JAK/STAT Inhibition in CNS Kohlmeier-Degos Disease

Study Overview
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Brief Summary
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Background: Kohlmeier-Degos (K-D) is a rare disease that leads to the blockage of small blood vessels in many organs; these can include the skin, eyes, stomach, lungs, heart, and the brain and spinal cord (central nervous system, or CNS). There are no known effective treatments for K-D that affects the CNS. Objective: To test a drug (ruxolitinib) in a person with K-D affecting the CNS. Eligibility: This study is designed to treat 1 subject, a 58-year-old male with K-D affecting the CNS. Design: The participant will be screened: He will have a physical exam and blood tests. He will have skin biopsies: Small samples of skin will be removed. He will have a lumbar puncture: A needle will be inserted in his back to draw fluid from the space around the spinal cord. He will have a magnetic resonance imaging (MRI) scan: He will lie on a table that slides into a tube to take pictures of his brain and spinal cord. He will see a doctor who specializes in nerves. Ruxolitinib is a tablet taken by mouth. The participant will take the drug twice a day for up to 26 weeks. The dosage may change over time. The participant will have up to 7 clinic visits in 28 weeks. Each visit will be 1 to 3 days. MRI scans, biopsies, lumbar punctures, and other tests will be repeated on different visits. The participant may receive follow-up phone calls between visits. He will report any adverse effects. Unscheduled visits may be needed if new symptoms develop. The last follow-up will be 4 weeks after the last dose of the study drug.

Detailed Description
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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 Kohlmeier Degos disease (K-D) with neurologic involvement. We hypothesize that ruxolitinib, which targets type I IFN (Interferons ) and IFN-y 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: 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 of ruxolitinib treatment. Assess changes in plasma/serum cytokines levels and IFN scores as well as biomarker assays in CSF/ blood samples after 3 weeks of ruxolitinib treatment. 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 of ruloxitinib (10 mg BID) compared to pre-treatment MRI images. Exploratory endpoints of this study are clinical and potential surrogate biomarker efficacy data, including: 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 of treatment. 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 of treatment. Stability OR improvement of motor and/or sensory function on clinical neurologic exams between the baseline visit and after 13 weeks of treatment.

Official Title
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Single Patient Study of JAK/STAT Inhibition in CNS Kohlmeier-Degos Disease

Conditions
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Kohlmeier Degos Disease With Neurologic Involvement

Intervention / Treatment
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* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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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. 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ruxolitinib<br>Ruxolitinib at 5 mg twice a day (BID) for 1 week and then at 10 mg BID for 13-24 weeks and 1 week of 5 mg BID before stopping ruxolitinib. | Drug: Ruxolitinib<br>* Ruxolitinib at 5 mg twice a day (BID) for 1 week and then at 10 mg BID for 13-24 weeks and 1 week of 5 mg BID before stopping ruxolitinib.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rare Small Vessel Vasculopathy Of Unknown Etiology, Kohlmeier Degos Disease With Neurologic Involvement