils 
QA………………………………………………………………………………………………………………………………… quality assurance 
RA  .................................................................................................................................. rheumatoid arthritis 
SAE  .............................................................................................................................. serious adverse event 
SC  .............................................................................................................................................. subcutaneous 
SDMT ……………………………………………………………………………………………………………Symbol Digit Modalities Test  
T  .............................................................................................................................................................. tesla 
TB ………………………………………………………………………………………………………………………………………….tuberculosis 
TNF …………………………………………………………………………………………………………………………tumor necrosis factor 
TEAE  ...................................................................................................... treatment-emergent adverse event 
TUG ………………………………………………………………………………………………………………………………..timed up-and-go  
ULN  ............................................................................................................................... upper limit of normal 
WHO ………………………………………………………………………………………………………………..world health organization 
9HPT ………………………………………………………………………………………………………………………………….9-hole peg test  
 
 


 
 
 
 
 
 
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1. Introduction and Background 
The purpose of this protocol is to test whether short-term treatment with anakinra, a recombinant, 
nonglycosylated form of the human interleukin-1 (IL-1) receptor antagonist (IL-1Ra), affects an imaging 
marker (the “paramagnetic rim”) associated with chronically inflamed (“chronic active” or “smoldering”) 
white matter lesions in multiple sclerosis (MS).  
Section 0 begins with a general overview of the rationale for studying chronic active MS lesions and the 
advantages of approaching this study with ultra-high-field (7T) MRI. In Section 1.2, we discuss the role of 
IL-1 and microglia in chronic active lesions. Section 1.3 describes anakinra, Section 1.4 the study 
rationale, Section 1.5 the risks and benefits based on preclinical and prior clinical testing, and Section 1.6 
the proposed dosing. Finally, Section 1.7 provides the rationale for our exploratory outcome measures. 
Rationale for studying chronic active MS lesions 
MS is a chronic immune-mediated disorder of the brain, spinal cord, and optic nerves (1). Since the early 
1980s (2), MRI has been recognized as a valuable tool for diagnosing and monitoring MS (3, 4). 
Moreover, the pathognomonic focal demyelinating plaques, also termed “lesions,” have been the 
subject of intense clinical and imaging research interest in MS.  
It is widely accepted in the scientific community that newly forming demyelinating lesions are associated 
with inflammation and the short-term, abrupt opening of the blood-brain barrier (BBB) at the level of 
medium and small-caliber parenchymal veins (5). The imaging correlate of these changes is the leakage 
of a peripherally injected MRI contrast agent, usually gadolinium-based, into the parenchyma 
surrounding the inflamed venule. In our former studies, we were able to image this dynamic process at 
high resolution, and we termed it “centrifugal enhancement” (6, 7). We described subsequent changes 
in the BBB in capillaries and venules at the lesion’s leading edge as “centripetal enhancement” 
(previously termed “ring” or “rim enhancement” in non-dynamic MRI acquisitions) (6, 7).  
The working hypothesis of the Translational Neuroradiology Section is that centripetal contrast 
enhancement is best considered as a manifestation of the immune response to focal inflammatory 
demyelination in new MS plaques. Metaphorically, this process can be thought of as a “controlled burn,” 
in which inflammation is used to counter inflammation as part of normal wound healing (8, 9). However, 
such controlled inflammation might also be detrimental. Indeed, we have evidence that inflammation of 


 
 
 
 
 
 
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this type can sometimes result in a 
persistent paramagnetic rim at the 
lesion edge, visualizable on MRI scans 
generated from the phase of the 
signal obtained via a T2*-weighted 
gradient-echo pulse sequence at 7T 
(10). Persistent paramagnetic rims 
develop more commonly in lesions 
that form in older people age (Fig. 1) 
(11), consistent with laboratory data 
suggesting that inflammatory cell-
mediated remyelination becomes 
progressively less successful with age 
(12, 13). Through our in vivo and 
postmortem investigations, we have 
found that paramagnetic-rim lesions 
are associated with extensive intralesional tissue damage (based on measurement of the T1 relaxation 
time by MRI), failed repair, apparently permanent demyelination, and iron deposition within activated 
macrophages/microglia (11). Further, we have shown that this lesion outcome is associated with a more 
pro-inflammatory peripheral blood cytokine and chemokine profile at baseline. 
Over the past decade, results from several labs have converged to indicate that the pathological basis of 
the paramagnetic rim is in fact iron accumulation within activated macrophages/microglia, which is 
visible on 7T MRI (11, 14, 15). These rims can be long-lasting (16) (potentially for several decades), and 
pathologically they mark the class of chronically inflamed lesions known, variously, as “chronic active,” 
“slowly expanding,” or “smoldering.” Such lesions make up approximately 10–30% of white matter 
lesions in MS and are substantially more common in longstanding, clinically progressive disease (17). 
Pathologically, they show evidence of ongoing myelin destruction at the lesion edge, even in lesions that 
may have been present for decades. Stopping the adverse inflammation in such lesions, potentially 
opening the door for remyelination, is therefore an important treatment target, for which none of the 
existing MS drugs is known to be effective. 
Role of IL-1 in chronic active lesions in MS 
IL-1β production is induced in response to inflammatory stimuli and mediates various physiologic 
responses, including inflammatory and immunological responses. Early in vitro studies showed that IL-1β 
in brain is produced mainly by ameboid microglia (18). In studies, evaluating postmortem brain material 
of MS patients, IL-1 was found to be expressed mostly by macrophages within the lesion center and by 
microglia at the lesion edge and beyond it (19, 20). More recent studies, using combined 
immunocytochemistry and in situ hybridization, confirmed the cellular source of IL-1β to be primarily 
microglia (21).   
Figure 1. Semi logarithmic plot of the longitudinal volume for each lesion 
according to participant age and lesion group (centripetal with persistent 
paramagnetic rim and centripetal with transient paramagnetic rim) (Absinta et 
al., 2016b). 


 
 
 
 
 
 
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Further studies, showed, that the chronic expression of IL-1 leads to the recruitment of PMN to the 
brain parenchyma and induces the activation of microglia and astrocytes, BBB breakdown, and 
reversible demyelination (22). 
 
In an animal model of MS (chronic relapsing experimental autoimmune encephalomyelitis), IL-1β and IL-
1ra mRNA and protein were found in white and grey matter areas during early clinical phases of the 
disease. The cells, that expressed IL-1β and IL-1Ra mRNA, were macrophages or activated microglia (23). 
Cerebrospinal fluid (CSF) analysis in MS has demonstrated elevated levels of members of IL-1 family, in 
particular IL-1β and IL-1Ra, with further elevations in IL-1Ra after high-dose corticosteroid therapy (24). 
Another study determined that detection of IL-1β in CSF correlated with higher cortical lesion volume 
and number, but there was no correlation with the presence of acute gadolinium-enhancing lesions (25).  
In preclinical studies in EAE, injections of IL-1α resulted in more severe disease, compared to controls. In 
addition soluble mouse recombinant IL-1R (sIL-1R), administered as an IL-1 antagonist, led to 
suppression of clinical paralysis and reduced wasting (26). Finally, IL-1β inhibition has not been 
previously investigated in MS, but, in subsequent studies, it was determined that intraventricular 
anakinra delays the repopulation of the microglia after their initial depletion (27). In addition, an early 
study with in vivo treatment with recombinant human IL-1 receptor antagonist (rhIL-1ra) showed 
suppression of clinical paralysis and reduction in level of wasting secondary to EAE, compared to control 
groups (28). 
Since the paramagnetic rim of chronic active lesions in MS is due to iron accumulation within activated 
macrophages/microglia, and since IL-1β is produced mainly by microglia, we hypothesize that 
antagonization of IL-1β by anakinra could inhibit microglial proliferation and possibly lead to resolution 
of the chronic active lesions in MS. This would be detectable by elimination, or perhaps reduction, of the 
paramagnetic rim around such lesions. 
Anakinra 
Anakinra is a recombinant, nonglycosylated form of the human interleukin-1 (IL-1) receptor antagonist 
(IL-1Ra), produced by recombinant DNA technology using an E. coli bacterial expression system. 
Anakinra consists of 153 amino acids and has a molecular weight of 17.3 kDa. Anakinra belongs to the 
pharmacological class of IL-1 inhibitors: it blocks the biological activity of IL-1β by competitively 
inhibiting IL-1β binding to the interleukin-1 type I receptor (IL-1RI), expressed in a wide variety of tissues 
and organs. Anakinra is FDA-approved for use in rheumatoid arthritis (RA) and the cryopyrin-associated 
periodic syndrome Neonatal-Onset Multisystem Inflammatory Disease (NOMID) (29). 
Pharmacokinetics: 
The absolute bioavailability of anakinra after a 70-mg subcutaneous (SC) bolus injection in healthy 
individuals (n=11) is 95%. In people with RA, maximum plasma concentrations of anakinra occurred 3–7 


 
 
 
 
 
 
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hours after SC administration of anakinra at clinically relevant doses (1 to 2 mg/kg; n=18); the terminal 
half-life ranged from 4–6 hours. In RA patients, no unexpected accumulation of anakinra was observed 
after daily SC doses for up to 24 weeks.  
The estimated anakinra clearance increases with increasing creatinine clearance and body weight, as 
established in the pharmacokinetic analysis encompassing 341 patients receiving daily SC anakinra 
injection at doses of 30, 75, and 150 mg for maximum of 24 weeks (29). In individuals with severe or end 
stage renal disease, the mean plasma clearance of Anakinra decreased by 70–75%. In patients with 
hepatic impairment, no formal studies have been conducted. 
Five clinical studies of anakinra in treatment of rheumatoid arthritis, with a total of 3055 patients, have 
been conducted. Collectively, these studies have shown significant improvement in clinical, laboratory, 
and radiographic parameters in the treated groups, although there was no additional benefit of anakinra 
in combination with a TNF inhibitor, etanercept (30-34). Safety data from these trials show that anakinra 
has been generally well-tolerated, with no difference in serious adverse events (SAEs) compared to 
placebo group. Concurrent administration of anakinra and etanercept for up to 24 weeks resulted in a 
7% rate of serious infections, vs. 0% in the etanercept-only group (0%); 2% of the concurrent therapy 
group patients developed neutropenia (absolute neutrophil count <109/L) (32, 34). Therefore, use of 
anakinra combined with a TNF-blocking agent is not recommended. 
 
Anakinra has also been approved by the FDA for treatment of neonatal onset multisystem inflammatory 
disease (NOMID), having produced improvement in neurological and systemic manifestations of disease, 
correlating with improvement in laboratory parameters; indeed, most NOMID patients have achieved 
sustained disease control (35). Further evidence suggests a benefit of IL-1β inhibition in other 
autoimmune disorders, including Schnitzler's syndrome, Behçet's disease, adult-onset Still disease, 
systemic juvenile idiopathic arthritis, gout, etc. (36). 
 
Study rationale 
Currently, no existing treatment for MS is known to impact chronically inflamed (also known as “chronic 
active,” “slowly expanding,” or “smoldering”) white matter lesions. In these lesions, in which 
inflammation may persist for decades, there is substantial destruction of the neuropil, and, as such, 
these lesions have been proposed to be part of the basis for clinical progression (17). Activated 
macrophages/microglia are the primary inflammatory cell type in chronic active lesions, and, as such, 
short-term depletion of these cells might prevent ongoing tissue damage and potentially allow 
endogenous repair mechanisms to commence. As described above, IL-1Ra is a natural inhibitor of IL-1, 
produced in the brain primarily by microglia; animal studies further provide evidence of clinical 
improvement with use of an  IL-1β antagonist (26, 28). 
Thus, we postulate that using recombinant human IL-1Ra, or anakinra, will inhibit proliferation of 
activated macrophages/microglia at the edge of chronic active lesions. Restriction of the study to 
participants with clinically progressive MS, or stable MS with at least mild disability, reflects the current 


 
 
 
 
 
 
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lack of good treatment options to arrest or reverse disability in MS, with the goal of ultimately 
forestalling impaired mobility and cognition. 
As there are no prior data by which to gauge the efficacy of anakinra on chronic active lesions in MS, we 
will initiate treatment at the FDA-approved dose of 100 mg/d SC and increase the dosage by 100 mg/d 
every 4 weeks to achieve a target dose of 300 mg/d. Dosing will increase if well tolerated by the patients 
or until the resolution of the paramagnetic rim lesions. Safety and tolerability measures, as well as 
pharmacokinetic and pharmacodynamic markers of IL-1Ra action in blood and CSF, will also be obtained 
as part of this study. 
Dosing Considerations 
FDA-approved dosage of anakinra for the treatment of RA is 100 mg/day subcutaneous injection. Doses 
up to 200 mg/day have shown to be safe in RA, and there are reports of safe administration of doses up 
to 300 mg/day in various rheumatological indications (37). In graft versus host disease (GVHD), doses 
from 400–3200 mg/d, by Q24H (every 24 hrs) continuous infusion for 7 days, have been attempted, and 
showed no significant side effects at the highest doses (the only toxicity was transient elevation of 
transaminases in two patients) (38). We therefore will initiate treatment with anakinra at a dose of 100 
mg/day SC, with dose escalation every 4 weeks to a maximum dose of 300 mg/day, unless endpoints 
(Section 8.4, Section 9.1) are met earlier.  
A study comparing anakinra at 3 mg/kg and 10 mg/kg doses showed that the CSF penetration of 
anakinra in nonhuman primates is 0.2–0.3%. CSF anakinra concentration peaked 1–2 hours post dose. 
The decline in CSF concentration of anakinra was slower than in serum, such that by the last measurable 
time point the CSF anakinra concentration was 56% of the serum concentration. Comparing the two 
doses, exposure in both serum and CSF increased by 3.7-fold at the higher dose, and the CSF 
penetration was similar (39). 
That this degree of brain penetration is potentially effective in clinical situations is demonstrated by the 
example of NOMID, which is characterized by substantial neuroinflammation. Study evaluating CSF 
cytokines levels in NOMID patients treated with anakinra showed, that cytokines elevated at baseline, 
including  IL-6, decreased in both plasma and CSF, whereas IP-10/CXCL10 decreased only in CSF 
(baseline blood levels being similar to controls) (40). 
Rationale for outcome measures 
7-tesla MRI. As described in Section 0, 7T MRI can detect iron deposition within activated 
macrophages/microglia at the edge of chronic active white matter lesions, which are the ultimate target 
of the therapy studied in this protocol. The availability of this outcome measure makes it possible to 
assess the effects of novel therapies on such lesions. 


 
 
 
 
 
 
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Since multiple sclerosis is an inflammatory disease of the nervous system, and active CNS inflammation 
can only be detected by leakage of gadolinium contrast by MRI, the majority of the scans performed 
under this protocol will require gadolinium contrast.  
Safety and tolerability. Safety and tolerability will be assessed through patient interview and logging of 
adverse events (AEs), as well as by lab work and imaging.  Since anakinra has not previously been used in 
the treatment of multiple sclerosis and it is not known if this drug could unexpectedly exacerbate 
disease inflammatory activity, safety monitoring by imaging will require gadolinium contrast for all scans 
under this protocol except the Month 24 post treatment follow-up scan; at this latter time-point, 
gadolinium will only be administered if clinically indicated. 
Blood and CSF biomarkers. We will collect blood and CSF samples for exploratory analysis of other 
potential biomarkers of anakinra’s efficacy. Techniques to be used may include (but are not limited to) 
flow cytometry immunophenotyping and cytokine/protein assessments. Specific molecules to be 
assessed may include (but are not limited to); IL-1β,  IL-1Ra, IL-2, IL-6, IL-10, IL-12, IL-18, TNF, IFNγ, IP-
10/CXCL10, neopterin, and neurofilament light chain. 
2. Study Objectives  
Primary objectives 
The primary objective of this protocol is to evaluate the effects of anakinra treatment on the 
paramagnetic rim of chronically inflamed white matter lesions, as seen on 7-tesla MRI. 
Secondary objectives 
The secondary objectives of this protocol are to collect and analyze additional clinical, imaging, and 
biological data relevant to the safety and tolerability of anakinra, as well as its mechanism of action. 
3. Subjects 
Description of study populations  
This protocol will enroll up to 10 individuals with progressive or stable MS, evidence of chronic active 
lesions in the white matter (by MRI), and no evidence of new lesion formation in the prior 3 months or 
clinical relapse in the prior 12 months (by analysis of prior off-protocol MRI scans). We aim to achieve 5 
study completers. NIH employees, regardless of their status as subordinates, relatives, or coworkers of 
investigators, are eligible. 


 
 
 
 
 
 
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Inclusion criteria 
 Inclusion criteria: 
• 
Age ≥18 
• 
Ability to give informed consent 
• 
If fertile, agreement to use an effective method of birth control during the study and for up to 3 
months after the last dose of the study drug 
• 
Agreement not to participate in any other interventional study while participating in this protocol 
• 
Diagnosis of MS, either stable or clinically progressive 
• 
Prior 7-tesla MRI scan, with high image quality in the judgment of the study neuroradiologist, 
demonstrating at least one white matter lesion with a paramagnetic rim (41) 
Exclusion criteria 
General exclusion criteria: 
• 
Pregnancy or current breastfeeding 
• 
Use of another investigational agent within 1 month of screening 
• 
Active infection and or neutropenia (ANC < 1000 cells/µL) 
• 
History of lymphoma 
• 
Known hypersensitivity to administration of anakinra 
• 
Previous treatment with anakinra and/or TNF-receptor inhibitor 
• 
History of asthma 
• 
QuantiFERON-TB gold positive  
• 
Prior treatment with anti-CD20 agent (ocrelizumab, rituximab) 
• 
Prior treatment with anti-CD52 agent (alemtuzumab) 
• 
History or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the trial or interfere with participation for the full duration of the trial; or 
not in the best interest of the subject to participate, in the opinion of the treating investigator 
• 
Renal dysfunction, as defined by Clinical Center guidelines for administration of gadolinium  
• 
Liver dysfunction, as indicated by baseline aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) greater than 1.5 times the upper limit of normal 
• 
Clinical relapse in the 12 months prior to dosing 
• 
New lesion formation (by comparison of screening MRI to a previous MRI of sufficient quality) in the 
3 months prior to dosing 
• 
One or more gadolinium-enhancing lesions on the screening scan 
• 
Change in disease-modifying therapy in the 6 months prior to dosing 
• 
Medical contraindication for 7-tesla MRI (including, but not limited to, any non-organic implant or 
other device such as a cardiac pacemaker or infusion pump or other metallic implants, objects, or 
body piercings, that are not MRI-compatible or cannot be removed) 


 
 
 
 
 
 
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• 
Psychological contraindication for 7-tesla MRI (e.g., claustrophobia) 
• 
Contraindication to gadolinium administration. 
• 
Active neoplastic disease or any medical condition, other than MS, that requires concurrent 
immunosuppression or immunomodulation 
4. Study Design and Methods 
Study overview  
Screening will be done under an existing Neuroimmunology Clinic protocol that allows collection of data 
required for determining eligibility. Prospective participants who meet eligibility requirements will then 
provide informed consent and undergo baseline procedures. Following training on self-administration of 
subcutaneous injections, subjects will be started on initial dose of study drug of 100 mg/d. Participants 
will have a scheduled follow-up phone call at 24–48 hours following the first dose to assess for any 
adverse reactions or concerns. Subsequent routine assessment of tolerability and safety will be made at 
the time of scheduled study visits. For the duration of the study, including dose escalation and follow-up 
phases, participants will undergo assessments at NIH. Telehealth may be used for conducting routine 
visits to the NIH Clinical Center. Participants will return at weeks 4 and 8, at which time they will 
undergo clinic visit, lab work, and 7T brain MRI. As long as no treatment-limiting toxicity is encountered 
(see “safety endpoints,” Section 8.4) AND the study endpoint is not met (see “efficacy study endpoint,” 
primary outcome, section 9), the dose will be escalated every 4 weeks to a target dose of 300 mg/day, 
which will be administered for a further 4 weeks. The final on-treatment study visit will be at week 12. 
At that time, the drug will be discontinued, with off-treatment visits at weeks 16 and 24 (4 and 12 weeks 
following treatment discontinuation). The study timeline is in Error! Reference source not found.. 
 
 


 
 
 
 
 
 
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Fig. 2 
• 
MRI at week 24 will be done without Gadolinium, unless clinically indicated. 
Should early drug discontinuation occur, either due to dose-limiting toxicity or to achievement of 
efficacy endpoint, off-treatment follow-up visits will proceed 4 and 12 weeks after treatment 
interruption. If a 7T scan cannot be obtained within window at any particular study visit, a 3T MRI can 
substitute. Leftover biological samples will be stored for future analysis. 
All study-related visits are expected to take place in outpatient facilities of the NIH Clinical Center and 
may last up to one full day, depending on the number of procedures to be performed. If more 
convenient for the participant or necessary for scheduling, visits may be split over several days (within 
the prescribed visit window). Participants may be hospitalized and treated for conditions that develop 
while on-protocol if medically necessary or for convenience. Data will be monitored in real time and 
fully analyzed once all 5 participants have completed all study procedures. 
In the event that circumstances beyond our control preclude the travel of one or more of the study 
participants to the NIH Clinical Center for a visit, or otherwise would put their health at greater risk (i.e. 
epidemic or pandemic), we will endeavor to establish capabilities for remote visits for new subjects and 
existing subjects. Specifically, for safety visits, the study team will arrange for local laboratory studies to 
be done, and conduct a telehealth visit with the participant. Unscheduled visits, due to safety, may also 
be conducted remotely through telehealth and/or offsite laboratory and radiologic studies and/or in 
conjunction with a local physician with the guidance of the study PI. The laboratory studies may be 
performed through LabCorp, Quest, or with the local physician, and results will be sent to the study 
team for safety monitoring and oversight. Radiology studies will be arranged through a local, non-study 
physician, or directly by the study team, at a site close to the participants home area if travel to the NIH 
is not possible. In the event that subjects are unable to come to the Clinical Center because of safety 
issues or travel restrictions, required in person procedures, physical exams, neurologic exams, research 
blood draws, lumbar punctures and MRIs, will be conducted as part of a make-up study visit at the next 
planned study visit time point or as soon as is safe and feasible. 
Since this is an open-label study, results of research procedures may be discussed with the participants. 
Recruitment 
Candidates for participation may enter this protocol in the following ways: 
• 
Self-referral. Advertisements and notifications may be placed on NIH or outside websites, either 
through established Clinical Center mechanisms or following specific approval by the IRB. 


 
 
 
 
 
 
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• 
The Clinical Center Recruitment Office and NIH Clinical Research Volunteer Program.  
• 
Through ongoing Neuroimmunology Clinic protocols. In this case, individuals with MS thought by the 
study team to meet eligibility criteria will be recruited by direct inquiry.  
Given the small sample size and short duration of this study, as well as the current unavailability of 
effective treatments for chronic inflammation in MS, recruitment is anticipated to be straightforward. 
Should recruitment prove unexpectedly challenging, the study team will reach out to clinicians in the 
local community who treat people with MS. Subject to IRB rules and specific approval, study information 
may also be placed in locations, such as National MS Society newsletters and websites, where it may be 
seen by prospective participants. In this event, any materials prepared for recruitment purposes will be 
submitted to the IRB for review and approval. 
NIH employees may also be recruited. NIH employees and staff will not be directly solicited by 
supervisors. Co-workers of investigators will not be directly solicited. Prior to enrollment, NIH employees 
will be asked to review the “Leave Policy for NIH Employees Participating in NIH Medical  Research 
Studies” (NIH Policy Manual 2300-630-3). 
Screening  
Candidates will be screened under one or more Neuroimmunology Clinic protocols (e.g., 89-N-0045, 15-
N-0158, 16-N-0055).   
Study procedures 
All procedures in this protocol are for research and are required; however, protocol deviations will only 
be filed for missed procedures if those procedures are necessary for primary outcome measures, or if 
more than 15% of procedures relating to secondary outcomes are missed. Missed collection of 
exploratory outcome measures will not be reported as study deviations. Data and leftover samples 
collected under this protocol may be used for other protocols on which the participant is enrolled, if 
allowed by the other protocol. Data and leftover samples collected under another protocol, if sufficient 
for study visits under this protocol, may be used.  
We may review the participant’s NIH medical records to obtain results of procedures conducted under 
another protocol which are consistent with the study procedures and time window outlined in Section 4, 
to minimize repeating procedures/tests, including medical history, clinical testing, biospecimen 
collection, and imaging. 
For women of childbearing age, urine or serum pregnancy testing will be performed prior to initial study 
drug dosing and to all MRI scans. MRI scans will include intravenous administration of an FDA-approved, 
macrocyclic, gadolinium-based MRI contrast agent. The gadolinium is needed in order to detect active 
CNS inflammation; at baseline, this would exclude a patient from study participation (see Section 3, 


 
 
 
 
 
 
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Exclusion Criteria), while at Weeks 4, 8, 12 and 16 this is needed for safety monitoring.  The Week 24 
MRI will be performed without gadolinium, unless clinically indicated.  Unless otherwise specified in the 
protocol, contrast agents will be used at FDA-approved doses. NIH Clinical Center Radiology and Imaging 
Sciences guidelines for gadolinium administration will be followed. If indicated by Clinical Center 
radiology guidelines, eGFR testing will be performed prior to MRI scans with gadolinium contrast. Any 
clinical testing required, including pregnancy testing and eGFR, will be done at the NIH Clinical Center. 
An FDA approved gadolinium guide is available on the FDA website: https://www.fda.gov/drugs/drug-
safety-and-availability/fda-drug-safety-communication-fda-warns-gadolinium-based-contrast-agents-
gbcas-are-retained-body .  We will give participants a copy of the gadolinium guide.   
An MRI evaluations of the brain may be performed at a field strength of 7T, under conditions designated 
by the FDA as constituting nonsignificant risk under 21 CFR 812.2(b)(1). Unless specifically designated 
below, MRI scans are performed on FDA-approved scanners and their use conforms to the 
corresponding FDA labels. Acquisition parameters may be modified within range. These studies may 
involve software modifications, including research pulse sequences. All research pulse sequences will 
conform to the FDA’s Criteria for Significant Risk Investigations of Magnetic Resonance Diagnostic 
Devices.  
The following non-FDA-approved systems are used in this study under conditions designated by the FDA 
as constituting nonsignificant risk, with assurances from the manufacturer that all measures found in 
FDA-approved MRI (Criteria for Significant Risk Investigations of Magnetic Resonance Imaging Devices) 
are operational: 
• 
MAGNETOM 7T scanner (manufactured by Siemens) 
For the purposes of this protocol, research postprocessing software is exempt from the IDE regulations 
under 21 CFR 812.2(c) because it is noninvasive, does not require an invasive sampling procedure that 
presents significant risk, and does not by design or intention introduce energy into a subject. It is 
unavoidable that results obtained with such software will sometimes have diagnostic implications in the 
context of this study. However, the diagnosis is always confirmed by another, medically established 
diagnostic product or procedure. 
The study is expected to be completed within 30 months of first dosing. Each of the first two 
participants will complete at least 4 weeks of dosing prior to the next participant being dosed; 
thereafter, participants may be enrolled and dosed concurrently. 
Additional clinical procedures may be ordered at any study visit, or at unscheduled follow-up visits, 
based on clinical judgment and would be obtained for clinical purposes. 
Specific procedures: 


 
 
 
 
 
 
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• 
Baseline. The baseline visit (which may occur over a period lasting up to 2 weeks) will include an 
interview to confirm that eligibility criteria are met, informed consent, urine or serum pregnancy 
testing for women of childbearing age, 7T MRI, bloodwork (to include clinical laboratory studies 
required for establishment of baseline values as well as pre-treatment research samples for 
exploratory outcomes detailed in Section 9), and lumbar puncture (LP, under fluoroscopy if required 
for scheduling or if judged by the study team to be in the best interest of the participant). We may 
collect up to 172.8 ml of blood at the screening/baseline visit. Data and samples collected at 
screening and sufficient for baseline procedures may be used if collected within one month of 
dosing and if there is no change in clinical history, but they may also be repeated at this time at the 
discretion of the PI. If the LP is not tolerated, the participant will be withdrawn and replaced. Clinical 
scales may include, but may not be limited to, Expanded Disability Status Scale (EDSS), MS 
Functional Composite (MSFC), Symbol Digit Modalities Test (SDMT), and timed up-and-go (TUG). 
• 
Dosing. Within one week of completion of baseline procedures, participants will be given their first 
supply of anakinra, to be self-administered at a dose of 100 mg/day by SC injection. Subjects will be 
provided with a sharps box to dispose of empty syringes and instructed to keep all used drug vials. 
After the first dose, participants will be contacted by telephone to assess tolerability. The dose will 
be escalated by 100 mg every 4 weeks, up to a target dose 300 mg/day, if tolerated well and as long 
as safety and efficacy end-points are not yet met. Participants will be instructed that missed doses 
should not be administered as a double dose at the next dosing time point. Participants will be 
asked to track daily dosage either electronically or in a written format per their preference. They will 
be provided with a template drug diary which they may opt to use. 
• 
Weeks 4, 8, and 12. At each visit, sharps boxes and empty vials will be collected. Participants will 
undergo a brief clinical interview/exam, lab work (to include clinical laboratory studies required for 
safety monitoring such as CBC with differential and blood collection for research purposes as 
detailed in Section 9, Exploratory Outcome Measures), clinical scales and LP (week 12 only), and 7T 
MRI (with gadolinium, if not contraindicated). We may collect up to 175 mL of blood  at the week 4, 
week 8, and week 12 visit not to exceed the Clinical Center’s policy for limits of blood drawn for 
research purposes. The window for these visits will be ±7 days. 
• 
Week 16 (or 4 weeks after dosing discontinuation). Participants will undergo a brief clinical 
interview, lab work (clinical and research), 7T MRI (with gadolinium, if not contraindicated). We may 
collect up to 155 ml of blood at the week 16 visit. The window for this visit will be ±7 days. 
• 
Week 24 (or 12 weeks after dosing discontinuation). Participants will undergo a brief clinical 
interview, lab work (clinical and research), clinical scales, LP, and 7T MRI (without gadolinium, unless 
clinically indicated). We may collect up to 175 mL of blood at the week 24 visit. The window for this 
visit will be ± 7 days. 
Criteria for Early Discontinuation of Dose Escalation 
Dose escalation will be discontinued in the following situations: 
• 
Dose Limiting Toxicity is observed, as defined in Section 8. 
• 
Efficacy Study Endpoint is achieved, as defined in Section 9. 


 
 
 
 
 
 
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• 
The patient is found to be pregnant. 
• 
The patient, for any reason, is unwilling to continue treatment with study drug. 
In the event of early discontinuation of dose escalation, the patient will proceed directly to the off-
treatment follow-up phase of this study. 
End of participation 
Following completion of this protocol, study participants who so desire, and who meet eligibility criteria, 
may be followed under another Neuroimmunology Clinic protocol. They will also continue in the care of 
their primary outside clinicians. No specific medical care will be offered at completion of study 
procedures. At the discretion of the study team, selected data collected under this protocol may be 
shared with participants and/or their clinicians (following participant request). 
5. Management of Data and Samples 
Storage 
At study completion, all leftover samples and data will be transferred to an appropriate repository 
protocol (11-N-0210 or a successor protocol) and may be pooled with similar data/samples collected 
under another protocol for exploratory analysis. Access to data and samples will be restricted to 
investigators on the repository protocol, or to appropriate designees. Loss or destruction of data and 
samples will be reported to the IRB per requirements of the repository protocol.  
Data and sample sharing plan 
The NIH Genomic Data Sharing policy does not apply to this protocol. Clinical, biological, and imaging 
data may be shared with other NIH protocols, other investigators, or databases/repositories, under the 
following guidelines:  
Sharing of identified samples and data. Identified samples and data obtained under this protocol, in 
participants who are also enrolled in other research protocols at NIH or outside NIH, may be shared with 
those protocols’ investigators with prospective IRB approval and informed consent from the subject. We 
may share existing identifiable data and/or specimens with other protocols when subjects are co-
enrolled to minimize subjects having to repeat any of the procedures outlined or to pool data for 
analyses allowed on the other protocol. Required institutional approval, including materials/data 
transfer and collaboration agreements, will apply in all cases. Materials/data will be shipped/transferred 
in accordance with NIH and federal regulations. Details of shared identified samples and data, and 
related agreements, will be reported to the IRB each year at the time of continuing review. 


 
 
 
 
 
 
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Sharing of coded and unlinked samples and data. Samples and data will be stripped of identifiers and 
may be coded (“de-identified”) or unlinked from an identifying code (“anonymized”). When coded 
samples and/or data are shared, the key to the code will not be provided to collaborators, but will 
remain at NIH. Required approvals from the collaborating institution will be obtained and materials will 
be shipped in accordance with NIH and federal regulations. 
Some analysis of coded data will be conducted at Johns Hopkins University (JHU) under a reliance 
agreement. Data analysis will be conducted by Dr. Martina Absinta, a prior NIH employee who 
previously had access to identifiable data for this study. While no identifiers will be available to Dr. 
Absinta at JHU, the subject-level data may still be identifiable to her given the small sample size 
associated with this protocol. 
Patients will not be consented to the study or participate in study interventions/procedures at JHU. 
Fellows, students, or other trainees in the investigators’ labs may work with coded samples and data 
while at NIH and after leaving NIH, if needed to complete a project or prepare data for publication. 
Those who have left NIH and who are not associate investigators on this study will not have access to 
identifying information or to the key to the data code. Departing fellows, students, and trainees will sign 
an agreement with NINDS requiring that coded study data will be maintained on password-protected 
computers, used only for the specified purposes of the protocol, not shared, and destroyed once the 
project is completed. Before sharing identifiable data with departing investigators, all necessary 
agreements will be obtained.  
This study is subject to the NIH Human Data Sharing (HDS) policy. De-identified study data may be 
shared with data repositories as described above. Furthermore, applicable (e.g., generated via CRIS) 
identified data may be shared via BTRIS following standard Clinical Center operating procedures 
including BTRIS data access policies. Data may be shared before the time of publication. 
6. Additional Considerations 
Research with investigational drugs or devices 
Anakinra is FDA-approved for the treatment of rheumatoid arthritis (100mg/day) and NOMID 
(8mg/kg/day maximum). Its use in MS will be investigational. Since dose and route to be used in this 
study do not differ from those for FDA-approved indications, an IND exemption has been approved by 
the FDA.  
The Clinical Center Pharmacy Department will be responsible for the receipt, storage, dispensing, and 
disposition of anakinra.  
 


 
 
 
 
 
 
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Gene therapy 
No gene therapy will be used. 
7. Risks and Discomforts 
Risks of study drug 
The following information is quoted (with minor changes) from the Kineret® (anakinra) package insert. 
The most common (incidence >5%) adverse reactions to anakinra are injection-site reaction (seen in 71% 
of anakinra-treated patients vs. 29% in placebo; of these, 73% were mild, 24% moderate, and 3% 
severe), upper respiratory tract infection (see below), headache (12% vs. 9%), nausea (8% vs. 7%), 
diarrhea (7% vs. 5%). Sinusitis, arthralgia, flu-like symptoms, and abdominal pain were observed with 
the same frequency among people treated with anakinra or placebo. Among NOMID patients, typically 
treated with a higher dose of anakinra (up to 8mg/kg/day), the most common adverse reactions during 
the first 6 months of treatment (incidence >10%) are injection-site reaction, headache, vomiting, 
arthralgia, pyrexia, and nasopharyngitis. 
Infections: Anakinra has been associated with an increased incidence of serious infections (2% vs <1% on 
placebo) in clinical trials in RA. People with asthma appear to be at higher risk of developing serious 
infections (4.5% vs. 0% on placebo). In patients receiving both anakinra and etanercept, the incidence of 
serious infections was 7%. The manufacturer recommends that health care providers follow current CDC 
guidelines to evaluate for and treat latent tuberculosis before initiating treatment with anakinra. 
Malignancies: Among 5300 RA patients treated with anakinra, a 3.6-fold higher rate of lymphoma was 
observed than expected in the general population. An increased rate of lymphoma has been previously 
reported in RA, and the specific role (if any) of IL-1β blockers in the development of malignancy is not 
known. Thirty-seven malignancies other than lymphoma were observed. Of these, the most common 
were in the breast and respiratory, digestive systems and melanoma.  
Hematological events: A decrease in total white blood cell counts (WHO toxicity grade I) is reported to 
occur in 8% of anakinra-treat patients vs. 2% on placebo. Only 0.4% of anakinra-treated patients 
developed neutropenia with absolute neutrophil count < 109/L; 9% presented hypereosinophilia (WHO 
toxicity grade I); and 2% developed thrombocytopenia (WHO toxicity grade I).  
Immunogenicity: 49% of patients tested positive for anti-anakinra antibodies; no correlation was 
observed between antibody development and AEs.  
Contraindications, Drug Interactions, Warnings, and Precautions 


 
 
 
 
 
 
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Anakinra is contraindicated in patients with known hypersensitivity to E. coli-derived proteins, anakinra, 
or any components of the product. Hypersensitivity reactions, including anaphylactic reactions and 
angioedema have been reported with anakinra.  
TNF-blocking agents: The use of anakinra in combination with TNF blocking agents is not recommended 
due to heightened risk of serious infections. In a 24-week study of concurrent anakinra and etanercept 
(a TNF-blocking agent) therapy in adults with rheumatoid arthritis, the rate of serious infections in the 
combination arm (7%) was higher than with etanercept alone (0%).  
Vaccinations/Immunizations: In a placebo-controlled clinical trial (n=126), no difference was detected in 
anti-tetanus antibody response between the anakinra and placebo treatment groups when the 
tetanus/diphtheria toxoids vaccine was administered concurrently with Kineret. No data are available on 
the effects of vaccination with other inactivated antigens in patients receiving Kineret. No data are 
available on either the effects of live vaccination or the secondary transmission of infection by live 
vaccines in patients receiving anakinra. 
Pregnancy/Breast-feeding mothers: There are no adequate and well-controlled studies of anakinra in 
pregnant women. Animal studies reveal no evidence of impaired fertility or harm to the fetus due to 
anakinra. Anakinra should not be used during pregnancy unless clearly needed. It is not known whether 
anakinra is secreted in human milk, and, therefore, it should be used with caution in nursing women.  
During the study, if the use of any concomitant treatment becomes necessary (e.g., for treatment of an 
AE), the treatment will be recorded in the electronic medical record, including the reason for treatment, 
name of the drug, dosage, route, and date of administration.  
Risks of study procedures 
• 
Risks of medical history, clinical examination, and clinical scale collection 
o There is minimal medical risk or discomfort from the clinical examination and clinical scale 
collection. The physical exam is for research purposes only. It does not replace any exam 
participants may receive from their own physicians. 
• 
Risks of blood draws and intravenous lines 
o There may be some discomfort and bruising from the needle insertion. Some people feel light-
headed or faint. 
o The risks of an intravenous catheter also include bleeding, infection, or inflammation of the skin 
and vein with pain and swelling. These will be treated if they occur. 
• 
Risks of MRI 
o People are at risk for injury from the MRI magnet if they have pacemakers or other implanted 
electrical devices, brain stimulators, dental implants, aneurysm clips (metal clips on the wall of a 
large artery), metallic prostheses (including metal pins and rods, heart valves, and cochlear 
implants), permanent eyeliner, implanted delivery pump, or shrapnel fragments. Welders and 
metal workers are also at risk for injury because of possible small metal fragments in the eye, of 


 
 
 
 
 
 
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which they may be unaware. All subjects will be screened for these conditions prior to the study, 
and if they have any, they will not receive an MRI scan.  
o It is not known if MRI is completely safe for a developing fetus. Therefore, all women of 
childbearing potential will have a pregnancy test performed no more than 24 hours before each 
MRI scan. The scan will not be done if the pregnancy test is positive.  
o People with fear of confined spaces may become anxious during an MRI. Participants may be 
offered an anxiolytic prior to scans if they express anxiety about undergoing MRI (see below). 
Those with back problems may have back pain or discomfort from lying in the scanner. The 
noise from the scanner is loud enough to damage hearing, especially in people who already 
have hearing loss. Everyone having a research MRI scan will be fitted with hearing protection. If 
the hearing protection comes loose during the scan, they will be instructed to let the 
technologist know right away. Subjects will be asked to notify the investigators if they have 
hearing or ear problems. Subjects will be asked to complete an MRI screening form for each MRI 
scan they have. There are no known long-term risks of MRI scans. 
o Anxiolytic agents, such as lorazepam, cause sedation. Other possible side effects include 
confusion, dizziness and agitation. Participants who receive an anxiolytic will be asked to stay in 
the clinic after the scan until an investigator determines it is safe for them to leave NIH. They 
will not be allowed to drive themselves home and will need to arrange for a driver; alternative, 
we will provide a taxi to take them home.  
o In this study, we will use an MRI scanner that has a strong 7-tesla magnet. Most people do not 
have any ill effects from the strong magnetic field, but some people have brief periods of muscle 
twitching, eye discomfort, dizziness, mild nausea, headache, a metallic taste in their mouth or a 
sensation of flashing lights. Many of these are from moving too rapidly in the magnetic field so 
the subject will be asked to walk slowly to the MRI table. Once on the table, the patient’s head 
will be secured with cushions or the subject will be given a bar to bite on to prevent his/her 
head from moving. The table will then be slowly moved into the scanner. The subject will be 
informed that the scan can be stopped at any time should he/she be too uncomfortable. There 
is no evidence that scanning at high magnetic field strengths is dangerous, but long-term effects 
are not known.  
o During MRI procedures, the NIH code team with full medical coverage is available for any 
emergency. NIH NMR Center medical coverage policies will be followed. Individuals being 
scanned can be observed directly with a video surveillance system displayed in the control 
rooms and can be removed immediately upon request or in case of emergency. Steps to 
minimize risk also include the use of hearing protection and the testing for pregnancy in female 
participants with childbearing potential. 
• 
Risks of gadolinium injection 
o Gadolinium is a contrast agent approved for use with MRI. The risks of an IV catheter include 
bleeding, infection, or inflammation of the skin and vein with pain and swelling. Symptoms from 
the contrast infusion are usually mild and may include feeling hot, burning or coldness in the 
arm during the injection, a metallic taste, headache, allergic reactions and nausea. In an 
extremely small number of individuals, more severe symptoms have been reported including 
shortness of breath, wheezing, hives, and lowering of blood pressure. Unless specifically allowed 


 
 
 
 
 
 
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by the protocol, participants will not receive gadolinium-based contrast agents for research 
purposes if they have previously had an allergic reaction to them. Individuals with a history of 
anaphylaxis to other agents or chronic asthma requiring treatment will not receive gadolinium 
under this protocol unless they have previously received gadolinium and tolerated it well. 
Participants will be asked about such allergic reactions and history of asthma before a contrast 
agent is administered.  
o People with kidney disease are at risk for a serious reaction to gadolinium contrast called 
“nephrogenic systemic fibrosis,” which has resulted in a very small number of deaths. If subjects 
are 60 years old or greater or have diabetes, kidney disease or liver disease, blood work to 
assess kidney function will be performed within 4 weeks before any MRI scan with gadolinium 
contrast. Participants may not receive gadolinium for a research MRI scan if kidney function is 
not normal. There is no evidence for the potential of gadolinium-related toxicity in people with 
normal kidney function. This protocol follows NIH Clinical Center guidelines for kidney-function 
screening related to gadolinium administration. 
o Most of the gadolinium contrast is eliminated in the urine. However, recent studies have found 
very small amounts of residual gadolinium in the body, including the brain, by imaging and at 
autopsy. There is presently no evidence that the retained gadolinium is associated with any 
adverse effects.    
• 
Risks of lumbar puncture 
o Adverse effects associated with lumbar punctures include brief pain or tingling paresthesias 
radiating down the lower extremity due to the needle brushing against a nerve. Should this 
occur, the needle can be repositioned. Mild lower back pain at the site of needle insertion 
following the procedure can occur; this can be managed with over the counter non-steroidal 
anti-inflammatory agents if needed. In approximately one third of patients, a post-dural 
puncture headache may develop and persist for a few days; in one in 50 to 200 lumbar 
punctures the post-dural puncture headache can last longer than 7 days. Generally, this 
headache is not severe and resolves spontaneously within days, but it can sometimes take up to 
2 weeks. Should the headache persist or be severe, a blood patch can be performed. The 
volume of CSF collected per procedure represents negligible risk. In humans, the rate of CSF 
synthesis is approximately 21.5 ml/hour or approximately 500 ml/24 hours, which represents 
roughly 4 times the total volume of CSF in an adult patient. Therefore, the volume of 20–30 ml 
of CSF that would be collected for both diagnostic and research purposes will be replenished in 
its entirety within approximately 1–1.5 hours after collection. Lumbar puncture may be done in 
the radiology department under fluoroscopic guidance for patient medical or scheduling needs. 
The radiation exposure during this procedure is 0.046 rem, which is well below the guideline of 
5 rem per year allowed for research subjects by the NIH Radiation Safety Committee. 
• 
Risks of urine collection 
o There is minimal medical risk or discomfort associated with giving a urine sample.  


 
 
 
 
 
 
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8. Subject Safety Monitoring 
Monitors for individual subjects during participation in study procedures 
The NIH PI will be responsible for the safety of the participants and for monitoring and reporting any 
unanticipated problems or AEs. The study personnel will closely monitor patient safety during study 
procedures. Credentialed clinical staff will monitor all contrast-enhanced MRI scans in accordance with 
NIH NMR Center policies.  
Each patient will be contacted within 24-48 hours following the first dose of anakinra to assess 
tolerability.  At each subsequent visit to NIH, prior to dose escalation, tolerability will be assessed; any 
subject found to meet dose-limiting toxicity criteria, will discontinue treatment and proceed into the off-
treatment follow-up phase of the study.  
Parameters to be monitored 
Parameters to be monitored include vital signs; clinical bloodwork (CBC and chemistry panel to include 
hepatic panel); neurological exam; brain MRI. Bloodwork will be performed for the purpose of safety 
monitoring only. 
Toxicity tables/criteria to be used 
Toxicity will be assessed according to the most recent version of the NCI Common Terminology Criteria 
for Adverse Events (CTCAE).  
Criteria for individual subject withdrawal 
Patients may be discontinued from the study at the discretion of the Investigator for medical, 
administrative or non-compliance issues. Pregnancy will constitute reason for individual subject 
withdrawal. Furthermore, any subject who wishes to discontinue study drug treatment has the right to 
withdraw from the study at any time and for any reason. Such participants will be asked to undergo a 
single concluding visit once off treatment, addressing only safety outcomes. 
The following specific criteria will be considered dose-limiting toxicity (DLT) and will define criteria for 
discontinuation of study drug: 
• 
Tolerability criteria. At the time of scheduled dose escalation, subjects will be asked if they are 
willing to initiate the next higher dosing regimen. Refusal to escalate based on poor tolerability will 
define the tolerability criteria and will constitute reason for withdrawal of individual patients from 


 
 
 
 
 
 
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the study. Tolerability criteria will further be met if subjects who escalated to the higher scheduled 
dose refuse to continue taking this dose due to poor tolerability.  
• 
General safety criteria. Development of any treatment-related SAE will constitute reason for 
withdrawal of individual patients from the study.  
• 
Neurological safety criteria. An increase in EDSS of ≥1 point and/or a decline of ≥20% on the 25-foot 
timed walk or 9-hole peg test (components of the MSFC) will prompt an extra follow up visit at 2 
weeks +/- 3 days. The extra follow up visit would include clinical scales assessment, and may include 
neurological examination and an additional MRI brain and/or spinal cord, per the discretion of the 
clinician.  Any confirmed sustained decline over the 2 clinic visits will constitute a reason for 
withdrawal of individual patients from the study. Changes will be measured with respect to average 
scores obtained during the screening phase. Relapses may constitute reason for withdrawal from 
the study; relationship to the study drug will be determined by the Independent Study Monitor.  
• 
Imaging safety criteria. Appearance of new contrast-enhancing lesions or obvious enlargement of 
existing lesions on any single scan, in the opinion of the study neuroradiologist, will constitute 
reason for withdrawal of individual patients from the study.  While new contrast enhancement 
could simply be due to the relapsing-remitting nature of this disease, it could also indicate 
unintended and unexpected exacerbation of CNS inflammation resulting directly or indirectly from 
modulation of the immune network by the study drug.  
The reasons for discontinuation of the study drug will be recorded in the participant’s Clinical Center 
patient file. These subjects will remain in the study and complete follow-up study visits (4 and 12 weeks 
following dosing discontinuation). 
If discontinuation was because of an AE, the participant will be followed until the event is resolved or 
stabilized. If the discontinuation was because of pregnancy, the participant will be followed until after 
delivery. 
 
9. Outcome Measures 
Primary outcome measures 
The primary outcome measure is the presence or absence of a paramagnetic rim around chronic active 
white matter MS lesions, assessed at the end of the dosing period. 
Definition of efficacy endpoint: disappearance of one or all paramagnetic phase rims. At each study visit, 
paramagnetic phase rims will be assessed. For the purposes of dose escalation, if at any on-treatment 
scan, all paramagnetic rims that were present at baseline are no longer seen, dose escalation will end 
and the subject will proceed into the post-treatment follow-up phase of the study. 


 
 
 
 
 
 
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Secondary outcome measures 
• 
Safety and tolerability: AE tables 
• 
Clinical 
o Expanded Disability Status Scale (EDSS) 
o 9-hole peg test (9HPT) 
o Symbol digit modalities test (SDMT) 
• 
MRI:  
o Proportion of paramagnetic rim lesions in which the rim has diminished or disappeared at any 
time point 
o Changes in T1 relaxation time within paramagnetic rim lesions at all time points, relative to non-
rim lesions 
o Changes in size of paramagnetic rim lesions at all time points, relative to non-rim lesions 
Exploratory outcome measures 
Exploratory outcome measures will be derived from clinical scales (may include those mentioned as 
secondary outcome measures and others, e.g. 25-foot timed walk, paced auditory serial addition test, 
and Scripps Neurological Rating Scale), MRI parameters ((characteristics/persistence of paramagnetic 
rims at all time points (qualitative)), and stored biofluids, with focus on immune cell populations (e.g. 
macrophages, lymphocytes, and subtypes thereof), cytokines (e.g., IL-1ß, IL-1Ra, IL-6), and also on 
protein and other biomarkers of neurodegeneration (e.g. neurofilament light chain). Additional assays 
(e.g. for anti-anakinra antibodies) may also be performed. These analyses will be performed in NIH labs 
or through collaboration, either intramural or extramural.  
10. Statistical Analysis 
Analysis of data/study outcomes 
The primary outcome is the per-patient proportion of lesions in which the paramagnetic rim has been 
modulated at the end of the dosing period. Proportion of diminished/resolved paramagnetic rims will be 
analyzed by investigators blinded to time point, reported descriptively, and compared to the assumption 
of no change off therapy (11, 16) — a reasonable assumption since we have never observed complete 
disappearance of a chronic rim — via Binomial exact tests. 
For the secondary outcome measures, safety and tolerability will be assessed qualitatively; AEs will be 
tabulated and compared to prior published and unpublished (to the extent possible) data on anakinra. 
Quantification will include the proportion of participants who start anakinra therapy and complete the 
full dosing. MRI outcomes will be reduced to scalar measures at various time points. Longitudinal 
changes in rim presence/absence, T1 relaxation time, and lesion volume will be analyzed by analysis of 
variance or mixed-effects models (which naturally handle missing data), the latter two in comparison to 


 
 
 
 
 
 
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non-rim lesions. Analyses will be performed both in completers and on an intent-to-treat basis. There 
will be no interim analysis. 
Analysis methods for exploratory outcome measures will be determined by the study team and 
collaborators at a later time point. 
Power analysis  
Given the previous natural history data, which indicates that only 1 out of 29 individuals experienced 
subtle changes in the paramagnetic rim over the long term (a period of several years), we would expect 
that very few to no untreated participants will experience changes in the short time period observed in 
this study. Thus, even 1 participant experiencing short term changes would potentially be clinically 
meaningful. Using an estimated null proportion of individuals with lesion changes of 0.01, a cohort of 5 
participants achieves 80% power to detect a difference of 0.27 using a one-sided binomial exact test 
with a significance level of 0.05. The null hypothesis will be rejected if 1 individual experiences at least 
one lesion change. 
Participants who drop out or in whom anakinra is stopped will be replaced, up to the accrual ceiling or 
until there are 5 completers — whichever comes first. 
11. Human Subjects Protection 
Subject selection 
Selection will be equitable among eligible participants. 
Justification for exclusion of children  
Participants under the age of 18 are excluded as progressive MS is exceedingly rare in this group, as is 
the development of rim lesions, suggesting a different biology from adult patients. For this reason, in 
this initial pilot study, pediatric patients will be excluded.  
Justification for exclusion of other vulnerable subjects  
Individuals without consent capacity at the time of enrollment are not eligible to enroll in this study as 
the study requires subjects to complete a large number of procedures over a relatively short time 
period.  


 
 
 
 
 
 
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Pregnant and lactating women will be excluded as the risk of anakinra in pregnancy and lactation is not 
known, and as the risk of MRI — a key outcome measure — would not outweigh the potential benefits 
of the study.   
Justification for inclusion of employees 
NIH staff will not be solicited for participation, but will not be excluded if they express the desire to 
enroll. Employees who participate in this protocol during work hours will be informed that they must 
obtain their supervisor’s permission.  
Justification for sensitive procedures  
Not applicable. 
Safeguards for vulnerable populations and sensitive procedures  
An approved method of birth control will be required of all fertile participants (male or female) during 
the study and for up to 3 months after the last dose of the study drug. Prospective participants who are 
pregnant will be evaluated clinically, and previously acquired diagnostic studies and clinical 
documentation will be reviewed. Such individuals will be invited to return for additional evaluation 
following delivery, if the study is still recruiting. Within 24 hours and prior to undergoing any MRI, urine 
or serum specimens from women with childbearing potential will be collected, and pregnancy tests will 
be performed.  
Protections for employees and staff participating in this study include: (1) assuring that the participation 
or refusal to participate will have no effect, either beneficial or adverse, on the participant’s 
employment, training or position at the NIH; (2) giving employees and staff who are interested in 
participating the “NIH Information Sheet on Employee Research Participation” prior to obtaining 
consent; (3) providing them with the NIH Frequently Asked Questions (FAQs) for Staff Who are 
Considering Participation in NIH Research and request that they review the FAQ document.; and (4) 
requesting them to review the Leave Policy for NIH Employees Participating in NIH Medical Research 
Studies (NIH Policy Manual 2300-630-3) prior to enrollment; and (5) assuring that there will be no direct 
solicitation of employees or staff.   
When possible, consent will be obtained by an individual in a non-supervisory relationship with the 
subject. When consent is conducted, a third party (e.g., a consent monitor) will be present to observe 
the consent process. This may be achieved by one of the following methods: 
• 
A consent monitor from the CC Department of Bioethics Consultation Service or by a Clinical 
Research Advocate from the NIMH Human Subjects Protection Unit (HSPU), or 
• 
Another party independent of the research team (such as an IC monitor), or 


 
 
 
 
 
 
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• 
If a consent monitor is not available, the consent process will be observed by another qualified 
investigator on the study who is independent of the NIH staff member’s work unit and not a 
supervisor to the NIH staff member. If no such person exists, consent observation may be 
performed by a qualified investigator on the study. 
The PI will train study staff regarding obtaining and handling potentially sensitive and private 
information about co-workers through staff discussions and written branch/section procedures. 
12. Anticipated Benefit 
Participants may benefit from participation if anakinra is able to decrease or resolve chronic 
inflammation in MS, as such inflammation may play an important role in disease progression (17). In 
addition, if we learn information during this study that may be important for a specific participant’s 
health, we will share that information with the participant. 
13. Consent Documents and Process 
Designation of those obtaining consent 
All study investigators obtaining informed consent have completed the NIMH Human Subjects 
Protection Unit “Elements of Successful Informed Consent” training.  
Consent procedures  
The informed consent document will be provided as a physical or electronic document to the participant 
for review prior to consenting. A designated study investigator will carefully explain the procedures and 
tests involved in this study, and the associated risks, discomforts and benefits. In order to minimize 
potential coercion, as much time as is needed to review the document will be given, including an 
opportunity to discuss with friends, family members and/or other advisers, and to ask questions of any 
designated study investigator. A signed informed consent document will be obtained prior to any 
research activities taking place. 
In the event that circumstances beyond our control preclude the travel to the NIH Clinical Center for a 
visit, or otherwise would put their health at greater risk (i.e. epidemic or pandemic), we will endeavor to 
establish capabilities for remote consent. The initial consent process as well as reconsent, when 
required, may take place in person or remotely (e.g., via telephone or other NIH approved remote 
platforms used in compliance with policy, including HRPP Policy 303) per discretion of the designated 
study investigator with the agreement of the participant. 


 
 
 
 
 
 
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A physical copy of the consent form may be sent to the subject if a telephone consent process is used. 
The consent interview may then be conducted when the subject can read the consent form during the 
discussion. Whether in person or remote, the privacy of the subject will be maintained. Consenting 
investigators (and participant, when in person) will be located in a private area (e.g., clinic consult 
room). When consent is conducted remotely, the participant will be informed of the private nature of 
the discussion and will be encouraged to relocate to a more private setting if needed. If the consent 
process is occurring remotely, participants and investigators will view individual copies of the approved 
consent document on screens at their respective locations; the same screen may be used when both the 
investigator and the participant are co-located but this is not required. 
Note: When required, the witness signature will be obtained similarly as described for the investigator 
and participant below. 
 
Consent will be documented with required signatures on the physical copy of the consent (which 
includes the printout of an electronic document sent to the participant), or on the electronic document. 
The process for documenting signatures on an electronic document is described below. 
When an electronic document is used for the documentation of consent, this study will use the 
iMedConsent platform which is 21 CFR, Part 11 compliant to obtain the required signatures. During the 
consent process, participants and investigators will view the same document simultaneously in their 
respective locations.  
The identity of the participant will be determined by a prompt which will require the provision of 
information from an official identification document, prior to obtaining the signature. Both the 
investigator and the participant will sign the electronic document using a finger, stylus or mouse.  
A copy of the informed consent document signed and dated by the subject are given to the subject. 
Confirmation of a subject’s informed consent is documented in the subject’s medical records prior to 
any testing under this protocol. 
If a non-English speaking participant is eligible for enrollment, the Clinical Center standard short written 
consent form in the appropriate language and a written summary of what the Investigator will say to the 
participant will be used as part of an oral consent process. The IRB-approved English written consent 
form will serve as the written summary if the short form process is used. The investigator will obtain an 
interpreter unless the investigator is fluent in the prospective participant’s language. Preferably, the 
interpreter will be someone who is independent of the participant (i.e., not a family member). 
Interpreters provided by the Clinical Center will be used whenever possible. The interpreters will 
translate the current IRB-approved English version of the consent verbatim and facilitate discussion 
between the participant and investigator.  
 


 
 
 
 
 
 
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The written summary will be signed by the investigator obtaining consent and a witness to the oral 
presentation. The short written consent form will be signed by the participant and a witness who 
observed the presentation of information. The interpreter may sign the consent documents as the 
witness and, in this case, will note “interpreter” under the signature line. A copy of the signed form will 
be provided to the participant to take home. 
 
Consent documents 
The consent form contains all required elements. A single consent document, for the patient population, 
is submitted with this protocol. No special documents are needed. 
14. Data and Safety Monitoring 
Data and safety monitor and monitoring plan 
Data and safety will be monitored by the Principal investigator and by the Independent Safety Monitor 
(ISM), Dr. Peter Grayson.  Data collection and participant safety is discussed and monitored on a weekly 
basis at the NINDS Neuroimmunology Clinic’s clinical care meetings when a subject is actively enrolled. 
The ISM’s responsibility will be to provide independent medical monitoring in a timely fashion. The ISM 
will be notified of all SAEs and serious unanticipated problems immediately, but not more than 7 days, 
after the PI first learns of the event, and will follow them up through resolution. The ISM will evaluate 
individual and cumulative participant data when making recommendations regarding the safe 
continuation of the study. Every 3 months, the ISM , Dr. Grayson, will be provided with reports on safety 
and enrollment as well as all protocol revisions. If no interval data were collected, the monitor will be 
informed, and a report will not be required. These reports will include information on laboratory tests 
and all AEs. The ISM will not have direct involvement in the conduct of the study.   
Criteria for stopping the study or suspending enrollment or procedures 
Enrollment will be suspended, until ISM assessment is completed, if 2 participants develop definite or 
probable treatment-related SAEs. Depending on the nature of the SAEs and their potential relationship 
to the study medication, the ISM may request additional clinical information and will decide on further 
action. If the SAEs are determined to be treatment-related, the study will be stopped. In this event, all 
enrolled participants still receiving treatment will have treatment discontinued and will proceed into the 
post-treatment follow-up. 
 


 
 
 
 
 
 
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15. Quality Assurance (QA) 
Quality assurance monitor 
This study is classified as “more than minimal risk” and thus will be audited with a target frequency of 
once during the first year following IRB approval, and then approximately every three years thereafter. 
Quality assurance plan 
Data obtained under this protocol will be reviewed by the study investigators and designees on a regular 
basis, and to the extent possible immediately after the data are collected. NINDS and NIH personnel 
with the appropriate authority may audit this protocol and associated data. Additionally, every 3 
months, the ISM , Dr Grayson, will be provided with reports on safety and enrollment as well as all 
protocol revisions. 
16. Reporting of Unanticipated Problems, Adverse Events and 
Protocol Deviations 
Reportable events will be tracked and submitted to the IRB as outlined in Policy 801. 
17. Alternative Therapies 
There are currently no therapies approved to treat chronic active lesions in MS. Participants are not 
required to forego approved disease-modifying therapy for MS (which is designed to limit new lesion 
and relapse development, not resolution of chronic active lesions). Anakinra, the study drug, is FDA-
approved for treatment of RA and NOMID, and may be obtained off-label by the patient’s treating 
physician.    
18. Privacy 
All research activities will be conducted in as private a setting as possible. 
19. Confidentiality 
For research data and investigator medical records 
Data and investigator medical records will be stored using codes that we assign; some data may also be 
stored in the NIH medical record system. The data will be kept on password-protected computers. Only 


 
 
 
 
 
 
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study investigators, or designees in the investigators’ groups who have completed appropriate 
requirements of the Office of Human Subjects Research Protection, will have access to the data, unless 
the data are shared according to the provisions of this protocol. Monitors and auditors may have access 
to identified information. De-identified data will be posted on clinicaltrials.gov per NIH policy. 
For stored samples 
Samples will be stored using codes that we assign and will be kept in locked storage. Only study 
investigators will have access to the samples, unless the samples are shared according to the provisions 
of this protocol. 
Special precautions  
Not applicable. 
20. Conflict of Interest 
Distribution of NIH guidelines 
NIH guidelines on conflict of interest have been distributed to all investigators.   
Conflict of interest  
There are no conflicts-of-interest to report for NIH investigators. Non-NIH investigators will abide by the 
conflict-of-interest policies of their own institutions/organizations. 
Role of a commercial company or sponsor  
Not applicable. 
21. Technology Transfer 
Sample and data derived from this protocol may be analyzed in conjunction with outside collaborators, 
and in these instances materials and data transfer agreements will be obtained, or existing agreements 
will be followed. If we obtain such agreements for use with this protocol, we will provide details to the 
IRB at the time of continuing review, together with information about samples and data that were 
shared. This is not sponsored research. 


 
 
 
 
 
 
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22. Research and Travel Compensation 
Participants will not be compensated for time and research-related inconveniences. Travel/lodging 
compensation may be provided for out-of-town participants or for those for whom traveling to NIH is a 
hardship. In such cases, an escort fee may be provided. 
NIH employees or staff who participate during work hours must have permission from their supervisor. 
NIH employees or staff must either participate outside of work hours or take leave in order to receive 
compensation. 
23. Attachments/ Appendices 
Appendix 1. Eligibility checklist 
Inclusion Criteria  
 Age ≥18 
 Ability to give informed consent 
 If fertile, agreement to use an effective method of birth control during the study and for up to 3 
months after the last dose of the study drug 
 Agreement not to participate in any other interventional study while participating in this 
protocol 
 Diagnosis of MS, either stable or clinically progressive 
 Prior 7-tesla MRI scan, with high image quality in the judgment of the study neuroradiologist, 
demonstrating at least one white matter lesion with a paramagnetic rim (41) 
Exclusion Criteria 
 Pregnancy or current breastfeeding 
 Use of another investigational agent within 1 month of screening 
 Active infection and or neutropenia (ANC < 1000 cells/µL) 
 History of lymphoma 
 Known hypersensitivity to administration of anakinra 
 Previous treatment with anakinra and/or TNF-receptor inhibitor 
 History of asthma 
 QuantiFERON-TB gold positive 
 Prior treatment with anti-CD20 agent (ocrelizumab, rituximab) 
 Prior treatment with anti-CD52 agent (alemtuzumab) 
 History or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the trial or interfere with participation for the full duration of the trial; 
or not in the best interest of the subject to participate, in the opinion of the treating investigator 


 
 
 
 
 
 
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 Renal dysfunction, as defined by Clinical Center guidelines for administration of gadolinium 
 Liver dysfunction, as indicated by baseline aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) greater than 1.5 times the upper limit of normal 
 Clinical relapse in the 12 months prior to dosing 
 New lesion formation (by comparison of screening MRI to a previous MRI of sufficient quality) in 
the 3 months prior to dosing 
 One or more gadolinium-enhancing lesions on the screening scan 
 Change in disease-modifying therapy in the 6 months prior to dosing 
 Medical contraindication for 7-tesla MRI (including, but not limited to, any non-organic implant 
or other device such as a cardiac pacemaker or infusion pump or other metallic implants, 
objects, or body piercings, that are not MRI-compatible or cannot be removed) 
 Psychological contraindication for 7-tesla MRI (e.g., claustrophobia) 
 Contraindication to gadolinium administration. 
 Active neoplastic disease or any medical condition, other than MS, that requires concurrent 
immunosuppression or immunomodulation 
 
Appendix 2. Expanded Disability Status Scale (EDSS) 
 


 
 
 
 
 
 
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Appendix 3. Drug diary  
 
 
 


 
 
 
 
 
 
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Appendix 4. Instructions for preparing the correct dose of Anakinra  
 
 
 


 
 
 
 
 
 
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24. Consent Forms 
• 
Adult subject 
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resistant graft-versus-host disease. Blood 1994;84(4):1342–1348. 


 
 
 
 
 
 
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page 44 of 44 
 
 
 
 
39. Fox E et al. The serum and cerebrospinal fluid pharmacokinetics of anakinra after intravenous 
administration to non-human primates. Journal of Neuroimmunology 2010;223(1-2):138–140. 
40. Rodriguez-Smith J et al. Cerebrospinal Fluid Cytokines Correlate With Aseptic Meningitis and Blood-
Brain Barrier Function in Neonatal-Onset Multisystem Inflammatory Disease: Central Nervous System 
Biomarkers in Neonatal-Onset Multisystem Inflammatory Disease Correlate With Central Nervous 
System Inflammation. Arthritis Rheumatol 2017;69(6):1325–1336. 
41. Absinta M, Sati P, Reich DS. Advanced MRI and staging of multiple sclerosis lesions. Nat Rev Neurol 
2016;12(6):358–368. 
 

ICF_001.pdf: 
Title: Anakinra for the Treatment of Chronically Inflamed White Matter Lesions 
in Multiple Sclerosis 
ClinicalTrials.gov ID: NCT04025554 
Date: March 19, 2024 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (1) 
IRB NUMBER: 19N0124 
IRB APPROVAL DATE: 11/03/2022 
Version Date: 10/19/2022 
Page 1 of 17 
CC ICF template v. 05.05.20 
 
 
PRINCIPAL INVESTIGATOR: Daniel Reich, MD, PhD 
STUDY TITLE: Anakinra for the Treatment of Chronically Inflamed White  Matter Lesions in 
Multiple Sclerosis (ATaC-MS) 
STUDY SITE: National Institutes of Health 
Cohort: Standard 
Consent Version: 10/19/2022 
 
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Daniel Reich, MD, PhD: (301) 496-3825, daniel.reich@nih.gov 
Shari Sawney, MS: (301) 496-3825, shari.sawney @ nih.gov 
 
KEY INFORMATION ABOUT THIS RESEARCH 
This consent form describes a research study and is designed to help you decide if you would 
like to be a part of the research study. 
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
This section provides the information we believe is most helpful and important to you in making 
your decision about participating in this study. Additional information that may help you decide 
can be found in other sections of the document. Taking part in research at the NIH is your choice. 
• Participation in this research study is voluntary. 
• In this study, we will test whether a drug called anakinra can reduce inflammation in 
multiple sclerosis (MS) brain lesions. This type of inflammation is not treated by 
available medications for treatment of multiple sclerosis. 
• Anakinra is an FDA approved drug, used for the treatment of some immune system 
mediated diseases, such as rheumatoid arthritis. This medication reduces the function of 
a certain type of immune cell that contributes to brain inflammation. We will use this 
medication in the doses that have been approved for the other indications. 
• This study will take approximately 24 weeks from the time you enroll. You will not be 
able to participate in any other treatment research studies during this time. 
• If you qualify for the study and decide to participate, you will undergo scheduled visits 
at NIH. 
• You will not be able to participate in this study if you have metal in your body or if you 
are pregnant. Other exclusions apply and will be discussed with you during your baseline 
visit. 
• There will be 4 study visits while you are taking anakinra and then 2 follow-up visits 
after you stop taking anakinra. At each study visit, you will have a clinic exam, 
bloodwork, and brain MRI. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (1) 
IRB NUMBER: 19N0124 
IRB APPROVAL DATE: 11/03/2022 
Version Date: 10/19/2022 
Page 2 of 17 
CC ICF template v. 05.05.20 
 
 
• Brain MRIs are being performed for safety and a gadolinium guide will be provided to 
you. 
• A lumbar puncture will be performed 3 times during this study at the Baseline, Week 12, 
and Week 24 study visit. 
• Anakinra is given as a daily subcutaneous (under the skin) injection. You will be taught 
how to give yourself these injections. 
• Your starting dose of anakinra will be 100 mg daily. As long as you tolerate the 
injections, every 4 weeks the dose of the injections will be increased up to the maximum 
dose of 300 mg daily. 
• If treatment is stopped early for whatever reason, you will still have 2 post-treatment 
follow-up visits at week 4 and 12 after stopping the drug. 
• All of the information collected during this study will be stored for future analysis. This 
includes clinical information, MRIs, blood and cerebrospinal fluid samples. 
• All study-related visits will take place in the outpatient clinic of the NIH Clinical Center 
and may last up to one full day. For convenience, you and the study team may choose to 
split your visits over several days or to have a study visit as inpatient in the NIH Clinical 
Center. 
• After you complete study participation, continued medical care will not be offered at 
NIH and you will return to the care of your primary outside provider. If you are eligible, 
you may choose to participate in other Neuroimmunology Studies at NIH. 
• The risks or discomforts of being in study are explained in detail in this consent form. 
• The common side-effects of anakinra are: 
o Skin reaction at the site of injection 
o Upper respiratory tract infection 
o Headache 
o Nausea 
o Diarrhea 
o Sinusitis 
o Joint aches 
o Flu-like symptoms 
o Abdominal pain 
o Allergic reaction 
• On rare occasions, anakinra may cause liver toxicity. This is reversible. Anakinra may 
also increase your risk of infections. 
• You may or may not receive direct benefit from participating in this research study. From 
your participation in this study, we also hope to learn more about multiple sclerosis and 
whether or not we can treat chronic inflammation in multiple sclerosis with anakinra. 
• You may choose not to take part, or you may leave the study at any time, for any reason. 
In either case, you will not lose any benefits to which you are otherwise entitled. 
However, to receive care at the NIH, you must be taking part in a study or be under 
evaluation for study participation. Additionally, if you choose to leave the study, please 
inform your study team. 
• We will not compensate you for time and research-related inconveniences. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (1) 
IRB NUMBER: 19N0124 
IRB APPROVAL DATE: 11/03/2022 
Version Date: 10/19/2022 
Page 3 of 17 
CC ICF template v. 05.05.20 
 
 
 
 
 
The remaining document will now describe the research study in more detail. This information 
should be considered before you make your choice. Members of the study team will talk with you 
about the information in this document. Some people have personal, religious, or ethical beliefs 
that may limit the kinds of medical or research treatments they would want to receive (such as 
blood transfusions). Take the time you need to ask any questions and discuss this study with NIH 
staff, and with your family, friends, and personal health care providers. 
 
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY 
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research. 
WHY IS THIS STUDY BEING DONE? 
This is a research study. The purpose of this study is to see if a drug called anakinra can help clear 
inflammation in multiple sclerosis lesions. 
This drug is approved for use in rheumatoid arthritis; however, it is not approved by the FDA for 
the treatment of multiple sclerosis and therefore is considered investigational for this research. 
Some multiple sclerosis lesions remain inflamed for very long periods of time (sometimes years). 
This type of inflammation is not affected by any of the available multiple sclerosis medications. 
We can see these lesions using advanced MRI scans. Research has shown that these lesions can 
lead to slow clinical worsening of symptoms in multiple sclerosis (often called “progressive MS”). 
In this research study, we will test whether anakinra can help clear the inflammation in these 
lesions by seeing if anakinra can change how the plaques appear on MRI. 
We are asking you to join this research study because we think you may be a good candidate for 
this trial. 
WHAT WILL HAPPEN DURING THE STUDY? 
If we think you can be included in this study and you are willing and able to take part, you will be 
asked to come to the NIH for a baseline visit. The baseline visit may take place over a few days. 
During the baseline visit, we will do the following research procedures: 
1) 
Clinical evaluation 
2) 
Blood and possibly urine testing 
3) 
MRI of the brain 
• We may provide travel and/or lodging compensation if you will be coming from out-of- 
town or if traveling to NIH for you is a hardship. In such cases, an escort fee may be 
provided. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (1) 
IRB NUMBER: 19N0124 
IRB APPROVAL DATE: 11/03/2022 
Version Date: 10/19/2022 
Page 4 of 17 
CC ICF template v. 05.05.20 
 
 
4) 
Lumbar puncture 
Once all baseline procedures are completed, and it is confirmed you are eligible to participate in 
this study, you will begin treatment with the study drug (anakinra). You will receive your first dose 
of anakinra in the clinic. We will teach you (and your caregiver) how to administer a subcutaneous 
injection. We will give you your first 4-week supply of anakinra at the starting dose of 100 mg to 
take at home. You will be given a sharps box to dispose of your used syringes. We will ask you to 
save all your empty drug vials to be returned to us at your next visit. We will provide you with a 
drug diary, that you can choose to use to log daily drug administration and any notes on side 
effects. We will contact you 1 to 2 days after your first dose of anakinra to ask about any side 
effects. 
You will return for your next study visit at week 4. At that time, we will collect your sharps box 
and empty drug vials. If you are doing well with anakinra injections, we will give you your second 
4-week supply and a new sharps box. Your second supply will be at the next dose of 200 mg. You 
will administer anakinra 200 mg daily at home for 4 weeks. You will then return for your week 8 
visit. At that time, we will collect your sharps box and empty drug vials. If you continue to do 
well, at your week 8 visit, you will receive your next 4-week supply of anakinra and a new sharps 
box. This supply will be 300 mg per day. You will administer anakinra 300 mg daily at home. 
You will then return for your week 12 visit. At that time, we will collect your sharps box and 
empty drug vials. After this visit, you will stop treatment with anakinra. After you stop treatment, 
you will have 2 more follow-up visits at week 16 and week 24. Details of what will happen at 
each study visit are in the table below. 
 
Procedure 
Study visit 
Baseline 
(within 
14d) 
1–2d 
after 
baseline 
Week 
4 
(±7d) 
Week 
8 
(±7d) 
Week 
12 
(±7d) 
Week 
16 
(±7d) 
Week 
24 
(±7d) 
Clinic visit with physical 
exam 
X 
X 
X 
X 
X 
X 
Laboratory testing 
X 
X 
X 
X 
X 
X 
Clinical scales 
X 
X 
X 
Phone call 
X 
MRI 
X 
X 
X 
X 
X 
X* 
Lumbar puncture 
X 
X 
X 
Anakinra supply 
X 
X 
X 
*Week 24 MRI will be performed without gadolinium (unless needed for clinical reasons) 
If you miss a dose of anakinra, you must inform the study team. You will restart the next day with 
the same dose. You should never inject a higher dose or more than one dose per day. 
If you request, you may be contacted via email to schedule appointments. 
We may access data in your medical record that was collected under other protocols and use it for 
research in this study, so you do not have to repeat procedures/tests. If you are co-enrolled in 
another NIH protocol, then research data and/or specimens, collected in either study, may be 
shared with and used for research in either study, with IRB approval 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (1) 
IRB NUMBER: 19N0124 
IRB APPROVAL DATE: 11/03/2022 
Version Date: 10/19/2022 
Page 5 of 17 
CC ICF template v. 05.05.20 
 
 
 
History and examination, including clinical scales 
We will ask you about your medical history and do a physical examination. This physical 
examination is for research purposes only and does not replace any examination you may receive 
from you own physicians. 
Blood work 
You will have blood drawn from a vein. This may require a needle stick in your arm or hand, or 
if you already have an IV catheter in place, we may be able to draw through that. Blood will be 
collected both for clinical monitoring and for research purposes. Details of the blood draw are in 
the table below. 
 
Visit 
Blood volume (teaspoons) 
Baseline, Week 12, Week 24 
12 
Week 4, Week 8, Week 16 
10 
 
The amount of blood drawn cannot exceed 37 tablespoons over an 8-week period for research. 
Please tell the study staff if you are participating in other studies that have blood draws. 
Urine testing 
We will collect less than 1 cup of urine to test for possible pregnancy in women of childbearing 
potential. Urine pregnancy test will be done before every MRI and before getting your first dose 
of anakinra. 
MRI 
Magnetic resonance imaging (MRI) uses a strong magnetic field and radio waves to take pictures 
of the body. We will obtain pictures of your brain, spinal cord or optic nerves for this study. The 
MRI scanner is a metal cylinder surrounded by a strong magnetic field. The MRI scanner is a metal 
cylinder surrounded by a strong magnetic field. During the MRI, you will lie on a table that can 
slide in and out of the cylinder. You will be in the scanner for about 120 minutes. While in the 
scanner you will hear loud knocking noises, and you will be fitted with earplugs or earmuffs to 
muffle the sound. You will be able to communicate with the MRI staff at all times during your 
scan, and you may ask to be moved out of the machine at any time. 
We will be using the MRI for investigational research. This means that the way the MRI is 
generating the images may be different than what is normally done in a routine clinical scan. 
However, all studies done under this protocol will be performed within FDA safety guidelines. 
Some of the MR machines that we use are considered investigational (not yet approved by the 
FDA for this use) but are used within the FDA safety guidelines. 
During part of the MRI you will receive gadolinium, a contrast agent, through an intravenous (iv) 
catheter (small tube). It will be done for research purposes. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (1) 
IRB NUMBER: 19N0124 
IRB APPROVAL DATE: 11/03/2022 
Version Date: 10/19/2022 
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CC ICF template v. 05.05.20 
 
 
It is not known if MRI with contrast is completely safe for a developing fetus. Therefore, all 
women of childbearing potential will have a pregnancy test performed no more than 24 hours 
before each MRI scan with contrast. The scan will not be done if the pregnancy test is positive. 
Lumbar puncture 
You will undergo a lumbar puncture (sometimes called a “spinal tap”) to obtain cerebral spinal 
fluid (CSF) samples at the baseline and week 28 visits. This procedure involves inserting a small 
needle into your lower back. The study staff will help position you either on your side or sitting 
up. The lower part of your back will first be cleaned with antiseptic, and then the study doctor 
will inject a small amount of local anesthetic to numb the area. Once numb, a very thin needle 
will be inserted into the spinal canal in your lower back [well below where the spinal cord ends]. 
About 1 ½ teaspoons of spinal fluid will be removed for analysis and storage. Your body usually 
replaces this fluid within 1-2 hours. 
After the lumbar puncture is complete, you will be monitored for about 30 minutes. To prevent 
side effects, it is important that you not do any strenuous physical activity for 24 hours following 
the procedure. This includes lifting, bending, doing housework and gardening, or exercising. 
Study Drug: Anakinra 
We will give you a 4-week supply of anakinra at your baseline visit, week 4, and week 8 visits. 
The starting dose will be 100 mg every day for the first 4 weeks. Every 4 weeks we will increase 
the dose by 100 mg. We will not increase the dose if you experience side effects of the medication 
or if the lesions on your MRI already appear improved at the lower dose. You will take anakinra 
by injecting it under your skin. We will give you instructions on how to inject this medication 
before the first dose. 
HOW LONG WILL THE STUDY TAKE? 
The study lasts about 24 weeks from the time you enroll. You will have a baseline visit; three 
visits while taking anakinra and then two follow up visits after you have stopped taking anakinra. 
Visits will last 4-6 hours. 
If you are interested and eligible, you may be followed under another Neuroimmunology Clinic 
protocol. 
HOW MANY PEOPLE WILL PARTICIPATE IN THIS STUDY? 
We plan to have 10 people participate in this study at the NIH. 
WHAT ARE THE RISKS AND DISCOMFORTS OF BEING IN THE STUDY? 
History and examination, including clinical scales 
There is minimal medical risk or discomfort from the physical exam 
Blood work 
Blood draws may cause pain, redness, bruising or infection at the site of the needle stick. Rarely 
some people faint. The study team member may apply numbing cream to the area so that the 
needle stick won’t hurt as much. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (1) 
IRB NUMBER: 19N0124 
IRB APPROVAL DATE: 11/03/2022 
Version Date: 10/19/2022 
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Urine collection 
There is minimal medical risk or discomfort from giving a urine sample. 
MRI 
People are at risk for injury from the MRI magnet if they have some kinds of metal in their body. 
It may be unsafe for you to have an MRI scan if you have pacemakers or other implanted electrical 
devices, brain stimulators, some types of dental implants, aneurysm clips (metal clips on the wall 
of a large artery), metal prostheses (including metal pins and rods, heart valves, and cochlear 
implants), permanent eyeliner, tattoos, an implanted delivery pump, or shrapnel fragments. 
Welders and metal workers may have small metal fragments in the eye. You will be screened for 
these conditions before having any MRI scan. If you have a question about metal in your body, 
you should inform the staff. You will be asked to complete an MRI screening form before each 
MRI scan you have. 
In addition, all magnetic objects (like watches, coins, jewelry, and credit cards) must be removed 
before entering the MRI scan room. 
People with fear of confined spaces may become anxious during an MRI. Those with back 
problems may have back pain or discomfort from lying in the scanner. The noise from the scanner 
is loud enough to damage hearing, especially in people who already have hearing loss. Everyone 
having a research MRI scan will be fitted with hearing protection. If the hearing protection comes 
loose during the scan, you should let us know right away. 
In this study, we are using an MRI scanner that has a strong 7 tesla magnet. Because of the strong 
magnetic field, some people have brief periods of muscle twitching, eye discomfort, dizziness, 
mild nausea, headache, a metallic taste in their mouth or a sensation of flashing lights. Many of 
these effects are from moving too quickly in the magnetic field, so you will be asked to walk 
slowly to the MRI table. Once you lie down, we will move the table slowly into the scanner. You 
can ask us to stop the scan at any time if you feel too uncomfortable. There is no evidence that 
scanning at high magnetic field strengths is dangerous, but we do not know if there are any long- 
term effects. 
There are no known long-term risks of MRI scans. 
The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein with 
pain and swelling. 
Mild symptoms from gadolinium infusion occur in fewer than 1% of those who receive it and 
usually go away quickly. Mild symptoms may include coldness in the arm during the injection, a 
metallic taste, headache, and nausea. In an extremely small number, fewer than one in 300,000 
people, more severe symptoms have been reported including shortness of breath, wheezing, hives, 
and lowering of blood pressure. You should not receive gadolinium if you previously had an 
allergic reaction to it. You will be asked about such allergic reactions before gadolinium is given. 
People with kidney disease are at risk for a serious reaction to gadolinium contrast called 
“nephrogenic systemic fibrosis (NSF)”. This condition always involves the skin and can also 
involve the muscles, joints and internal organs. NSF has resulted in a very small number of deaths. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
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IRB NUMBER: 19N0124 
IRB APPROVAL DATE: 11/03/2022 
Version Date: 10/19/2022 
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A blood test of your kidney function may be done within the month before an MRI scan with 
gadolinium contrast. You will not receive gadolinium for a research MRI scan if your kidney 
function is below the safe level. 
Most of the gadolinium contrast leaves the body in the urine. However, the FDA has issued a 
safety alert that indicates small amounts of gadolinium may remain in the body for months to years. 
The effects of the retained gadolinium are not clear. At this time, retained gadolinium has not been 
linked to health risks in people whose kidneys work well. Some types of gadolinium contrast 
drugs are less likely to remain in the body than others. In this study, we will use the gadolinium 
contrast drugs that are less likely to remain in the body, whenever possible. We will also give you 
additional information called a “Medication Guide.” Upon request, we will give you individual 
information about retained gadolinium we see on your studies. 
Lumbar puncture (spinal tap) 
The lumbar puncture may cause pain at the site where the needle goes in and the spinal fluid is 
taken. There is a small risk of infection or bleeding. After the lumbar puncture you may get a 
headache. About a third of adults report a headache after an LP. To minimize the risk of a 
headache, the doctor will use a small needle and may prescribe bed rest for one or more hours after 
the procedure. If a headache occurs, it is usually mild and can be controlled by bed rest, drinking 
lots of fluids and a pain pill, such as acetaminophen. Rarely, the headache is severe and may 
require additional treatment with a “blood patch”. In this procedure, a small amount of your own 
blood is injected into the lumbar puncture site. This procedure is generally effective in stopping 
the headache. A rare but serious complication of a LP, if it is done when the pressure inside the 
head is higher than normal (such as when a brain tumor is present), is known as medullary 
herniation which can result in death. Increased intracranial pressure is very unlikely to be present. 
The LP will not be done if there are any clinical indications that you have increased intracranial 
pressure, a skin infection in the lower back area, or bone malformation of the lower back (including 
severe scoliosis) which would make a LP difficult. 
To minimize these risks, the lumbar puncture procedure will be performed by a medical 
professional specifically trained to do this procedure. 
Contraception 
The risks of anakinra administration on your ability to become pregnant and on a fetus is not 
known. Therefore, people who are planning to become pregnant should not enter this study, and 
participants who are physically able to get pregnant must use effective contraception (birth control) 
or remain completely abstinent from sexual intercourse from the time you enroll in the study until 
12 weeks after your last dose of anakinra (Week 24 of the study). 
Effective methods of birth control for this study include: 
1) 
Hormonal contraception (birth control pills, injected hormones or vaginal ring) 
2) 
Intrauterine device 
3) 
Barrier methods (condom or diaphragm) used with spermicide 
4) 
Surgical sterilization (hysterectomy, tubal ligation, or vasectomy of a partner) 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
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IRB NUMBER: 19N0124 
IRB APPROVAL DATE: 11/03/2022 
Version Date: 10/19/2022 
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It is important for you to know that no method of birth control is totally effective in preventing 
pregnancy except for surgical sterilization (hysterectomy, tubal ligation or partner’s vasectomy) 
or total abstinence from sexual intercourse. 
Study Drug: Anakinra 
Anakinra is given by a shot under the skin. Most people take anakinra without any problems. The 
common side-effects of anakinra are listed below. If you have any of these, you should tell our 
study team right away: 
• 
Skin reaction at the site of injection 
• 
Upper respiratory tract infection 
• 
Headache 
• 
Nausea 
• 
Diarrhea 
• 
Sinusitis 
• 
Joint aches 
• 
Flu-like symptoms 
• 
Abdominal pain 
• 
Allergic reaction, rarely severe 
On rare occasions, anakinra may cause liver toxicity. This is reversible. While you are in this study, 
we will monitor your liver function tests. Anakinra may also increase your risk of infections. For 
this reason, we will monitor your white blood cell counts. Before starting a new medication during 
this study, you must notify the research team to make sure it is safe with anakinra. 
What are the risks related to pregnancy? 
Anakinra has not been studied in pregnant women. The risks to pregnant women and unborn 
children are not known. For this reason, you may not participate in this study if you are pregnant. 
If you are able to become pregnant, we will ask you to have a pregnancy test before starting this 
study and before any brain MRI or exposure to radiation (for example, if your lumbar puncture is 
done with x-ray guidance. You must tell us if you may have become pregnant within the previous 
14 days because the pregnancy test is unreliable during that time. You must use effective birth 
control methods and try not to become pregnant while participating in this study. If you become 
pregnant, there may be unknown risks to the fetus or unborn child, or risks that we did not 
anticipate. There may be long-term effects of the treatment being studied that could increase the 
risk of harm to a fetus. You must tell the study doctor if your birth control method fails while you 
are in the study. If you think or know you have become pregnant while participating in this research 
study, please contact the study team as soon as possible. If you plan to become pregnant in the 
future, please discuss with the study team how long you need to wait before becoming pregnant 
after completing the course of this study drug or procedures on this study. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (1) 
IRB NUMBER: 19N0124 
IRB APPROVAL DATE: 11/03/2022 
Version Date: 10/19/2022 
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If you are a sexually active person with a partner able to become pregnant, it is important that your 
partner not become pregnant during your participation in this study. There may be unknown risks 
to a fetus or risks we did not anticipate. You and your partner must agree to use birth control if 
you want to take part in this study. If you think your partner has become pregnant during your 
participation in this study, please contact the study team as soon as possible. If you and your 
partner plan for your partner to become pregnant after your participation in this study, please 
discuss this with the study team. 
What are the risks of radiation from being in the study? 
What if you are pregnant? If you are pregnant or nursing, you cannot be in this research study 
because the radiation may harm your baby. If you are nursing a baby, please tell your doctor. If 
you are able to have a baby and are not pregnant now, and you want to be in this study, we will 
give you a pregnancy test. If you join in this study, you should use contraception to keep from 
getting pregnant while you are in the study. If you get pregnant while you are in this study, or if 
you think you are pregnant, please tell the study doctor right away. 
During your participation in this research study, you may be exposed to radiation from a lumbar 
puncture performed under x-ray guidance. This is considered a low exposure. The risk of this 
exposure is too low to be reliably measured. 
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them. This type of radiation is called “background radiation”. No one knows 
for sure whether exposure to these low amounts of radiation is harmful to your body. The radiation 
you will get by participating in this study is less than the average yearly background radiation in 
the United States. 
WHAT ARE THE BENEFITS OF BEING IN THE STUDY? 
You might not benefit from being in this study. 
However, the potential benefit to you might be if anakinra helps clear inflammation in multiple 
sclerosis lesions. If anakinra has no effect on multiple sclerosis inflammation in the brain, you may 
not benefit. Even if anakinra reduces brain inflammation, this may not improve your symptoms. 
Are there any potential benefits to others that might result from the study? 
In the future, other people might benefit from this study because we may be able to learn more 
about multiple sclerosis, how we can best study inflammation in multiple sclerosis, and whether 
or not we can treat inflammation in multiple sclerosis with anakinra.. 
WHAT OTHER OPTIONS ARE THERE FOR YOU? 
Before you decide whether or not to be in this study, we will discuss other options that are 
available to you. Instead of being in this study, you could choose to continue treating your 
multiple sclerosis as you are now. Because anakinra is FDA approved for the treatment of other 
conditions, you could receive it without taking part in this research study. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (1) 
IRB NUMBER: 19N0124 
IRB APPROVAL DATE: 11/03/2022 
Version Date: 10/19/2022 
Page 11 of 17 
CC ICF template v. 05.05.20 
 
 
DISCUSSION OF FINDINGS 
New information about the study 
If we find out any new information that may affect your choice to participate in this study, we 
will get in touch with you to explain what we have learned. This may be information we have 
learned while doing this study here at the NIH or information we have learned from other 
scientists doing similar research in other places. 
Return of research results 
We may discuss the results of the research tests with you. If we learn information during this study 
that may be important for your health, we will share that information with you. 
EARLY WITHDRAWAL FROM THE STUDY 
We may stop your participation in the study if: 
• 
You are unable to come to the study visits 
• 
You are unable to tolerate the medication due to significant side effects 
• 
You develop a clinical relapse 
• 
You develop new or gadolinium-enhancing lesions on MRI 
• 
You become pregnant 
• 
Your MRI shows that your chronically inflamed multiple sclerosis plaques have resolved 
If you take anakinra for any length of time during the course of this study, even if you do not 
finish the full 12 weeks of treatment, we will ask that you come back for 2 follow-up visits after 
the last dose. 
STORAGE, SHARING AND FUTURE RESEARCH USING YOUR SPECIMENS AND 
DATA 
Will your specimens or data be saved for use in other research studies? 
As part of this study, we are obtaining blood, specimens and data from you. We will remove all 
the identifiers, such as your name, date of birth, address, or medical record number and label 
your specimens and data with a code so that you cannot easily be identified. However, the code 
will be linked through a key to information that can identify you. We plan to store and use these 
specimens and data for studies other than the ones described in this consent form that are going 
on right now, as well as studies that may be conducted in the future. These studies may provide 
additional information that will be helpful in understanding multiple sclerosis, or other diseases 
or conditions. This could include studies to develop other research tests, treatments, drugs, or 
devices, that may lead to the development of a commercial product by the NIH and/or its research 
or commercial partners. There are no plans to provide financial compensation to you if this 
happens. Also, it is unlikely that we will learn anything from these studies that may directly 
benefit you. 
I give permission for my coded specimens and data to be stored and used for future research as 
described above. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (1) 
IRB NUMBER: 19N0124 
IRB APPROVAL DATE: 11/03/2022 
Version Date: 10/19/2022 
Page 12 of 17 
CC ICF template v. 05.05.20 
 
 
 
 
Yes 
 
No 
Initials 
Initials 
 
Will your specimens or data be shared for use in other research studies? 
We may share your coded specimens and data with other researchers. If we do, while we will 
maintain the code key, we will not share it, so the other researchers will not be able to identify 
you. They may be doing research in areas that are similar to this study or in other unrelated 
areas. These researchers may be at NIH, other research centers and institutions, or commercial 
entities. 
I give permission for my coded specimens and data to be shared with other researchers and used 
by these researchers for future research as described above. 
 
 
Yes 
 
No 
Initials 
Initials 
 
If you change your mind and do not want us to store and use your specimens and data for future 
research, you should contact the research team member identified at the top of this document. 
We will do our best to comply with your request but cannot guarantee that we will always be 
able to destroy your specimens and data. For example, if some research with your specimens and 
data has already been completed, the information from that research may still be used. Also, for 
example, if the specimens and data have been shared already with other researchers, it might not 
be possible to withdraw them. 
In addition to the planned use and sharing described above, we might remove all identifiers and 
codes from your specimens and data and use or share them with other researchers for future 
research at the NIH or other places. When we or the other researchers access your anonymized 
data, there will be no way to link the specimens or data back to you. We will not contact you to 
ask your permission or otherwise inform you before we do this. We might do this even if you 
answered "no" to the above questions. If we do this, we would not be able to remove your 
specimens or data to prevent their use in future research studies, even if you asked, because we 
will not be able to tell which are your specimens or data. 
NIH policies require that your clinical and other study data be placed in an internal NIH database 
that is accessible to other NIH researchers for future research. Usually, these researchers will not 
have access to any of your identifiers, such as your name, date of birth, address, or medical 
record number; and your data will be labeled with only a code. We cannot offer you a choice of 
whether your data to be placed in this database or not. If you do not wish to have your data 
placed in this database, you should not enroll in this study. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (1) 
IRB NUMBER: 19N0124 
IRB APPROVAL DATE: 11/03/2022 
Version Date: 10/19/2022 
Page 13 of 17 
CC ICF template v. 05.05.20 
 
 
How long will your specimens and data be stored by the NIH? 
Your specimens and data may be stored by the NIH possibly indefinitely. 
Risks of storage and sharing of specimens and data 
When we store your specimens and data, we take precautions to protect your information from 
others that should not have access to it. When we share your specimens and data, we will do 
everything we can to protect your identity, for example, when appropriate, we remove information 
that can identify you. Even with the safeguards we put in place, we cannot guarantee that your 
identity will never become known or someone may gain unauthorized access to your information. 
New methods may be created in the future that could make it possible to re-identify your specimens 
and data. 
COMPENSATION, REIMBURSEMENT, AND PAYMENT 
Will you receive compensation for participation in the study? 
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines. 
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation? 
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines. 
This study will offer reimbursement for, or payment of, travel or lodging if you will be coming 
from out-of-town or if traveling to NIH for you is a hardship. In such cases, an escort fee may be 
provided. 
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 
• 
You will receive study treatment at no charge to you. This may include 
medicines, laboratory testing, x-rays or scans done at the Clinical Center, 
National Institutes of Health (NIH) 
• 
Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH. 
• 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 
 
CONFLICT OF INTEREST (COI) 
The NIH reviews NIH staff researchers at least yearly for conflicts of interest. This process is 
detailed in a COI Guide. You may ask your research team for a copy of the COI Guide or for more 
information. Members of the research team who do not work for NIH are expected to follow these 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (1) 
IRB NUMBER: 19N0124 
IRB APPROVAL DATE: 11/03/2022 
Version Date: 10/19/2022 
Page 14 of 17 
CC ICF template v. 05.05.20 
 
 
guidelines or the guidelines of their home institution, but they do not need to report their personal 
finances to the NIH. 
The National Institutes of Health and the research team for this study have developed imaging 
techniques being used in this study. This means it is possible that the results of this study could 
lead to payments to NIH. By law, the government is required to share such payments with the 
employee inventors. You will not receive any money from the development of imaging techniques. 
 
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
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 Web 
site will include a summary of the results. You can search this Web site at any time. 
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY 
Data will be stored using codes that we assign and will be kept in password-protected computers. 
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private. However, we cannot guarantee total privacy. Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include: 
• The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people. 
• National Institutes of Health Intramural Institutional Review Board 
• The study Sponsor National Institute of Neurological Disorders and Stroke 
• Qualified representatives from Swedish Orphan Biovitrum, the pharmaceutical company 
who produces anakinra. 
 
The researchers conducting this study and the NIH follow applicable laws and policies to keep 
your identifying information private to the extent possible. However, there is always a chance 
that, despite our best efforts, your identity and/or information about your participation in this 
research may be inadvertently released or improperly accessed by unauthorized persons. 
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission. However, your information may be shared as described in the section of 
this document on sharing of specimens and data, and as further outlined in the following sections. 
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality 
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (1) 
IRB NUMBER: 19N0124 
IRB APPROVAL DATE: 11/03/2022 
Version Date: 10/19/2022 
Page 15 of 17 
CC ICF template v. 05.05.20 
 
 
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court. 
The Certificate does not protect your information when it: 
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research; 
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent. 
Privacy Act 
The Federal Privacy Act generally protects the confidentiality of your NIH medical information 
that we collect under the authority of the Public Health Service Act. In some cases, the Privacy 
Act protections differ from the Certificate of Confidentiality. For example, sometimes the Privacy 
Act allows release of information from your record without your permission, for example, if it is 
requested by Congress. Information may also be released for certain research purposes with due 
consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit. However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act. 
POLICY REGARDING RESEARCH-RELATED INJURIES 
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action. 
PROBLEMS OR QUESTIONS 
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Daniel Reich, 
MD, (301) 496-3825, daniel.reich@nih.gov. Other researchers you may call are: Shari Sawney, 
MS at (301) 496-3825. You may also call the NIH Clinical Center Patient Representative at 301- 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (1) 
IRB NUMBER: 19N0124 
IRB APPROVAL DATE: 11/03/2022 
Version Date: 10/19/2022 
Page 16 of 17 
CC ICF template v. 05.05.20 
 
 
496-2626, or the NIH Office of IRB Operations at 301-402-3713, if you have a research-related 
complaint or concern. 
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
CC ICF template v. 05.05.20 
 
 
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study. 
 
 
 
Signature of Research Participant 
Print Name of Research Participant 
Date 
Investigator: 
Signature of Investigator 
Print Name of Investigator 
Date 
 
 
Witness should sign below if either: 
1. A short form consent process has been used to enroll a non-English speaking subject or 
2. An oral presentation of the full consent has been used to enroll a blind or illiterate subject 
 
 
 
Signature of Witness* 
Print Name of Witness 
Date 
 
 
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER: 
 
    An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated 
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness. 
  
 An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated 
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:  
. 
 
 
 
 
 
 
 
 
 
 
 
 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (1) 
Version Date: 10/19/2022 
Page 17 of 17 
IRB NUMBER: 19N0124 
IRB APPROVAL DATE: 11/03/2022