Single Patient Study of JAK/STAT Inhibition in CNS Kohlmeier-Degos Disease
Phase: PHASE1
Conditions: Kohlmeier Degos Disease With Neurologic Involvement, Kohlmeier-Degos Disease
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

 
 Protocol with Statistical Analysis Plan Cover Page:   
 
Official Title: 
 
Single Patient Study of JAK/STAT Inhibition in CNS Kohlmeier-Degos Disease 
NCT number: 
 
NCT05998395 
Document Type:  
Protocol with Statistical Analysis Plan (SAP)  
Document Date: 
July 26, 2024 
 
 

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Abbreviated Title: JAK/STAT Inhibition in Degos
Version Date: 07/26/2024
Interventional Template v6 01.25.2023
Abbreviated Title: JAK/STAT Inhibition in Degos
NIH IRB #: 001517
Version Date: 07/26/2024
Title: Single Patient Study of JAK/STAT Inhibition in CNS Kohlmeier-Degos Disease
NIH Principal Investigator:
Cornelia Cudrici, M.D.
Translational Vascular Medicine Branch
NHLBI Institute
Building 10, Rm 53232
9000 Rockville Pike
Bethesda, MD 20892
Phone: 240-515-5540
E-mail: cudricicd@mail.nih.gov
Investigational Agents (if applicable): N/A
Drug Name:
Ruxolitinib (Jakafi )
IND Number:
Exempt
Sponsor:
NIH
Manufacturer:
Incyte

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TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................2
STATEMENT OF COMPLIANCE ................................................................................................6
1
PROTOCOL SUMMARY.......................................................................................................7
1.1
Synopsis ............................................................................................................................7
1.2
Schema..............................................................................................................................8
1.3
Schedule of Activities (SOA) ...........................................................................................9
2
INTRODUCTION .................................................................................................................12
2.1
Study Rationale...............................................................................................................12
2.2
Background .....................................................................................................................13
2.3
Risk/Benefit Assessment.................................................................................................17
2.3.1
Known Potential Risks ............................................................................................17
2.3.2
Known Potential Benefits........................................................................................21
2.3.3
Assessment of Potential Risks and Benefits............................................................21
3
OBJECTIVES AND ENDPOINTS.......................................................................................22
4
STUDY DESIGN ..................................................................................................................23
4.1
Overall Design ................................................................................................................23
4.2
Scientific Rationale for Study Design.............................................................................23
4.3
Justification for Dose ......................................................................................................23
5
STUDY POPULATION........................................................................................................24
5.1
Inclusion Criteria.............................................................................................................24
5.2
Exclusion Criteria ...........................................................................................................24
5.3
Inclusion of Vulnerable Participants...............................................................................24
5.3.1
Participation of NIH Staff or family members of study team members..................24
5.4
Inclusion of Pregnant Women, fetuses or neonates ........................................................24
5.5
Lifestyle Considerations .................................................................................................24
5.6
Screen Failures................................................................................................................24
5.7
Strategies for Recruitment and Retention .......................................................................24
5.7.1
Costs ........................................................................................................................24
5.7.2
Compensation ..........................................................................................................25
6
STUDY INTERVENTION ...................................................................................................25

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6.1
Study Interventions(s) Administration............................................................................25
6.1.1
Study Intervention Description................................................................................25
6.1.2
Dosing and Administration......................................................................................25
6.2
Preparation/Handling/Storage/Accountability................................................................26
6.2.1
Acquisition and Accountability ...............................................................................26
6.2.2
Formulation, Appearance, Packaging, and Labeling...............................................26
6.2.3
Product Storage and Stability ..................................................................................26
6.2.4
Preparation...............................................................................................................26
6.3
Measures to Minimize Bias: Randomization and Blinding ............................................26
6.4
Study Intervention Compliance ......................................................................................27
6.5
Concomitant Therapy......................................................................................................27
7
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .....................................................................................27
7.1
Discontinuation of Study Intervention............................................................................27
7.2
Participant Discontinuation/Withdrawal from the Study................................................28
7.3
Lost to Follow-up............................................................................................................28
8
STUDY ASSESSMENTS AND PROCEDURES.................................................................29
8.1
Screening Procedures......................................................................................................29
8.1.1
Screening activities performed prior to obtaining informed consent ......................29
8.1.2
Screening activities performed after a consent for screening has been signed........29
8.2
Study Evaluations & Procedures.....................................................................................29
8.2.1
Biospecimen Evaluations.........................................................................................30
8.2.2
Correlative Studies for Research/Pharmacokinetic Studies ....................................32
8.2.3
Samples for Genetic/Genomic Analysis..................................................................32
8.3
Safety and Other Assessments ........................................................................................32
8.4
Adverse Events and Serious Adverse Events .................................................................33
8.4.1
Definition of Adverse Event....................................................................................33
8.4.2
Definition of Serious Adverse Events (SAE) ..........................................................33
8.4.3
Classification of an Adverse Event..........................................................................34
8.4.4
Time Period and Frequency for Event Assessment and Follow-Up........................36
8.4.5
Adverse Event Reporting.........................................................................................36
8.4.6
Serious Adverse Event Reporting............................................................................36

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8.4.7
NIH Intramural IRB and NHLBI Clinical Director Reporting................................37
8.4.8
Events of Special Interest ........................................................................................37
8.4.9
Reporting of Pregnancy ...........................................................................................37
8.5
Unanticipated Problems ..................................................................................................37
8.5.1
Definition of Unanticipated Problems (UP) ............................................................38
8.5.2
Unanticipated Problem Reporting ...........................................................................38
8.5.3
Unanticipated Problem Reporting ...........................................................................38
9
STATISTICAL CONSIDERATIONS ..................................................................................38
9.1
Statistical Hypothesis......................................................................................................38
9.2
Sample Size Determination.............................................................................................38
9.3
Populations for Analyses ................................................................................................38
9.3.1
Evaluable for toxicity ..............................................................................................38
9.3.2
Evaluable for objective response.............................................................................39
9.3.3
Evaluable Non-Target Disease Response................................................................39
9.4
Statistical Analyses .........................................................................................................39
9.4.1
General Approach....................................................................................................39
9.4.2
Analysis of the Primary Endpoints..........................................................................39
9.4.3
Analysis of the Secondary Endpoint(s) ...................................................................39
9.4.4
Safety Analyses .......................................................................................................39
9.4.5
Baseline Descriptive Statistics.................................................................................40
9.4.6
Planned Interim Analyses........................................................................................40
9.4.7
Sub-Group Analyses................................................................................................40
9.4.8
Tabulation of individual Participant Data................................................................40
9.4.9
Exploratory Analyses...............................................................................................40
10
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................40
10.1
Informed Consent Process...........................................................................................40
10.1.1
Consent/Assent Procedures and Documentation.....................................................40
10.1.2
Consent for minors when they reach the age of majority........................................41
10.1.3
Considerations for Consent of NIH staff, or family members of study team 
members.................................................................................................................................41
10.1.4
Consent of Subjects who are, or become, decisionally impaired ............................41
10.2
Study Discontinuation and Closure.............................................................................42

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10.3
Confidentiality and Privacy.........................................................................................42
10.4
Future use of Stored Specimens and Data...................................................................43
10.5
Safety Oversight..........................................................................................................43
10.6
Clinical Monitoring .....................................................................................................43
10.7
Quality Assurance and Quality Control ......................................................................44
10.8
Data Handling and Record Keeping............................................................................44
10.8.1
Data Collection and Management Responsibilities.................................................44
10.8.2
Study Records Retention .........................................................................................44
10.9
Protocol Deviations and Non-Compliance..................................................................45
10.9.1
NIH Definition of Protocol Deviation .....................................................................45
10.10
Human Data Sharing, including Genomic Data Sharing, and Publication .................45
10.10.1 NIH Data Management and Sharing Policy and NIH Genomic Data Sharing Policy 
Compliance............................................................................................................................46
10.10.2 NIH Public Access Policy Compliance ...................................................................46
10.11
Collaborative Agreements...........................................................................................46
10.11.1 Agreement Type ......................................................................................................46
10.12
Conflict of Interest Policy ...........................................................................................46
11
ABBREVIATIONS ...............................................................................................................46
12
REFERENCES ......................................................................................................................49
12.1.1
Appendix 1...............................................................................................................53

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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.

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1
PROTOCOL SUMMARY
1.1
SYNOPSIS
Title:
Single Patient Study of JAK/STAT Inhibition in CNS Köhlmeier 
Degos Disease
Study Description:
This single patient protocol will provide off-label treatment with a 
JAK/STAT ( Janus kinases/ Signal transducer and Activator of 
Transcription proteins) inhibitor to a patient with Köhlmeier Degos 
disease (K-D) with neurologic involvement. We hypothesize that 
ruxolitinib, which targets type I IFN (Interferons ) and IFN- 
signaling, will attenuate various neurological manifestations of K-D 
that are observed clinically, radiologically or in abnormal laboratory 
findings in our K-D patient. This will help reduce IFN signaling in a 
manner that may slow or halt the disease progression as measured by 
the endpoints established below. 
Objectives:
Primary Objective: To test the hypothesis that JAK/STAT 
inhibition by ruxolitinib will delay progression of neuroradiological 
manifestations of our one patient with neurological involvement of 
K-D disease.
Exploratory Objectives: 
1) Assess changes in immune cell proportion using single cell 
RNAseq (scRNA-seq) in biospecimens such as skin,  
cerebrospinal fluid (CSF) and blood after 13 weeks and up to 
73 weeks of ruxolitinib treatment.
2) Assess changes in plasma/serum cytokines levels and IFN 
scores as well as biomarker assays in CSF/ blood samples after 
13 weeks and up to 73 weeks of ruxolitinib treatment..
3) To test the hypothesis that ruxolitinib will stabilize or improve 
clinical neurologic exams in this patient. 
Endpoints:
Primary Endpoint: 
The primary endpoint is stability or regression of existing enhancing 
lesions or no development of new enhancing lesions in the brain and 
spine observed in MRI evaluation after 13 weeks and up to 73 weeks  
of ruloxitinib (10 mg BID) compared to pre-treatment MRI images.

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Exploratory endpoints of this study are clinical and potential 
surrogate biomarker efficacy data, including: 
1. Changes in transcriptome/RNA expression determined by 
scRNA-seq in skin, CSF and peripheral blood mononuclear 
cells (PBMCs) between baseline measurements and after 13 
weeks and up to 73 weeks  of treatment.
2. Attenuation of plasma/serum cytokine levels and IFN scores as 
well as biomarker assays in CSF and blood samples between 
the baseline visit and after 13 weeks and up to 73 weeks  of 
treatment.
3. Stability OR improvement of motor and/or sensory function on 
clinical neurologic exams between the baseline visit and after 
13 weeks and up to 73 weeks  of treatment.
Study Population:
A 58 year old male with neurological involvement of K-D disease.
Phase:
N/A
Description of 
Sites/Facilities 
Enrolling 
Participants:
This study will be conducted only at the NIH Clinical Center. 
Description of Study 
Intervention:
Ruxolitinib at 5 mg twice a day (BID) for 1 week and then at 10 mg 
BID for 13-73 weeks and 1 week of 5 mg BID before stopping 
ruxolitinib.
Study Duration:
1 year
Participant 
Duration:
17-77 weeks
1.2
SCHEMA
N/A

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1.3
SCHEDULE OF ACTIVITIES (SOA)
Procedures
Visit 1: 
Baseline 
Research 
Testing 
Week 0
Visit 2: 
Day 7 
after start 
of study 
drug
(+/- 3 
days). 
Telehealth 
visit.
Visit 3: 
Day 28
(+/-7 
days)
Telehealth 
Visit
Visit 
4: 
End 
of 
Week 
13
(+/- 7 
days)
Visit 5: End 
of week 
14+/- 7 
days 
Telehealth 
Visit for 
drug 
continuation
*Visit 
6: 
End 
of 
Week 
25
(+/- 7 
days)
*Visit 7: 
End of 
Week 49
(+/- 7 
days)
Visit 8: End 
of week 61 
(+/- 7 days)
Telehealth 
visit
*Continuati
on Visit 9: 
Up to the 
end of week 
73 or End 
of 
Treatment 
**Telephon
e/or at NIH 
Safety Visit
4 weeks 
after last 
dose of 
study drug 
(+/- 7 days) 
or prn
Informed consent
X
-
-
-
-
-
-
-
-
History/Physical 
X
-
X
X
X
X
X
X
X
Concomitant 
Medication
X
-
X
X
X
X
X
X
-
Vital signs/Wt.
X
-
X
X
X
X
-
X
X
Research Labs
X
-
X
X
X
X
X
X
X
Clinical Labs
CBC with diff
X
X
X
X
X
X
X
X
X
Mineral panel
X
X
X
X
X
X
X
X
X
Acute care panel
X
X
X
X
X
X
X
X
X
Liver function panel
X
X
X
X
X
X
X
X
X
Lipid panel
X
X
X
X
X
X
X
X
X

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Procedures
Visit 1: 
Baseline 
Research 
Testing 
Week 0
Visit 2: 
Day 7 
after start 
of study 
drug
(+/- 3 
days). 
Telehealth 
visit.
Visit 3: 
Day 28
(+/-7 
days)
Telehealth 
Visit
Visit 
4: 
End 
of 
Week 
13
(+/- 7 
days)
Visit 5: End 
of week 
14+/- 7 
days 
Telehealth 
Visit for 
drug 
continuation
*Visit 
6: 
End 
of 
Week 
25
(+/- 7 
days)
*Visit 7: 
End of 
Week 49
(+/- 7 
days)
Visit 8: End 
of week 61 
(+/- 7 days)
Telehealth 
visit
*Continuati
on Visit 9: 
Up to the 
end of week 
73 or End 
of 
Treatment 
**Telephon
e/or at NIH 
Safety Visit
4 weeks 
after last 
dose of 
study drug 
(+/- 7 days) 
or prn
Lymphocyte 
peripheral blood 
phenotyping
X
X
X
X
X
X
X
X
Oligoclonal 
banding, serum
X
-
-
X
X
X
-
X
-
IgG Index, serum
X
-
-
X
X
X
-
X
-
Procedures
Brain /Spine MRI 
with contrast
X
-
-
X 
X
X
-
X***
-
Neurological 
Consult
X
-
X
X
X
X
-
X
-
CSF collection with 
LP
•
Glucose
•
Protein
•
Oligoclonal 
Banding, 
CSF 
•
L-lactate 
•
Albumin 
X
-
-
X
X
X
-
X***
-

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Procedures
Visit 1: 
Baseline 
Research 
Testing 
Week 0
Visit 2: 
Day 7 
after start 
of study 
drug
(+/- 3 
days). 
Telehealth 
visit.
Visit 3: 
Day 28
(+/-7 
days)
Telehealth 
Visit
Visit 
4: 
End 
of 
Week 
13
(+/- 7 
days)
Visit 5: End 
of week 
14+/- 7 
days 
Telehealth 
Visit for 
drug 
continuation
*Visit 
6: 
End 
of 
Week 
25
(+/- 7 
days)
*Visit 7: 
End of 
Week 49
(+/- 7 
days)
Visit 8: End 
of week 61 
(+/- 7 days)
Telehealth 
visit
*Continuati
on Visit 9: 
Up to the 
end of week 
73 or End 
of 
Treatment 
**Telephon
e/or at NIH 
Safety Visit
4 weeks 
after last 
dose of 
study drug 
(+/- 7 days) 
or prn
•
CSF, Cell 
Count and 
Diff
•
IgG Index, 
CSF 
Skin biopsies
X
-
-
X
X
X
-
X***
-
Begin study 
medication
X
-
-
-
-
-
-
-
-
Dose increase
-
X
-
-
-
-
-
-
-
Pill count
-
X
X
X
X
X
X
X
-
AE review and 
collection
-
X
X
X
X
X
X
X
X
Analysis of primary 
endpoint
-
-
-
X
-
-
-
-
-
Determine if 
medication 
continuation or 
weaning
-
-
-
-
X
-
-
-
-
-

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All visits may occur either in person in NIH or via Telehealth platform, based on subject’s ability 
to travel to NIH, except for visits 4, 6, 7, and 9  which should be in person NIH visits. 
If the visit occurs via telehealth platform all activities are optional and only minimal risk 
activities may be performed. 
*This visit will only occur if patient continues therapy 
**This visit will occur 4 weeks after last dose of study drug (+/- 3 days) and as needed per 
subjects AE review and safety assessment throughout the study. It may occur via 
Telephone/Telehealth or in person in NIH. If it happens in NIH all tests/procedures are optional, 
except for AE review and collection. If subject continues to have AEs during last safety visit 
(4weeks after last dose), we will see him atin NIH for additional unscheduled safety visits, until 
all AEs are resolved, return to baseline or are stabilized.
***These tests will be optional at Visit 9
Telehealth Visit 2 blood draw may take place at local doctor’s office or phlebotomy laboratory. 
2
INTRODUCTION
2.1
STUDY RATIONALE
Köhlmeier-Degos disease (K-D) disease is a rare small vessel vasculopathy of unknown etiology 
leading to small blood vessel occlusions in multiple organs including the skin, central nervous 
system (CNS), eye, gastrointestinal (GI) tract, lungs and heart. Approximately 300 K-D cases have 
been reported in the literature to date 1-3. K-D commonly presents as a benign cutaneous form with 
lesions that appear as erythematous papules and evolve to form a scar with an atrophic, porcelain-
white center surrounded by a telangiectatic border. Progression to systemic K-D, or malignant 
atrophic papulosis, occurs in 2/3 of the patients, is often debilitating and can be fatal (60-70% 
mortality rate within 2-5 years after diagnosis) due to GI perforations, brain infarcts, spinal lesions, 
cardiac or pulmonary failure, sepsis or cachexia3 .
Among patients with systemic involvement, the GI tract is affected in more than 70%, followed 
by CNS involvement (40-50%). CNS manifestations have been present in more than 60 % of K-D 
patients with GI involvement 4. In part due to the lack of insight into K-D pathophysiology, no 
standard of care exists and there are currently no clinical trials available for K-D patients. 
Eculizumab and treprostinil have been used as off-label treatment for systemic K-D with GI 
involvement and have shown some moderate-term symptom control4-6. However, there are no 
known effective treatments for CNS K-D, driving poor outcomes and high mortality rates in these 
patients.
The patient selected for this study is a 58 year-old male with a history of systemic K-D disease 
with GI and CNS manifestations, who is currently being treated with eculizumab and treprostinil. 

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He had no significant past medical history until 2008 when he developed his first K-D skin lesion, 
although he was not diagnosed with K-D disease until 2021 based on a skin biopsy. This delay in 
diagnosis is due to lack of knowledge and specific diagnostic tests of this rare disease. He began 
to develop neurologic symptoms of peripheral neuropathy in 2018, which rapidly progressed 
resulting in bowel and bladder incontinence necessitating self-catheterization and bowel 
evacuation, and leg weakness (left worse than right) affecting ambulation. The patient has had an 
extensive infectious, immunological work-up and all the reports were negative. Cerebrospinal fluid 
analysis showed elevated protein, but the other labs were within normal limits.
 
He additionally developed unilateral sensorineural hearing loss and cognitive complaints. A brain 
MRI in September of  2021 revealed multiple leptomeningeal enhancing lesions, most significantly 
in the left anterior frontal lobe as well as multifocal enhancements along the lumbosacral cauda 
equina. He was first seen at NIH in 2022 and CSF collected with a lumbar puncture (LP) 
demonstrated elevated CSF protein, albumin, IgG, neopterin levels, IL-2 Rsol and IL-6. At that 
time, he was started on eculizumab and treprostinil. Nevertheless, his neurologic symptoms have 
continued to worsen, and he is now wheelchair-bound. Along with these worsening symptoms, he 
has developed new areas of leptomeningeal enhancement in the brain and spinal cord, consistent 
with the progression of K-D disease. 
2.2
BACKGROUND 
The pathogenesis of K-D disease remains unknown, but it is diagnosed by biopsy of skin lesions, 
which on pathology review reveal a wedge-shaped ischemia-driven fibrosis with obliterative 
intimal arteriopathy and adjacent vascular ectasia. Magro et al described a thickening of venules 
and capillary basement membrane and pauci-inflammatory thrombogenic microangiopathy with 
endothelial cell injury and mucin deposition within the dermis and subcutaneous fat6,7. An increase 
in interferon-alpha (IFN-) activity in the pathogenesis of the K-D lesions by increased Myxovirus 
resistance protein 1 (MxA) protein deposits and Rho Associated Coiled-Coil Containing Protein 
Kinase 2 (ROCK-2) upregulation in endothelium has been previously reported 7,8.
The pathology of gastrointestinal and neurological K-D lesions are less clearly defined. GI lesions 
appear grossly similar to cutaneous lesions and they present with extravascular sclerosis with 
arteriopathy limited to the sub serosal fat4. Information on the pathology of CNS lesions is even 
more limited, but case reports describe thickened leptomeningeal vessels with perivascular 
inflammation. Cortical vessels with fibrin thrombus and vessel wall inflammation are present 9. It 
is known that the complement pathway plays an essential role in endothelial cell injury in systemic 
and cutaneous lesions10. While the contribution of inflammation in K-D remains undetermined, 
dysregulation of type I IFN-α response has been reported in skin biopsies 8,10. Our preliminary 
studies using scRNA-seq analyses have shown increased interferon  (IFN-) activity in skin, 
blood and cerebral spinal fluid (CSF) of one patient with neurological involvement of K-D. This 
appears to be driven by CD8 T cells, suggesting a role for adaptive immunity facilitated by IFN- 
in patients with systemic K-D. Additionally, we have observed a chronic elevation of the type I 

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IFN and IFN- response genes in blood measured with NanoString technology and ten increased 
cytokines in plasma samples of systemic K-D patients.
JAK Inhibitors in Neurologic Disease
Ruxolitinib interferes with the signaling of several cytokines and growth factors that are important 
for immune function as noted in the ruxolitinib package insert. JAK signaling involves recruitment 
of signal transducers and activators of transcription (STATs) to cytokine receptors, activation, and 
subsequent localization of STATs to the nucleus leading to modulation of gene expression. 
Dysregulation of the JAK/STAT pathway has been associated with multiple autoimmune and 
autoinflammatory disorders with CNS involvement38 including various interferonopathies: 
Aicardi-Goutières syndrome39,40 39,41 and STING-associated vasculopathy with onset in infancy ( 
SAVI 42. Aicardi-Goutières syndrome is a rare autosomal recessive leukodystrophy, in which type 
I interferon plays a pivotal role were ruloxitinib was used with a favorable outcome. 
In stroke animal models, ruxolitinib treatment improved neurological score, decreased infarct size 
and cerebral edema 43 and has neuroprotective effect on traumatic brain injury44. Secondary-
hemophagocytic lymphohistiocytosis (HLH) is a life-threatening clinical syndrome that can lead 
to rapid mortality. Ruxolitinib has been used in several HLH patients, including those with CNS 
involvement and resulted in improvement in overall survival45. Ruloxitinib can cause weight gain 
in patients with myeloproliferative neoplasms by blocking leptin signaling in the brain46.Taken 
together, data from these studies suggests that ruloxitinib can be used in this patient with CNS K-
D. 
JAK Inhibitors in Autoimmune Diseases
JAK inhibitors have shown efficacy in a number of autoimmune disorders and are currently being 
used in clinical practice. To date, ruxolitinib has not been extensively studied or licensed in patients 
without hematologic or oncologic diagnoses. In rheumatoid arthritis, three JAK inhibitors are 
currently FDA approved: tofacitinib (JAK1/JAK3 and mild JAK2 inhibition), baricitinib 
(JAK1/JAK2 + some moderate TYK2 inhibition), and upadacitinib (JAK1 with some mild 
JAK2/JAK3 inhibition). JAK inhibitors show efficacy in patients with active rheumatoid arthritis 
that does not inadequately respond to methotrexate compared with placebo or a standard-of-care 
disease modifying antirheumatic drug (DMARD), adalimumab, a TNF inhibitor. 47.
Preliminary Results:
Laboratory Evaluation of CSF Cytokines/Biomarkers:
This neurological K-D patient has had four lumbar punctures, taken over the course of 28 months 
while enrolled in one of our natural history protocols, 18-H-0108 (Vascular Disease Discovery 
Protocol, VDDP). We examined a panel of 13 cytokines in these CSF samples (IL-2, Interleukin 
2 Receptor Soluble, IFN-γ, IL-10, IL-12, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, IL-17, and TNF-α) 

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with a CLIA certified quantitative multiplex bead assay. Through this assay, we found increased 
levels of soluble IL-2 receptor and IL-6 in the CSF. In fact, high CSF levels of both cytokines have 
been previously reported in various infectious, inflammatory, and degenerative CNS disorders, 
where these molecules have been shown to correlate with disease activity status and expanded 
disability status scale score 11,12. High levels of neopterin were also noted in the CSF with a mean 
value of 70 nmol/L with 2.5 fold higher levels than those observed in healthy volunteers (8-28 
nmol/L normal values in CSF). Neopterin is an immune activation biomarker produced by 
microglia and astrocytes after the immune activation of IFN-γ. The elevation of neopterin in CSF 
has also been reported in multiple diseases including acute viral and bacterial infections, multiple 
sclerosis, Parkinson disease, autoimmune encephalitis, and CNS lymphoma 13.Further, high 
neopterin values have been previously reported as a valuable marker to differentiate between 
inflammatory and non-inflammatory neurological disorders, but doesn’t appear to be a specific 
marker that can differentiate between various neuroinflammatory diseases. From other CSF 
standard parameters, we found an increase in protein (mean 106 mg/dL, normal <40 mg/dL) and 
albumin quotient (22.13 ratio, normal <9) in our neurological K-D patient over a period of 18 
months. 
More than 15 patients with 
cutaneous and systemic K-D 
are currently enrolled in our 
VDDP 
and 
Biospecimen 
Procurement 
and 
Analysis 
(15-H-0190) protocols since 
2013. Most of these patients 
are evaluated annually at the 
NIH 
Clinical 
Center 
for 
comprehensive clinical and 
laboratory assessments. We 
have analyzed their samples 
with a BioRad Bio-Plex Pro 
Human Chemokine 40-plex 
Panel (No. #171AK99MR2) 
to identify plasma cytokines 
that are increased in K-D. 
Among 40 chemokines tested 
in this panel, four (CCL19, 
CCL23, CCL17 and CCL25) 
were elevated as compared to 
healthy volunteers at a P<0.05 significance level using a two-tailed t-test and an additional six 
(IFN-γ, IL-6, CCL11,CCL26, CCL7, and CXCL9) were increased at P<0.1 significance level (Fig 
1A). Consistent with chronic elevation of the type I IFN and IFN- responses, signaling network 
analysis performed by MetaCore software (Clarivate) (figure 1B) demonstrated that these ten 
cytokines lie within an IFN- and IFN--dependent signaling network downstream of JAK1 and 
JAK2 (figure 1C). This result suggests that JAK1/JAK2-dependent signaling may be upregulated 
in K-D patients and we plan to use these cytokines to monitor the efficacy of ruxolitinib treatment. 
Figure 1. Elevated JAK/STAT–dependent cytokine levels in K-D patient 
plasma . A) Ten cytokines with increased levels in K-D patients, B) Signaling 
network demonstrating that 10 cytokines are upregulated by IFN/JAK/STAT 
signaling, C) Combined Z-score derived from 10 cytokines, calculated 
relative to mean and standard deviation (SD) of healthy volunteer (HV) 
group.

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We also evaluated a standardized 28 gene interferon score (IFNs) previously developed for 
CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature) 
and SAVI patients 14,15 in 5 of our own patients with systemic K-D and 2 with cutaneous K-D. We 
found that the IFN signatures with increased expression of IFN regulated genes in peripheral blood 
were significantly higher in patients with systemic K-D than those with cutaneous K-D, which 
appeared to be similar to healthy control samples (Figure 2). Taken together, this data shows enhanced 
IFN responses in K-D patients confirmed by multiple different approaches.
In order to characterize the 
immune responses at the single-cell 
level, 
we 
examined 
the 
K-D 
transcriptome from 4 patients using 
scRNA-seq (Figure 3). Major skin 
cell 
subsets 
were 
successfully 
captured, and comparison of cell 
compositions revealed that K-D skin 
was enriched in the lymphoid cluster, 
consistent with what was observed in 
histology. Importantly, similar to 
blood and CSF, we found that K-D 
CD8 T cells upregulated IFN-.
Furthermore, analysis of non-T cells 
showed enrichment of JAK/STAT-
associated genes across multiple cell types. In particular, STAT1 and JAK1 were upregulated in 
keratinocytes, vascular endothelial cells (EC), fibroblasts and dendritic cells (DCs) (Figure 3). 
These results demonstrate directly in affected tissue that K-D is characterized by an inflammatory 
milieu driven by type I IFN and IFN- responses with enhanced JAK-STAT pathways, supporting 
potential benefit of ruxolitinib in these patients.
Figure 3. Upregulated JAK1-STAT1 molecules in non-immune cell 
(Keratinocytes, Vacular_ECs, Fibroblast) and immune cells (CD8, 
DCs) of K-D skin, supporting a Type I and II IFN response and 
suggesting an inflammatory milieu within tissue micro-environment.

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Notably, scRNA-seq analyses on PBMC from 10 
patients revealed that circulating K-D immune cells 
were characterized by type I and II (IFN-) signatures. 
In particular, whereas both cutaneous and systemic K-D 
harbored CD8 T cells with upregulated IFN-, those 
from systemic K-D displayed prominent upregulation of 
type I IFN-related genes such as MX1 and IRF7 and 
cytotoxic molecules encoding granzymes and perforins 
(Figure 4A). Furthermore, scRNAseq analysis of CSF 
from one patient with K-D has demonstrated activated 
JAK-STAT pathways not only in PBMCs, but also in 
CSF as revealed by increased STAT1 and JAK2 
expressions. CXCL10, an IFN--induced chemokine 
was also upregulated in both PBMCs and CSF of K-D 
patients, suggestive of their enhanced responses against 
type I IFN and IFN- (Figure 4B). These findings are 
supplemented by significantly elevated neopterin levels, 
soluble IL-2 receptor and IL-6 in CSF samples from 
four different lumbar punctures of one CNS K-D 
patient. Taken together, our data highlight an 
inflammatory milieu in tissues from K-D patients that is 
potentially driven by type I and IFN- responses, 
pointing to these cytokines and their receptor signaling as attractive therapeutic targets for 
ruxolitinib. 
Our preliminary data shows that the spinal fluid of this patient with neurological involvement 
contains high levels of STAT1 and JAK 2 (Figure 4), suggesting that JAK/STAT signaling 
pathway is activated in the spinal cord. Further, our data highlights an inflammatory milieu in 
tissues from K-D patients, which appears to be driven by type α/β and IFN- responses, pointing 
to these cytokines as attractive therapeutic targets. JAK/STAT inhibitors, like ruxolitinib can 
reduce both type α/β IFN and IFN- signaling and have been used in various immune-mediated 
conditions, including monogenic interferonopathies and are often used to treat patients with 
various inflammatory diseases 16. We hypothesize that inhibition of JAK/STAT signaling using 
ruxolitinib has potential utility in reducing IFN signaling in our patient with neurological 
involvement of K-D. 
2.3
RISK/BENEFIT ASSESSMENT
2.3.1
Known Potential Risks
Figure 4: Upregulated Interferon responsive 
genes in K-D suggesting an activated JAK-
STAT signaling both in peripheral blood and 
CSF immune cells.

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Ruxolitinib:
Ruxolitinib is an orally administered small molecule inhibitor of Janus kinase JAK1/2. 
Ruxolitinib is FDA approved for the treatment of intermediate or high-risk myelofibrosis 
(MF) in adults, refractory acute and chronic graft-versus-host disease (GVHD) and 
polycythemia vera (PV) at dose ranges of 5mg-20mg. It has also been safely and effectively 
used in children with type I interferonopathy17. It has an established safety profile that includes 
more than 550 healthy volunteers and subjects with various degrees of renal (n=32) or hepatic 
(n=24) impairment. In healthy volunteers, the most frequent Adverse Events (AEs) reported 
were headache (13.0% overall), diarrhea (13.0% overall), and blood sampling catheter site 
hemorrhage (13.0% overall). AEs were mild and resolved without interventions18-26. There 
was no dose dependency for the frequency of AE with 25 mg BID and 100 mg QD established 
as the maximum tolerated doses. 
Further, the AE profile of ruxolitinib has been assessed in over 14,000 patients with 
myelofibrosis, polycythemia vera, graft-versus-host disease, COVID-19, essential 
thrombocythemia, advanced malignancies, and other immune mediated inflammatory 
diseases18-26. The primary clinical risks with ruxolitinib treatment in these populations are the 
potential sequelae of decreased hematopoietic proliferation attributable to the inhibition of 
growth factor pathways associated with JAK inhibition.
In two pivotal studies, discontinuation of ruloxitinib  due to AEs (regardless of causality)  was 
observed in 8-10 % of patients27,28. The most frequently reported adverse drug reactions 
(ADRs) were thrombocytopenia and anemia. Hematological adverse reactions of grade 3 or 4 
in patients with myelofibrosis included anemia (45.2% versus 19.2 %in placebo), 
thrombocytopenia (12.9% versus 1.3 %placebo) and neutropenia (7.1% versus 2 % placebo). 
Anemia, thrombocytopenia and neutropenia were dose-related effects. The three most 
frequent non-hematological adverse reactions were bruising (18.7%), dizziness (14.8 %) and 
headache (14.8%). The three most frequent non-hematological laboratory abnormalities were 
raised alanine aminotransferase (ALT) (27.2%), raised aspartate aminotransferase (AST) 
(18.6%) and hypercholesterolemia (16.9%)29-31. 
In patients with steroid-refractory acute graft versus host disease (SR-aGVHD) (REACH 1 
study), ruxolitinib 10 mg BID was well tolerated when added to corticosteroid-based 
treatment. Treatment-emergent AEs led to discontinuation of ruxolitinib treatment in 32.4% 
of patients, with the most common being sepsis (5.6%), and thrombocytopenia, acute kidney 
injury, and respiratory failure (2.8% each). The most frequently reported ADRs were 
thrombocytopenia (33% versus 18 % in control group), anemia (30%), and neutropenia (16%). 
The incidence of cytomegalovirus infection occurred in 26% of patients receiving ruxolitinib 
versus 21% in control32. 
In healthy volunteers, rheumatoid arthritis patients, and patients with pancreatic cancer or 
hormone-refractory prostate cancer, the effects on hematopoietic proliferation are less 
pronounced, presumably because of greater bone marrow reserve33,34
The most frequent non-hematologic AEs were mild, reversible increases in ALT and AST ; 
bruising; hypercholesterolemia; dizziness; headache; and urinary tract infections. 
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myelofibrosis. The symptoms of tuberculosis include chronic cough with blood-tinged 
sputum, fever, night sweats, and weight loss. 
There may also be risks associated with rapid discontinuation of ruxolitinib. Patients with 
myelofibrosis, particularly those who have stopped taking ruxolitinib suddenly, have reported 
return of MF symptoms such as fatigue, bone pain, fever, pruritus, night sweats, symptomatic 
splenomegaly and weight loss35. In very few patients, respiratory distress, disseminated 
intravascular coagulation (DIC), multiorgan failure have been reported 35. 
A rare disease called progressive multifocal leuko-encephalopathy (PML), has been reported 
with ruxolitinib36. It is important to note that PML and infections are complications associated 
with MF that has been previously described in the absence of ruxolitinib. Additionally, 
nonmelanoma skin cancers (NMSCs), including basal cell, squamous cell, and a rare and 
aggressive type of skin cancer called merkel cell carcinoma has been reported in patients who 
took ruxolitinib, it is unknown whether this was due to ruxolitinib treatment 37. 
Ruxolitinib has no known contraindications. Detailed information about ruxolitinib is 
available in the Package Insert.
In summary, the expected risks of ruxolitinib treatment in our patient are:
•
Thrombocytopenia, anemia and neutropenia
•
Risk of infection 
• Symptom exacerbation following interruption or discontinuation of treatment with 
ruxolitinib
•
Non-melanoma skin cancer 
•
Lipid elevations
•
Major Adverse Cardiovascular Events (MACE)
•
Thrombosis 
•
Secondary malignancies
History and Physical Exam: 
No known risks
Phlebotomy: 
Standard precautions for obtaining human blood samples will be taken. There are no major 
risks involved with blood draws. Minor complications include bleeding, pain, bruising at the 
site of phlebotomy, vasovagal reactions or infections may rarely occur. This protocol will 
follow the NIH Clinical Center MAS policy M95-9 guidelines for limits of blood drawn for 
research purpose in the Clinical Center.

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Skin Biopsy: 
Discomfort at the biopsy site is usually mild and transient. This can be treated with minor 
analgesics. Most common risks include a reaction to the local anesthetic and the slight 
possibility of local bleeding or infection. A stitch may be placed at the discretion of the 
performing clinician to minimize bleeding in susceptible individuals. Scarring always occurs 
at the biopsy site.
Lumbar Puncture: 
Adverse effects associated with lumbar punctures include brief pain or tingling radiating down 
the lower extremities 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 and 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 1 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 to 2 weeks. Should the headache persist or be severe, 
a blood patch can be performed. Extremely rare complications of lumbar puncture include 
temporary double vision related to abducens nerve palsy, and infection. Strict aseptic 
technique will be followed. In adults, CSF replaces itself at a rate of approximately 
21.5cc/hour, or 500cc/24hours. Thus, the maximum volume of 20cc of CSF that would be 
collected will be replenished in its entirety within approximately 1-1.5 hours after collection. 
Headache and mild low back pain are expected and will not be reported or collected in 
database unless Grade 2 or higher. 
Magnetic Resonance Imaging of the Brain and Spine: 
There are no known adverse effects from having an MRI scan performed. Standard 
precautions will be taken including review of any implanted devices. We will use gadolinium-
based (e.g., gadobutrol) agents. 
Line placement:
The placement of a peripheral intravenous line may result in mild discomfort, vasovagal 
reactions or bruising. 
Gadolinium-based contrast agents:
The contrast agents that may be used are commercially available and are routinely employed 
in hospitals and radiology practices. The most commonly used are gadolinium-based contrast 
agents. Experience with many subjects has shown that commercially available gadolinium 
chelates are safe and without side effects in the majority (>98%) of subjects. When side effects 

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do occur, they are usually mild and transient. These include coldness in the arm during the 
injection, a metallic taste, headache and nausea. More severe reactions (shortness of breath, 
wheezing, or hypotension) are extremely rare. 
Gadolinium-based contrast agents (GBCAs) are injected medications used to change the 
image contrast in MRI and thus providing information not available without GBCA. Most 
patients experience a metallic taste when gadolinium contrast is injected. Some (2%) report 
mild symptoms such as headache, nausea or vomiting, or a rash near the injection site. Rarely 
(<0.1%) patients experience severe symptoms such as wheezing, shortness of breath, and low 
blood pressure as part of an allergic (anaphylactoid) reaction that may require emergency 
medical treatment. In a few cases per million, usually in patients with severe kidney disease, 
gadolinium contrast can cause a rare, debilitating or even fatal, skin disease called 
Nephrogenic Systemic Fibrosis (NSF) that cause thickening of the skin and other organs. 
Since physicians became aware of the disease and began screening patients at risk of kidney 
disease, they switched to safer (“macrocyclic”) forms of gadolinium contrast. New reports of 
NSF are much rarer.
In accordance with the FDA Drug Safety Communication of 05/16/2018, the Medication 
Guide for gadobutrol (or other macrocyclic gadolinium contrast agents if applicable) will be 
made available to outpatients with scans that will involve gadolinium-based contrast agent 
administration.
2.3.2
Known Potential Benefits
The efficacy of ruxolitinib in subjects with K-D has not yet been established. However, 
available pre-clinical data provide rationale for the use of JAK inhibitors in K-D. The JAK-
STAT pathway plays an important role in immune cell development and function, including 
antigen presenting cells, B and T cells, and its activation leads to a cascade promoting a 
proinflammatory cytokine milieu. Ruxolitinib is an oral JAK1/JAK2 inhibitor, with an 
established safety and efficacy profile in the treatment of myeloproliferative neoplasms 
(myelofibrosis) and in acute and chronic GVHD. 
Multiple studies are ongoing looking at JAK inhibitors in various autoimmune disorders. It is 
thus noteworthy that many of the cytokines elevated in K-D, such an IFN-, IL-2 R, IL-6, 
signal through the JAK/STAT pathway48 . By dampening signaling downstream of these 
cytokines, the interruption of the JAK-STAT pathway holds promise to effectively lessen K-
D associated immunopathology. There are no current standard of care treatment for patients 
with K-D. If successful, this study will provide preliminary evidence which may provide a 
new therapy for K-D where there remains a clear unmet need.
2.3.3
Assessment of Potential Risks and Benefits
Despite the aggressive nature of systemic K-D disease and more than 70 years since the first 
description of the disease there has been no cure with limited therapy options and no clinical 
trials conducted. The pathophysiology of K-D disease is poorly understood and there are no 
known markers of disease activity. There is a high mortality rate in K-D patients with systemic 
disease, including pediatric K-D patients.

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This study will evaluate the effect of ruxolitinib 10 mg BID in a patient with progressive and 
unremitting neurological manifestation of K-D disease despite treatment with eculizumab and 
treprostinil. The data from this study is intended to inform the benefit-risk relationship of 
ruxolitinib in K-D patients. We seek to gain crucial insight into the potential efficacy of 
JAK/STAT inhibitors in ameliorating neurologic manifestations of disease and attenuating 
immunoinflammatory parameters in the skin, blood and CSF. If this profile is found to mirror 
disease activity, this expression profile could be used in future clinical trials.
This patient has baseline lymphopenia, which we believe is related to the disease. Serious 
infection is a risk with ruxolitinib and this subject will be on concomitant therapy with 
eculizumab and steroids, which may also increase the risk of infection. We will continuously 
monitor for infection and ruxolitinib treatment will be interrupted if a serious infection 
develops. The patient will receive either the Shingrix vaccine or viral prophylaxis with 
acyclovir prior to initiation of ruxolitinib, and has already received meningitis vaccination.
Although bowel perforation is not listed in the package insert as a risk for ruxolitinib, it has 
been reported in clinical studies of other JAK inhibitors. This patient has K-D lesions on his 
intestines and is at-risk of perforation. For this reason, there may be an additional risk of 
perforation with the use of ruxolitinib and we will monitor closely for symptoms of impending 
perforation. 
Overall, we believe the benefits will outweigh the risks in this patient with a rare, life-
threatening and untreatable disease based on our current research findings and the safety 
profile of ruxolitinib. 
3
OBJECTIVES AND ENDPOINTS
OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS
Primary
To test the hypothesis that 
JAK/STAT inhibition by 
ruxolitinib will delay 
progression of 
neuroradiological 
manifestations of one 
patient with neurological 
involvement of K-D 
disease.
The primary endpoint is 
stability or regression of 
existing enhancing lesions or no 
development of new enhancing 
lesions the brain and spine on 
MRI after 13 weeks of 10 mg 
BID ruloxitinib treatment 
compared to pre-treatment 
images.
This subject has experienced 
progressive neurological 
decline in parallel with 
development new lesions on 
brain and spine MRI so we 
hypothesize that these can be 
followed as markers of K-D 
disease progression.
Tertiary/Exploratory 

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OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS
Assess changes in immune 
cell proportion using 
scRNA-seq analysis in skin, 
CSF and blood after 13 
weeks or up to 73 weeks of 
ruxolitinib treatment.
 
Assess changes in 
plasma/serum cytokine 
levels and IFN scores as 
well as biomarker assays in 
CSF and blood samples 
after treatment with 
ruxolitinib.
To test the hypothesis that 
ruxolitinib will stabilize or 
improve the clinical 
neurologic exam in this 
patient. 
Changes in transcriptome/RNA 
expression determined by 
scRNA-seq analysis in skin, 
CSF and peripheral blood 
mononuclear cells (PBMCs) 
between baseline measurements 
and after 13 weeks or up to 
73weeks of treatment.
Attenuation of plasma/serum 
cytokine levels and IFN scores 
as well as biomarker levels in 
CSF and blood samples.
Stability OR improvement of 
motor and/or sensory function 
on clinical neurologic exam.
Increased levels of type I and 
II interferon signature are 
present in skin, blood and 
CSF in patients with K-D 
disease.
Observed improvement in 
upregulation of blood 
cytokines and 28 gene 
interferon scores.
Functional improvement is 
an indicator of reduction in 
disease burden.
4
STUDY DESIGN
This is a single patient treatment protocol to assess effectiveness of 13, 25, 49, and up to 73  weeks 
of JAK/STAT inhibition on progression of CNS K-D disease.
4.1
OVERALL DESIGN
Referring to the SOA.
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
N/A
4.3
JUSTIFICATION FOR DOSE
It is unknown what the effective dose of ruxolitinib would be in K-D disease. Considering the 
subject will also be on a concomitant immunosuppressing agent eculizumab and has baseline 
lymphopenia, we will start with a low dose (5 mg BID) and escalate to a maximum dose of 10 mg 
BID while closely monitoring for toxicity.

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5
STUDY POPULATION
5.1
INCLUSION CRITERIA
The study design was constructed to treat one subject, a 58 year old male with CNS Kohlmeier 
Degos Disease. Therefore, there are no specific inclusion criteria.
5.2
EXCLUSION CRITERIA
•
Active life-threatening infections 
•
Hemoglobin <7 g/dL
•
Platelet counts < 50 K /mcL
•
Neutropenia (ANC <0.5 x k/mcL)
•
Lymphopenia (ALC <0.2x k/mcL)
•
LFTs (liver function test) > 3x time upper limit
•
eGFR/CreatCr < 30 mL/min 
5.3
INCLUSION OF VULNERABLE PARTICIPANTS
N/A
5.3.1
Participation of NIH Staff or family members of study team members
N/A
5.4
INCLUSION OF PREGNANT WOMEN, FETUSES OR NEONATES
N/A
5.5
LIFESTYLE CONSIDERATIONS
N/A
5.6
SCREEN FAILURES
N/A
5.7
STRATEGIES FOR RECRUITMENT AND RETENTION
N/A 
5.7.1
Costs
Study related procedures and any clinical testing provided at the NIH CC will be provided free of 
charge. Medications will be supplied by the NIH CC on this protocol.

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5.7.2
Compensation
Reimbursement for protocol participation, travel, food, and lodging will be consistent with NHLBI 
DIR Travel and Lodging Compensation of Clinical Research Subjects policy or institutional 
guidelines.
6
STUDY INTERVENTION
6.1
STUDY INTERVENTIONS(S) ADMINISTRATION
6.1.1
Study Intervention Description
There will be no IND obtained for the use of any of the commercial agents used in this study. This 
study meets the criteria for an IND exemption as this investigation is not intended to support a new 
indication for use or any other significant change to the ruxolitinib labeling. This drug is already 
approved and marketed and the investigation is not intended to support a significant change in 
advertising. Further, the investigation does not involve a route of administration or dosage level in 
use in a patient population or other factor that significantly increases the risks (or decreases the 
acceptability of the risks) associated with the use of the drug product. 
6.1.2
Dosing and Administration
Ruxolitinib will be administered to maximum dose as follows:
•
5 mg BID x 1 week
•
10 mg BID x 13-up to 73 weeks
•
5mg BID x 1 week
The patient will have clinical labs checked to assess for hematologic toxicity prior to dosage 
increase. The dose will be increased to the maximum of 10 mg BID if no toxicity is observed based 
on criteria below: 
Definition of Hematologic Toxicity:
•
Hemoglobin  less than  6 g/dL (60 g/L)
•
Reduction in peripheral cytopenias >50% compared to pre-treatment levels in patients with 
a pre-treatment ANC >500 or platelets >50
6.1.2.1
DOSE ESCALATION
See section 6.1.2 above.
6.1.2.2
DOSE LIMITING TOXICITY
N/A
6.1.2.3
DOSE MODIFICATIONS
Hematologic toxicity is defined in section 6.1.2
If hematologic toxicity develops while on 10 mg BID, patient will decrease dose to 5 mg BID.

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If hematologic toxicity develops while on 5 mg BID, patient will decrease dose to 5 mg QD.
If hematologic toxicity develops while on 5 mg QD, patient will stop drug.
6.1.2.4
DRUG ADMINISTRATION
Ruxolitinib is dosed orally and can be administered with or without food. If a dose is missed, the 
subject should not take an additional dose, but should take the next usual prescribed dose.
6.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
Refer to package insert.
6.2.1
Acquisition and Accountability
The study drug will be obtained and dispensed by the NIH pharmacy. The tablets for this study are 
available as 5 and 10 mg tablets.
6.2.2
Formulation, Appearance, Packaging, and Labeling
Ruxolitinib (Jakafi) tablets are available as follows:
6.2.3
Product Storage and Stability
Store at room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 
30°C (59°F and 86°F).
Shipping:This medication is on formulary. 
6.2.4
Preparation
N/A
6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING
N/A

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6.4
STUDY INTERVENTION COMPLIANCE
No formal assessment will take place. The study subject will be asked to bring any remaining study 
medications to landmark visits, during which tablets will be counted.
6.5
CONCOMITANT THERAPY
For this protocol, a prescription medication is defined as a medication that can be prescribed only 
by a properly authorized/licensed clinician. Medications to be reported in the Case Report Form 
(CRF) are concomitant prescription medications, over-the-counter medications, and supplements.
All medications, administered after the participant was enrolled into the study must be recorded 
on the appropriate electronic Case Report Forms (eCRFs). The patient must be told to notify the 
Treating Physician about any new medications he/she takes after the start of study drug.
Patient may receive: anti-virals, inhaled or systemic corticosteroids, treprostinil, eculizumab, 
heparin, low molecular weight heparin (LMWH), direct oral anticoagulants, anti-emetics, 
calcineurin inhibitors, azole fungal prophylaxis (acyclovir prophylaxis), broad spectrum 
antibiotics (either semi-synthetic penicillin or third generation cephalosporin with vancomycin, 
gentamycin or equivalent), bactrim prophylaxis, steroid pre-meds prior to RBC/platelet 
transfusions, narcotics, and sedatives warranting close monitoring of potential drug-drug 
interaction effects of these concurrent drugs.
If the patient is started on warfarin, heparin, LMWH, or direct oral anticoagulants, the degree of 
thrombocytopenia should be considered, platelet counts and coagulation parameters will be 
monitored, and the dose of anti-coagulant or non-steroidal anti-inflammatory drug adjusted 
accordingly.
If the patient is started on any drugs that affect platelet function/count, platelet counts and 
coagulation parameters will be monitored, and the dose of drug adjusted accordingly. In the 
presence of potent CYP3A4 inhibitors, there is the possibility of increased exposure to ruxolitinib 
and more frequent monitoring of hematology parameters is recommended, although no automatic 
dose adjustment is required. See Appendix 1 for a list of cytochrome P450 3A4 (CYP3A4) 
inhibitors and inducers.
The following medications are prohibited until treatment discontinuation:
•
Concomitant use of another JAK inhibitor
•
Aspirin in doses >150 mg/day
•
Fluconazole > 200 mg daily
7
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1
DISCONTINUATION OF STUDY INTERVENTION
Discontinuation from ruxolitinib does not mean discontinuation from the study, and the remaining 
study procedures should be completed as indicated by the study protocol. If a clinically significant 
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investigator or qualified designee will determine if any change in participant management is 
needed. Any new clinically relevant finding will be reported as an adverse event (AE).
The data to be collected at the time of study intervention discontinuation will include the following:
•
CBC + blood smear
•
Mineral panel
•
Acute care panel
•
Liver function tests
If subject is permanently discontinued from study medication than we will also collect:
•
Brain and spine MRI
•
LP with CSF collection
•
Research blood
•
Skin biopsies
•
Neurologic consult
Study drug discontinuation may be temporary due to hematologic toxicity, acute 
infection or other clinically-indicated reasons at the PI’s discretion. Before reinitiation 
of ruxolitinib, we will use the same eligibility criteria as in 5.2, and if the patient meets 
criteria will restart the ruxolitinib at 10 mg bid ( without titration at 5 mg bid ) and 
continue treatment until the patient has completed the full 13 or 24  or  49  or up to 73 
weeks course actually on therapy.
7.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY
Prior to removal from study, every effort must be made to have the subject complete a safety visit 
approximately 2 weeks following the last dose of study therapy.
The participant is free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw the participant from the study for the following 
reasons:
•
Disease progression which requires discontinuation of the study intervention.
•
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the participant.
•
Investigator discretion.
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
Case Report Form (CRF). 
7.3
LOST TO FOLLOW-UP

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N/A
8
STUDY ASSESSMENTS AND PROCEDURES
8.1
SCREENING PROCEDURES
8.1.1
Screening activities performed prior to obtaining informed consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 
•
Email, written communication, in person or telephone communications with prospective 
subjects. 
•
Review of existing medical records to include H&P, laboratory studies, etc. 
•
Review of existing MRI, x-ray, or CT images.
•
Review of existing photographs or videos.
•
Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes.
8.1.2
Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the subject has signed the consent this study. 
Assessments performed at outside facilities or on another NIH protocol within the timeframes 
below may also be used to determine eligibility once a participant has signed the consent.
All screening tests and procedures must be performed within 60 days prior to enrollment unless a 
time period is specifically mentioned.
-
CBC with differential.
8.2
STUDY EVALUATIONS & PROCEDURES
The following activities will be performed based on the SOA, section 1.2.
Physical Examination and Medical History: Medical history and physical examination 
including vital signs and biophysical data (including but not limited to blood pressure, heart 
rate, respiratory rate, temperature, and weight) may be collected at each visit.
Phlebotomy: Blood draw for clinical and research assays. Up to 150 mL of research blood 
may be collected at the time of protocol enrollment, at each visit at the clinical center, and 
research blood collected will  be under 550 ml or 10.5mL/kg subject body weight within 8 
weeks.
.

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Brain and spine MRI: Standard test run in non-research mode to answer research questions.
Lumbar Puncture: Lumbar puncture (LP) may be obtained to collect cerebrospinal fluid 
(CSF) during any scheduled Clinical Center visit. The LP will be performed at the Clinical 
Center as an inpatient, or at the outpatient day hospital, or in interventional radiology if done 
under fluoroscopy. We will collect up to 20 cc of CSF per lumbar puncture. Sedation with 
low-dose benzodiazepines may be used for subjects with expressing anxiety during the LP. 
Analysis of CSF may include cell count, total protein, albumin , glucose, oligoclonal band, 
IgG index, cytokine assays, neopterin etc. CSF will also be aliquoted and stored for future 
use. Additionally, specialized laboratory testing such as detection of autoantibodies to novel 
antigens, proteomic analysis of the fluid, markers of neurodegeneration like neurofilament, 
culture and functional assays on the cells in the CSF and microRNA profile, proteomics, 
scRNA-seq will be performed as needed.
8.2.1
Biospecimen Evaluations
Blood Samples: In addition to blood sent to the DLM laboratory for evaluation, blood may 
be collected for isolation of plasma, serum, RNA and cells (such as PBMCs or platelets) for 
analysis. Cell lines derived from blood may be used to generate transformed cell lines, for 
fluorescence activated cell sorting (FACS) analysis, cell biological and molecular analysis 
Additional specialized laboratory tests may be performed to study disease processes and 
specific testing will be tailored to the patient’s clinical findings. Research blood may be 
collected to study components of plasma and serum, including but not limited to biomarkers. 
Blood samples will be processed using standard procedures currently used at the NIH CC. 
Skin Biopsy: 
Biopsies of K-D lesions may be obtained. Separate signed procedure informed consent forms 
will be utilized. Up to two skin biopsies may be obtained with local anesthetic at baseline and 
again at end of treatment with a maximum of six total skin biopsies allowed. Standard skin 
biopsies (e.g. punch biopsy, excision) will be obtained with a sterile cylindrical or straight 
blade as determined by a credentialed care provider. Individual biospecimens will measure 
approximately 3-4mm in width as is routinely collected in Dermatology clinic. Biopsy 
specimens may be split prior to processing. Samples of K-D lesions will be used for 
histology/microscopy, cultured for the isolation of distinct cell populations for subsequent 
biochemical, cell biological and molecular analyses, and scRNA-seq analysis. 
Lumbar Puncture: Analysis of CSF may include (but will not be limited to) cell count, total 
protein, glucose, Immunofixation electrophoresis, oligoclonal band, IgG index, cytokine 
assays, etc. CSF will also be aliquoted and stored for future use. Additionally, specialized 
laboratory testing such as detection of autoantibodies to novel antigens, proteomic analysis of 
the fluid, markers of neurodegeneration like neurofilament, culture and functional assays on 

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the cells in the CSF and microRNA profile, proteomics, scRNA-seq will be performed as 
needed.
Single Cell RNA Sequencing: To ensure that high quality data is generated from scRNAseq, 
rigorous quality control (QC) efforts will be performed for this study for both the experimental 
procedures and computational analysis. 
Experimental QC: Tissue dissociation will be performed using an optimized protocol to
ensure a standardized procedure. Skin biopsy, blood (PBMC) and CSF fluid will be 
processed in a rapid manner so that the profile of cellular RNA will remain as authentic as 
possible. By the end of the process, every sample will be assessed for cellular viability, the 
presence of ambient debris, and cell number. This QC test will determine if the sample is 
ready for further processing for sequencing or if additional steps are needed to improve the 
quality of the sample. If the quality of the sample needs to be improved, it will be treated 
with a magnetic bead-based method to enrich for viable cells, deplete debris, and reduce 
ambient RNA. If a second QC test confirms improvement in the quality of the sample, the 
cells will then be further processed. Quality control measures will be included for library 
construction. Bulk RNAseq will be performed on samples and the RNA integrity number 
(RIN) scores will be checked.
Computational QC: scRNAseq data is noisy, and includes false negatives (“drop-outs”): 
genes expressed in the cell but not detected by the assay. The Klarman Cell Observatory 
(KCO) at the Broad Institute has developed and leveraged state of the art tools, many 
developed within the laboratory as well as from other groups, for pre-processing and QC of 
scRNAseq data. The KCO pipeline uses RNAseq analysis tools such as Trinity, Tuxedo, and 
RSEM to align reads, transcript reconstruction/annotation, abundance estimation, read 
quality trimming, and sample quality analysis. Library quality is scored based on alignment 
rates to the genome and transcriptome, the proportion of ribosomal (rRNA) reads, the 
uniformity of coverage, 3′ and 5′ biases, biases associated with length or sequence 
composition, library complexity, reproducibility of expression estimates, and the 
relationship between single cell and bulk population profiles. The pipeline is optimized for 
plate, single nucleus sequencing (sNuc-Seq), Droplet-sequencing (Drop-Seq), DroNc-Seq, 
and 10x Genomics data, addressing each data type’s unique characteristics (e.g., unique 
molecular identifiers [UMIs], 3′-directed libraries, etc.). Tools will be incorporated that 
increase efficiency by pseudo-alignment, and address unique quality issues that arise at 
polymerase chain reaction, such as cell barcode chimeras. To calculate expression levels, 
alternatives to standard approaches that typically rely on assumptions that are violated in 
single cell profiles of heterogeneous cell populations will be considered. For example, in a 
population of T-cells, some may be active and others “quiescent” with the former having 
radically larger and more complex transcriptomes. This is addressed by introducing a 
scaling factor reflecting the expected number of transcripts (or UMIs) in each condition and 
by revising differential expression tests, to account for the varying number of transcripts and 
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8.2.2
Correlative Studies for Research/Pharmacokinetic Studies
N/A
8.2.3
Samples for Genetic/Genomic Analysis
8.2.3.1
DESCRIPTION OF THE SCOPE OF GENETIC/GENOMIC ANALYSIS
Single cell RNA-seq analysis from skin, CSF, and PBMC will be employed to determine 
changes in transcriptome/RNA expression  and will allow us to to study individual cells at a 
molecular level. We will be able  identify what  specific genes that are changes in each type of 
cell from the tisses mentione above  ;characterize cell states and understand how cells interact in 
various tissues in our  patient with neuro KD disease.
8.2.3.2
DESCRIPTION OF HOW PRIVACY AND CONFIDENTIALITY OF MEDICAL 
INFORMATION/BIOLOGICAL SPECIMENS WILL BE MAXIMIZED
Samples will be coded and stored in the laboratory of the Accountable Investigator with limited 
access. Patient identification will only be available through locked password –protected database 
repository archives. Access to the password and hard copy files will be only provided to the PI and 
the research staff. 
8.2.3.3
MANAGEMENT OF PRIMARY RESULTS
Single-cell RNA-seq data will have no immediate use in the care or well-being of the study 
participant.  Therefore, no genetic information will be conveyed to the participant. 
8.2.3.4
RETURN OF SECONDARY GENOMIC RESEARCH RESULTS
No secondary genomic information is being collected through the analysis of scRNA-seq.
8.2.3.5
GENETIC COUNSELING
N/A
8.3
SAFETY AND OTHER ASSESSMENTS
Physical examination 
Physical examination including vital signs and medication reviews with interval histories will be 
performed at baseline, and at the times described in the protocol   ( per SOA ) will be conducted 
in this patient   while on study.Physical exam will be performed and may include height, weight, 
BP, heart rate, respiratory rate, oxygen saturation, eye exam for scleral icterus, cardiopulmonary 
exam (including heart and lung exam ), abdominal exam (including presence/absence of 
hepatosplenomegaly), and neurologic exam (including cranial nerve exam and assessment of 
strength, sensation, and reflexes in upper and lower extremities). Performance status may also be 
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Vital signs: Vital signs will be monitored during each study visit. 
Blood draw: Blood specimens for the measurement and evaluation of serum chemistries and 
hematology will be collected at each visit.
Assessment of Adverse Events: Assessment of adverse events will be performed during 
study visits by the study team. Adverse events that have not resolved after completion of study 
drug administration will be followed until 14 days after the last dose. 
8.4
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
Definition of Adverse Event: Adverse event means any untoward medical occurrence associated 
with the use of an intervention in humans, whether or not considered intervention-related (21 
CFR 312.32 (a)). 
Non-hematologic abnormal laboratory findings used to evaluate the safety of this protocol 
regimen will include any change from baseline laboratory assessments that result in a 
progression to a grade 3 or 4 laboratory toxicity or are characterized by any of the following:
•
Results in discontinuation from the study.
•
Is associated with clinical signs or symptoms.
•
Requires treatment or any other therapeutic intervention.
•
Is associated with death or another serious adverse event, including hospitalization.
•
Is judged by the Investigator to be of significant clinical impact.
•
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome.
Hematologic toxicity will be assessed as described in Section 6.1 and will be subject to 
independent assessment and stopping rules compared to non-hematologic AE/SAE. Grade 1 
and Grade 2 lab abnormalities that are not associated with any clinical symptoms will not be 
considered an AE.
8.4.1
Definition of Adverse Event
Adverse event means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)).
8.4.2
Definition of Serious Adverse Events (SAE)
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: death, a life-

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threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the participant and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse.
8.4.3
Classification of an Adverse Event
8.4.3.1
SEVERITY OF EVENT
AEs will be graded by severity utilizing the Common Terminology Criteria for Adverse 
Events (CTCAE). For internal consistency, the most current version at the writing of this 
protocol (version 5.0, published November 27, 2017) shall be used for the duration of this 
study and its analysis. The CTCAE can be downloaded at the above link or through the CTEP 
homepage at https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm. 
For AEs not specified by the CTCAE, the following guidelines will be used to describe 
severity:
General classification of AEs
Grad
e
Category
Description
1
Mild
Mild; asymptomatic; clinical or diagnostic 
observations only; intervention not indicated
2
Moderate
Moderate; minimal, local or noninvasive 
intervention indicated; limiting age-
appropriate instrumental Activities of Daily 
Living (ADL)1
3
Severe
Severe or medically significant but not 
immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; 
disabling; limiting self-care ADL2
4
Life 
threatening
Life-threatening consequences; urgent 
intervention indicated
5
Death
Death related to AE
1 Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.
2  Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden.

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For adverse events (AEs) not included in the protocol defined grading system, the following 
guidelines will be used to describe severity:  
•
Mild – Events require minimal or no treatment and do not interfere with the participant’s 
daily activities. 
•
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning.
•
Severe – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating. Of note, the term “severe” does not necessarily equate to “serious”.
8.4.3.2
RELATIONSHIP TO STUDY INTERVENTION
•
Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study intervention 
administration and cannot be explained by concurrent disease or other drugs or chemicals. 
The response to withdrawal of the study intervention (dechallenge) should be clinically 
plausible. The event must be pharmacologically or phenomenologically definitive, with 
use of a satisfactory rechallenge procedure if necessary.
•
Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test 
result, occurs within a reasonable time after administration of the study intervention, is 
unlikely to be attributed to concurrent disease or other drugs or chemicals, and follows a 
clinically reasonable response on withdrawal (dechallenge). Rechallenge information is 
not required to fulfill this definition.
•
Possibly Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly related” 
soon after discovery, it can be flagged as requiring more information and later be 
upgraded to “probably related” or “definitely related”, as appropriate.
•
Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study intervention administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the study intervention) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments).
•
Not Related – The AE is completely independent of study intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. There must 
be an alternative, definitive etiology documented by the clinician.]

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8.4.3.3
EXPECTEDNESS 
The PI or designated AI will be responsible for determining whether an adverse event (AE) is 
expected or unexpected. An AE will be considered unexpected if the nature, severity, or 
frequency of the event is not consistent with the risk information previously described for the 
study intervention in the package insert. The subject will be receiving two additional FDA-
approved medications for treatment of KD disease and AE’s associated with these medications 
as reported in their package inserts will be considered when determining AE expectedness.
8.4.4
Time Period and Frequency for Event Assessment and Follow-Up
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel during study visits and interviews of the study participant 
presenting for medical care, or upon review by a study monitor.
Grade 2 or greater AEs, including local and systemic reactions not meeting the criteria for 
SAEs and all SAEs, will be captured on the appropriate case report form (CRF). Information 
to be collected includes event description, time of onset, clinician’s assessment of severity, 
relationship to study product (assessed only by those with the training and authority to make 
a diagnosis), and time of resolution/stabilization of the event. All AEs occurring while on 
study must be documented appropriately regardless of relationship. All AEs will be followed 
to adequate resolution.
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.
Changes in the severity of an AE will be documented to allow an assessment of the duration 
of the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode.
All clearly related signs, symptoms, and results of diagnostic procedures performed because 
of an AE should be grouped together and recorded as a single diagnosis. If the AE is a 
laboratory abnormality that is part of a clinical condition or syndrome, it should be recorded 
as the syndrome or diagnosis rather than the individual laboratory abnormality.
Trained member of the study team will record all reportable events with start dates occurring 
any time after informed consent is obtained until 7 (for non-serious AEs) or 15 days (for 
SAEs) after the last day of study drug. At each study visit, the investigator will inquire about 
the occurrence of AE/SAEs since the last visit. Events will be followed for outcome 
information until resolution or stabilization.
8.4.5
Adverse Event Reporting 
See section 8.4.6 below.
8.4.6
Serious Adverse Event Reporting 

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In consultation with the PI, a trained member of the study team will be responsible for 
conducting an evaluation of all adverse events and shall report the results of such evaluation 
to the NIH Institutional Review Board (IRB) as per Policy 801.
All events listed in section will be reported to the Principal Investigator of this study: 
Cornelia Cudrici M.D.
Translational Vascular Medicine Branch
NHLBI Institute
Building 10, Rm 53232
9000 Rockville Pike
Bethesda, MD 20892
Phone: 240-515-5540
E-mail: cudricicd@mail.nih.gov
8.4.7
NIH Intramural IRB and NHLBI Clinical Director Reporting
Expedited Reporting 
Events requiring expedited reporting will be submitted to the IRB per HRPP Policy 801 
“Reporting Research Events”. 
Reports to the NIH Intramural IRB at the Time of Continuing Review (CR)
The PI or designee will refer to HRPP Policy 801 “Reporting Research Events” to determine 
IRB reporting requirements. 
Reports to the NHLBI Clinical Director (CD)
The PI or designee will refer to NHLBI DIR guidelines to determine CD reporting 
requirements and timelines. 
8.4.8
Events of Special Interest 
N/A
8.4.9
Reporting of Pregnancy
N/A 
8.5
UNANTICIPATED PROBLEMS

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8.5.1
Definition of Unanticipated Problems (UP)
8.5.2
Unanticipated Problem Reporting 
Any incident, experience, or outcome that meets all of the following criteria:
•
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; and
•
Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been caused 
by the procedures involved in the research); and
•
Suggests that the research places participants or others (which many include research 
staff, family members or other individuals not directly participating in the research) at a 
greater risk of harm (including physical, psychological, economic, or social harm) than 
was previously known or expected.
8.5.3
Unanticipated Problem Reporting 
The investigator will report unanticipated problems (UPs) to the NIH Institutional Review Board 
(IRB) as per Policy 801.
9
STATISTICAL CONSIDERATIONS
9.1
STATISTICAL HYPOTHESIS
We hypothesize that blocking type I IFN and IFN- signaling for 13 weeks with ruxolitinib has 
potential utility in improving clinical, neurological and CNS radiological manifestations in our K-
D patient. Only descriptive analysis will be conducted given the nature of the study. 
Primary Endpoint: Stability OR regression of existing enhancing lesions OR no development of 
new enhancing lesions in the brain and spine on MRI after 13 weeks of ruxolitinib treatment. This 
will be determined by a neuroradiologist experienced in Degos disease MRI evaluation. 
Exploratory Endpoint(s): (a) changes in transcriptome/RNA expression determined by single 
scRNA-seq in skin, CSF and peripheral blood mononuclear cells (PBMCs) between baseline 
measurements and 13- up to 73 weeks of treatment, (b) attenuation of plasma/serum cytokine 
assays and IFN scores as well as biomarker assays in CSF and blood samples and (c) improvement 
or stabilization of motor and sensory function on clinical neurologic exam.
9.2
SAMPLE SIZE DETERMINATION
This protocol is for treatment of one patient protocol.
9.3
POPULATIONS FOR ANALYSES
N/A
9.3.1
Evaluable for toxicity

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The study participant will be evaluated for toxicity during the duration of treatment with 
ruxolitinib.
 
9.3.2
Evaluable for objective response 
N/A
9.3.3
Evaluable Non-Target Disease Response
N/A
9.4
STATISTICAL ANALYSES
9.4.1
General Approach
With a single study participant, we will report the baseline measurements and 13 week treatment 
period changes of primary and exploratory endpoints.
9.4.2
Analysis of the Primary Endpoints
The primary endpoint is stability OR regression OR no development of new enhancing lesions of 
existing enhancing lesions in the brain and spine on MRI after 13 weeks of ruxolitinib treatment. 
We will report the baseline measurements and 13 week treatment period changes  of brain and 
spine lesions.
9.4.3
Analysis of the Secondary Endpoint(s)
Analysis of the Secondary Endpoint(s): There will be no secondary endpoints. We will report the 
baseline to 13-up to 73 weeks change of the various exploratory endpoints.
9.4.4
Safety Analyses
The subject will be monitored for the study duration and all grade 2 or greater AEs will be 
collected. We will also monitor the occurrence of a specified set of treatment related serious 
adverse events (TRSAEs) during the trial.
The following TRSAEs will be monitored for early stopping of the study:
•
 Death considered to be probably or definitely related to ruxolitinib.
•
Any grade 4 toxicity (except cytopenia) considered to be probably or definitely related to 
ruxolitinib.
•
For cytopenias, a TRSAE will be considered if the patient permanently stops ruxolitinib 
due to hematologic toxicity.

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The study will be monitored using the stopping rules as outlined above for early stopping if the 
subject in the study will develop one or more of the above specified TRSAEs. TRSAEs are those 
attributed as definitely or probably related to ruxolitinib. 
9.4.5
Baseline Descriptive Statistics
N/A
9.4.6
Planned Interim Analyses
With one patient, there will be no formal interim analyses.
9.4.7
Sub-Group Analyses
With one patient, there will be no formal interim analyses.
9.4.8
Tabulation of individual Participant Data
This data will be captured in the analysis of the patient’s primary and exploratory endpoints.
9.4.9
Exploratory Analyses
The exploratory analyses will include
1. Changes in transcriptome/RNA expression determined by single cell RNAseq (scRNA-
seq) in skin, CSF and peripheral blood mononuclear cells (PBMCs) between baseline 
measurements and 13 weeks and up to73  weeks after start of treatment.
2. Attenuation of plasma/serum cytokine assays and IFN scores as well as biomarker assays 
in CSF and blood samples.
3. Stability OR improvement of motor and /or sensory function on clinical neurologic exam.
10
REGULATORY AND OPERATIONAL CONSIDERATIONS
10.1 INFORMED CONSENT PROCESS
10.1.1 Consent/Assent Procedures and Documentation
Informed consent will be conducted following OHSRP Policy 301- Informed Consent. An IRB-
approved consent form will be provided to the participant electronically or by hard copy for review 
prior to consenting. The initial consent process as well as re-consent, when required, may take 
place in person or remotely (e.g., via telephone or other NIH approved platforms). The 
investigational nature and objectives of this trial, the procedures, and their attendant risks and 
discomforts and potential benefits will be carefully explained to the participant in a private setting. 
The participant will be given as much time as they need to review the document and to consult 
with their family, friends, and personal health care providers. In addition, a study team member 
will be available to answer any questions.

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A signed and dated informed consent document will be obtained by any investigator authorized to 
consent prior to entry onto the study. Consent may be obtained with required signatures on the 
hard copy of the consent or on the electronic document.
When a document that is in electronic format is used for obtaining consent, this study may use the 
iMed platform which is 21 CFR, Part 11 compliant, to obtain the required signatures.
During the consent process, the participant and investigator may view the same approved consent 
document simultaneously when the participant is being consented in person at the Clinical Center 
or both may view individual copies of the approved consent document on screens in their 
respective locations remotely. Signatures may be obtained either by both directly signing on the 
device that the consenting investigator is using (when in person) or through iMed Mobile Signature 
Capture (remotely) which allows texting or emailing a link to the participant. That link allows the 
participant to review the consent, then proceed to sign on the device they are using.
Whether hard copy or electronic, both the investigator and the participant will sign the document 
with a hand signature using a pen (if using hard copy), finger, stylus, or mouse (if electronic). 
When done remotely, if the participant prefers to sign a hard copy, they may be instructed to sign 
and date the consent document during the discussion and mail, secure email or fax the signed 
document to the consenting investigator.
Whether in person or remotely, the privacy of the participant will be maintained. 
Finally, the fully signed informed consent document will be stored in the electronic medical record, 
and the participant will receive a copy of the signed informed consent document.
Following the enrolment of the subject, the research coordinator will be informed of the enrolment. 
The research coordinator will conduct a Quality Control (QC) review of the consent process and 
documentation periodically to confirm compliance.
10.1.2 Consent for minors when they reach the age of majority 
N/A
10.1.3 Considerations for Consent of NIH staff, or family members of study team members
N/A
10.1.4 Consent of Subjects who are, or become, decisionally impaired
This study offers the potential to improve or delay progression of the subject’s neurological 
manifestations. The subject will be evaluated for his cognitive ability at the time of consent and if 
needed,  an LAR will be identified consistent with Policy 403 and informed consent obtained from 
the LAR, as described in Section 10.1.1. 

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10.2 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to the study participant, 
investigator, funding agency, and regulatory authorities. If the study is prematurely terminated or 
suspended, the Principal Investigator (PI) will promptly inform the study participant, the 
Institutional Review Board (IRB), and Clinical Director of NHLBI and will provide the reason(s) 
for the termination or suspension. The study participant will be contacted, as applicable, and be 
informed of changes to study visit schedule.
 Circumstances that may warrant termination or suspension include, but are not limited to:
•
Determination of unexpected, significant, or unacceptable risk to the participant
•
Demonstration of efficacy that would warrant stopping  
•
Insufficient compliance to protocol requirements
•
Data that are not sufficiently complete and/or evaluable
•
Determination that the primary endpoint has been met
•
Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and, as applicable, the Food and Drug Administration 
(FDA).
10.3 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to the participant. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participant in this study. The clinical study 
site will permit access to such records.
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements.
To further protect the privacy of the study participant, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH). This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 

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research records to refuse to disclose identifying information on research participation in any civil, 
criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local 
level. By protecting researchers and institutions from being compelled to disclose information that 
would identify the research participant, Certificates of Confidentiality help achieve the research 
objectives and promote participation in studies by helping assure confidentiality and privacy to the 
participant.
10.4 FUTURE USE OF STORED SPECIMENS AND DATA
We may share specimens and data with other researchers for future use.
Stored Specimens: Following analyses of biospecimens for primary research purposes, remaining 
samples suitable for future research will be stored in manner that conforms with DIR policy (such 
as BSI) or in a publicly accessible research biospecimen repository following IRB approval, as 
applicable. Biospecimens may be destroyed only when permitted by the clinical director and the 
IRB. Any future research use of identifiable biospecimens not defined in the research protocol will 
occur only after IRB review and approval.
10.5 SAFETY OVERSIGHT
The principal investigator will be responsible for the safety oversite of the study.
10.6 CLINICAL MONITORING
Clinical site monitoring is conducted to ensure that the rights and well-being of the trial participant 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct 
of the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s). 
Monitoring for this study will be performed by Clinical Research Associates (CRAs)/Monitors 
working under an agreement with NHLBI to monitor aspects of the study in accordance with the 
appropriate regulations and the approved protocol.
The objectives of a monitoring visit will be:
1) to verify the existence of signed informed consent form (ICF) and documentation of the ICF 
process for each monitored subject;
2) to verify the prompt and accurate recording of all monitored data points, and prompt reporting 
of all SAEs;
3) to compare abstracted information with individual subjects’ records and source documents 
(subject’s charts, laboratory analyses and test results, physicians’ progress notes, nurses’ notes, 
and any other relevant original subject information); and

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4) to help ensure investigators are in compliance with the protocol. The monitors also will inspect 
the clinical site regulatory files to ensure that regulatory requirements (Office for Human Research 
Protections-OHRP), FDA and applicable guidelines (ICH-GCP) are being followed. During the 
monitoring visits, the investigator (and/or designee) and other study personnel will be available to 
discuss the study progress and monitoring visit.
The investigator (and/or designee) will make study documents (e.g., consent forms and pertinent 
hospital or clinical records readily available for inspection by the local IRB, the FDA, the site 
monitors, and the NHLBI staff for confirmation of the study data.
10.7 QUALITY ASSURANCE AND QUALITY CONTROL
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Conference 
on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements 
(e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities.
10.8 DATA HANDLING AND RECORD KEEPING
10.8.1 Data Collection and Management Responsibilities
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. All source documents should be completed in a 
neat, legible manner to ensure accurate interpretation of data. 
Data recorded in the electronic case report form (eCRF) in password protected excel database 
derived from source documents should be consistent with the data recorded on the source 
documents. Data will be entered directly from the source documents.
10.8.2 Study Records Retention
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Conference on Harmonisation (ICH) region and until there are no 
pending or contemplated marketing applications in an ICH region or until at least 2 years have 
elapsed since the formal discontinuation of clinical development of the study intervention, and as 
per the NIH Intramural Records Retention Schedule. No records will be destroyed without the 

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written consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform the 
investigator when these documents no longer need to be retained.
10.9 PROTOCOL DEVIATIONS AND NON-COMPLIANCE
It is the responsibility of the investigator to use continuous vigilance to identify and report 
deviations and/or non-compliance to the NIH Institutional Review Board as per Policy 801. All 
deviations must be addressed in study source documents, reported to NHLBI Program Official. 
The investigator is responsible for knowing and adhering to the reviewing IRB requirements.
10.9.1 NIH Definition of Protocol Deviation
A protocol deviation is any changed, divergence, or departure from the IRB-approved research 
protocol. 
•
Major deviations: Deviations from the IRB approved protocol that have, or may have the 
potential to, negatively impact the rights, welfare or safety of the subject, or to substantially 
negatively impact the scientific integrity or validity of the study.
•
Minor deviations: Deviations that do not have the potential to negatively impact the rights, 
safety or welfare of subjects or others, or the scientific integrity or validity of the study.
10.10 HUMAN DATA SHARING, INCLUDING GENOMIC DATA SHARING, AND PUBLICATION
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations:
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access 
to the published results of NIH funded research. It requires scientists to submit final peer-reviewed 
journal manuscripts that arise from NIH funds to the digital archive PubMed Central upon 
acceptance for publication.
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-
Funded Clinical Trial Information and the Clinical Trials Registration and Results Information 
Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and results information 
from this trial will be submitted to ClinicalTrials.gov. In addition, every attempt will be made to 
publish results in peer-reviewed journals. Data from this study may be requested from other 
researchers 1 year after the completion of the primary endpoint by contacting Cornelia Cudrici, 
MD, NHLBI.
Research data will be deposited in BioData Catalyst (BDC) at the time of study publication or 
closure, whichever comes first. BDC is a controlled access repository and in order to access the 
data, an investigator must have an approved Data Access Request (DAR) through dbGaP. Data 
will be available for access indefinitely.

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10.10.1NIH Data Management and Sharing Policy and NIH Genomic Data Sharing Policy 
Compliance
N/A
10.10.2NIH Public Access Policy Compliance
N/A
10.11 COLLABORATIVE AGREEMENTS 
N/A
10.11.1Agreement Type
N/A
10.12 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial. The study leadership in conjunction with NHLBI has established policies and 
procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest.
11
ABBREVIATIONS
The list below includes abbreviations utilized in this template.  However, this list should be 
customized for each protocol (i.e., abbreviations not used should be removed and new 
abbreviations used should be added to this list).
AE
Adverse Event
CANDLE
Chronic atypical neutrophilic dermatosis with 
lipodystrophy and elevated temperature
CFR
Code of Federal Regulations
CMP
Clinical Monitoring Plan
CNS
Central Nervous System
COC
Certificate of Confidentiality
CRF
Case Report Form
CSF
Cerebrospinal Fluid
DCC
Data Coordinating Center
DHHS
Department of Health and Human Services

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DIC
Disseminated iIntravascular Coagulation
DSMB
Data Safety Monitoring Board
EC
Ethics Committee
eCRF
Electronic Case Report Forms
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments 
Act of 2007
GBCAs
Gadolinium-based contrast agents
GCP
Good Clinical Practice
GI
Gastro Intestinal
GLP
Good Laboratory Practices
GMP
Good Manufacturing Practices
GVHD
Graft-versus-host disease
HIPAA
Health Insurance Portability and 
Accountability Act
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IDE
Investigational Device Exemption
IFN
Interferons
IND
Investigational New Drug Application
IRB
Institutional Review Board
ISM
Independent Safety Monitor
ISO
International Organization for Standardization
JAKs
Janus kinases
KD
Kohlmeier Degos disease
LP
Lumbar Puncture
MACE
Major Adverse Cardiovascular Events
MedDRA
Medical Dictionary for Regulatory Activities
MF
Myelofibrosis
MOP
Manual of Procedures
MxA
Myxovirus resistance protein 1
NCT
National Clinical Trial
NIH
National Institutes of Health

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NIH IC
NIH Institute or Center
NMSCs
Nonmelanoma skin cancers
NSF
Nephrogenic Systemic Fibrosis
OHRP
Office for Human Research Protections
PBMCs
Peripheral blood mononuclear cells 
PI
Principal Investigator
PML
Progressive Multifocal Leuko-encephalopathy
QA
Quality Assurance
QC
Quality Control
ROCK-2
Rho Associated Coiled-Coil Containing 
Protein Kinase 2
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAVI
STING-associated vasculopathy with onset in 
infancy
SMC
Safety Monitoring Committee
SOA
Schedule of Activities
SOP
Standard Operating Procedure
SR-aGVHD
Steroid-refractory acute graft versus host 
disease
STAT
Signal transducer and Activator of 
Transcription proteins
UP
Unanticipated Problem
US
United States

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12
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Abbreviated Title: JAK/STAT Inhibition in Degos
Version Date: 07/26/2024
Interventional Template v6 01.25.2023
12.1.1 Appendix 1
List of CYP3A4 inhibitors and inducers
Dual CYP2C9/CYP3A4 inhibitor:
Fluconazole: Avoid the concomitant use of ruxolitinib with fluconazole doses ≥ 200 mg daily;
If clinically necessary to use doses ≥ 200 mg daily will consult at the pharmacy and the 
company
 
Category 
Drug name 
Strong inhibitorsa of CYP3A
boceprevir, clarithromycin, cobicistat,
conivaptan, danoprevir/ritonavir,
eltegravir/ritonavir, grapefruit juice1, idelalisib,
indinavir, itraconazole, ketoconazole,
lopinavir/ritonavir, LCL161, mibefradil,
nefazodone, nelfinavir, posaconazole, ritonavir,
saquinavir, sequinavir/ritonavir, telaprevir,
telithromycin, voriconazole, indinavir/ritonavir,
tipranoavir/ritonavir, troleandomycin,
Moderate inhibitorsb of CYP3A
amprenavir, aprepitant, atazanavir,
atazanavir/ritonavir,, casopitant, cimetidine,
ciprofloxacin, crizotinib, cyclosporin, duranavir,
darunavir/ritonavir, diltiazem, dronedarone,
erythromycin, faldaprevilr, fluconazole2,
fosamprenavir, grapefruit juice1, imatinib,
lomitapide, netupitant,nilotinib, schisandra
sphenanthera3, tofisopam, verapamil
Strong inducersc of CYP3A
avasimibe, carbamazepine, enzalutamide,
mitotane,phenytoin, rifampin, St. John’s wort3,
rifabutin, phenobarbital,
Moderate inducersd of CYP3A
bosentan, efavirenz, etravirine, genistein3,
lersivirine, lopinavir, modafinil, nafcillin, ritonavir,

54
Abbreviated Title: JAK/STAT Inhibition in Degos
Version Date: 07/26/2024
Interventional Template v6 01.25.2023
thioridazine,
tipranavir,
The list of CYP inhibitors and inducers was compiled from the FDA’s “Guidance for Industry, Drug
Interaction Studies;” from the Indiana University School of Medicine’s “Clinically Relevant” Table
and from the University of Washington’s Drug Interaction Database. Note that this may not be an
exhaustive list. For a complete and most updated drug list, please check the website
https://.crediblemeds.org/healthcareproviders/drug-list.
1 Effect seems to be due to CYP2C19 inhibition by ethinyl estradiol.
2 Fluconazole is a dual CYP3A4 and CYP2C9 inhibitor. Fluconazole is a strong CYP2C9 inhibitor
based on the AUC ratio of omeprazole, which is also metabolized by CYP3A; fluconazole is a
moderate CYP3A inhibitor.
3 Herbal product.
a. A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a
sensitive substrate for that CYP by equal or more than 5-fold.
b. A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of
a sensitive substrate for that CYP by less than 5-fold but equal to or more than 2-fold
Novartis / Incyte Confidential Page 74 of 74
Amended Protocol Version 01 (Clean) Protocol No. CINC424J12301
c A strong inducer for a specific CYP is defined as an inducer that decreases the AUC of a
sensitive substrate for that CYP by equal or more than 80%.
d. A moderate inducer for a specific CYP is defined as an inducer that decreases the AUC of a
substrate for that CYP by 50-80%.
.