IVIG in the Treatment of Autoimmune Small Fiber Neuropathy With TS-HDS, FGFR-3, or Plexin D1 Antibodies

Study Overview
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Brief Summary
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This study will enroll patients with small fiber neuropathy (SFN). The study will look at an intravenous immunoglobulin (IVIG) called Panzyga. Panzyga is approved by the FDA as a therapy for Primary humoral immunodeficiency (PI) in patients 2 years of age and older; Chronic immune thrombocytopenia (ITP) in adults and Chronic inflammatory demyelinating polyneuropathy (CIDP) in adults. It has not been approved by the FDA for use in SFN. There is mounting evidence that Intravenous Immunoglobulin (IVIG) can cause pain reduction and improve objective nerve fiber densities on skin biopsies in great numbers in SFN patients. The primary outcome is quantified improvement in intraepidermal nerve fiber density (IENFD) on repeat skin punch biopsy after 6 months of IVIG treatment.

Detailed Description
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Small fiber neuropathy (SFN) is an increasingly prevalent diagnosis in neurology and neuromuscular centers. Modern diagnostic techniques, including skin biopsies and autonomic nervous testing are helping to find SFN in many patients with undiagnosed pain syndromes including fibromyalgia. The prevalence is rising for SFN, and an immune etiology may underlie 19%-34% of cases. While there is no standard of care treatment, current treatment strategies for SFN include long-term steroid therapy which come with a host of side effects. There is mounting evidence that Intravenous Immunoglobulin (IVIG) can cause pain reduction and improve objective nerve fiber densities on skin biopsies in great numbers in SFN patients, as well as improving validated questionnaire scores monitoring symptom burden and disability. However, neither IVIG nor any other immunosuppressant has been studied in a sufficiently powered and adequately dosed controlled, randomized clinical trial to demonstrate efficacy.

Official Title
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Intravenous Immunoglobulin (IVIG) in the Treatment of Small Fiber Neuropathy Due to TS-HDS, FGFR-3, or Plexin D1 Antibodies: a Double Blinded Placebo-controlled Phase II Trial

Conditions
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Small Fiber Neuropathy, Autoimmune Small Fiber Neuropathy, Inflammatory Polyneuropathy, Immune-Mediated Neuropathy

Intervention / Treatment
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* Drug: Panzyga IVIG
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients ≥ age 18 Patient with clinical and biopsy evidence of pure small fiber neuropathy (with or without dysautonomia) as evidenced by reduced IENFD on skin biopsy using PGP 9.5 as the immunostain. Biopsy must have been performed within 12 months of study enrollment, and using Corinthian Reference Laboratory (Benbrook, TX). Patients must have elevated and/or abnormal titers of autoantibodies to TS-HDS-IgM or FGFR3-IgG or Plexin-D1, measured by the Washington University Neuromuscular Laboratory (St Louis) within 12 months of study enrollment. Patients must have a baseline pain score on a visual analogue scale (VAS) of Greater or equal to 4/10 Patients must have a baseline Utah Early Neuropathy Scale (UENS) score of Greater or equal to 4/10 Small Fiber Neuropathy Screening List (SFNSL) score of 11/84 or greater Non-pregnant, non-lactating female Exclusion Criteria: Any other known cause for small fiber neuropathy other than the presence of the elevated titers of the novel auto-antibodies. Patients with generalized, severe musculoskeletal conditions other than SFN that prevent a sufficient assessment of the patient by the physician. Electromyography/nerve conduction study (EMG/NCS) evidence of large fiber polyneuropathy, to be confirmed by study PI Underlying severe heart, kidney, liver disease, or HIV infection, (Note: If there is no previous HIV test result documented, a test may be performed in order to confirm eligibility) Patients with a history of deep vein thrombosis within the last year prior to baseline visit or pulmonary embolism ever; patients with susceptibility to embolism or deep vein thrombosis. Known significant IgA deficiency with antibodies to IgA. History of hypersensitivity, anaphylaxis or severe systemic response to immuno-globulin, blood or plasma derived products, or any component of IVIG 10%, Known blood hyperviscosity, or other hypercoagulable states, Use of IgG products within six months prior to enrollment, Patients with a history of drug or alcohol abuse within the past five years prior to enrollment, Patients unable or unwilling to understand or comply with the study protocol

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a randomized, double-blind, placebo-controlled study with 10 patients in the treatment arm and 10 in the placebo arm. Patients in the treatment arm will receive 2g/kg IVIG every 4 weeks (over 2 days, 1g/kg dose on Day 1 and 1g/kg dose on Day 2) for 24 weeks (6 doses total). Patients in the placebo arm will receive 0.9% NaCl infusions on the same schedule as the active treatment group (Day 1 and Day 2 every 4 weeks for 24 weeks total, (6 doses)).
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (IVIG)<br>Patients in the treatment arm will receive 2g/kg IVIG every 4 weeks (over 2 days, 1g/kg dose on Day 1 and 1g/kg dose on Day 2) for 24 weeks (6 doses total). | Drug: Panzyga IVIG<br>* Immune Globulin Infusion 10% (Human)<br>|
| Placebo Comparator: Placebo<br>Patients in the placebo arm will receive 0.9% NaCl infusions on the same schedule as the active treatment group (Day 1 and Day 2 every 4 weeks for 24 weeks total, (6 doses). | Drug: Placebo<br>* 0.9% NaCl prepared as the calculated dose equivalent volume to IVIG.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| quantified change in intraepidermal nerve fiber density (IENFD) | 3mm skin punch biopsy at 3 sites | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in visual analogue pain scale responses | Self-reported pain intensity on a scale of 0-10 using the Wong-Baker FACES Pain Rating Scale, with 0 being no pain and 10 being pain as bad as can be | baseline and Week 28 | 
| Change in Small Fiber Neuropathy-Rasch Overall Disability Scale (SFN-RODS) score | The SFN-RODS is a 32-item scale measuring disability in daily activities. Scores range from 0 - 64, with a lower score correlating with worse disease | baseline and Week 28 | 
| Change in Small Fiber Neuropathy-Symptom Inventory Questionnaire (SFN-SIQ) score | The SFN-SIQ is a validated 13-item scale measuring various SFN and autonomic symptoms. Scores range from 0 -39, with a higher score correlating with more severe disease. | baseline and Week 28 | 
| Change in Utah Early Neuropathy Scale (UENS) examination scores | The UENS is a validated physical exam score from 0-42 points to look for small fiber neuropathy. It includes measures of sensation, reflexes, and strength in both lower extremities. A higher score indicates increased impairment. | baseline and Week 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Small Fiber Neuropathy, Neuropathy, Intravenous Immunoglobulin, IVIG, TS-HDS antibody, FGFR-3 antibody, FGFR3 antibody, Immune mediated small fiber neuropathy, Panzyga, Plexin D1 antibody