IVIg for Small Fiber Neuropathy With Autoantibodies TS-HDS and FGFR3

Study Overview
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Brief Summary
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The objective of this study is to develop a rationale for the selective treatment of small fiber neuropathy with immune globulin (IVIG) in the appropriate patients. The investigators hypothesize that individuals with auto-antibodies targeting neuronal antigens (TS-HDS and FGFR3) and confirmed evidence of small fiber neuropathy (by skin biopsy analysis of intra-epidermal nerve fiber density) will have an improvement in both nerve fiber density and pain after treatment with immune globulin. The co-primary endpoints will be a change in neuropathic pain (by VAS pain score) and a change in intra-epidermal nerve fiber density (by punch skin biopsy). The data gained from this pilot study will establish a rationale, with an appropriate screening test, for the use of immune globulin for the treatment of small fiber neuropathy.

Detailed Description
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Small fiber neuropathies, and mixed small and large fiber neuropathies, have many potential causes including diabetes, vitamin deficiencies, environmental and toxic exposures, HIV, autoimmune and paraproteinemias. However, despite this broad differential at least 30% of cases of small fiber neuropathies remain idiopathic. There is therefore a growing interest in the potential for using IVIG in small fiber neuropathy without direct proof that the disorder is caused by immune reactions. We have recently uncovered two novel autoantibodies, TS-HDS and FGFR-3, that are targeted again peripheral neural structure. TS-HDS is a disaccharide component of glycosylation of heparin and heparin sulfate. Patients with elevated levels of IgM against TS-HDS display clear small fiber loss with IgM deposits around the outside of medium- & larger-sized capillaries with C5b-9 complement deposits. FGFR-3 is a secreted cell surface receptor; genetic defects of FGFR-3 are linked to achrondroplasia and other bony abnormalities. The antibodies to TS-HDS and FGFR-3 are detected in up to 20% of patients with otherwise idiopathic small fiber neuropathy, but are rare in patients without small fiber neuropathy. Dr. Levine (a co-investigator on this project) recently presented 3 cases of small fiber associated with elevated levels of auto-antibodies to TS-HDS or FGFR-3 who were treated with IVIG at 2 gm/kg/month for 6 months. He examined skin biopsies for intra-epidermal nerve fiber density and patient self-reported pain scores at baseline and after six months of therapy. All 3 cases showed marked improvement in pain scores. The average reduction in pain was 54%. In addition there was a clear increase in the intra-epidermal nerve fiber density (IENFD) after 6 months of therapy. Pre-treatment IENFD was 1.6, 1.7, and 2.4 at the calf. After 6 months of therapy the IENFD was 8.4, 5.7, 3.3 respectively (these are clinically significant improvement in nerve fiber density. The investigators believe these anecdotal cases suggest that TS-HDS and FGFR-3 antibodies may be a marker for a group of SFN patients that are immune mediated and may respond to IVIG. (This case series was presented as a poster at the American Academy of Neurology meeting in 2017)

Official Title
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A Double-Blind, Placebo Controlled Trial of Intravenous Immunoglobulin Therapy in Patient With Small Fiber Neuropathy Associated With Autoantibodies to TS-HDS and FGFR3

Conditions
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Small Fiber Neuropathy, Idiopathic Peripheral Neuropathy

Intervention / Treatment
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* Drug: Intravenous immunoglobulin
* Drug: 0.9% Sodium Chloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with clinically evident and biopsy proven pure small fiber neuropathy as evidenced by reduced intra-epidermal nerve fiber density seen on skin biopsy using PGP 9.5 as the immunostain. Patients must have a baseline pain score on a VAS scale of Greater or equal to 4/10 Patients must have elevated titers of autoantibodies to TS-HDS or FFR3 as measured in Dr Alan Pestronk's lab at Washington University in St Louis. Exclusion Criteria: Any other known cause for small fiber neuropathy other than the presence of the elevated titers of auto-antibodies. For example patients with diabetes, HIV, Sjogrens, Vitamin deficiency etc. Patients with generalized, severe musculoskeletal conditions other than SFN that prevent a sufficient assessment of the patient by the physician Cardiac insufficiency (New York Heart Association III/IV), cardiomyopathy, significant cardiac dysrhythmia requiring treatment, unstable or advanced ischemic heart disease). Severe liver disease (ALAT 3x > normal value). Severe kidney disease (creatinine 1.5x > normal value). Known hepatitis B, hepatitis C or HIV infection. Patients with a history of deep vein thrombosis (DVT) within the last year prior to baseline visit or pulmonary embolism ever; patients with susceptibility to embolism or deep vein thrombosis. Body mass index (BMI) ≥40 kg/m2. Medical conditions whose symptoms and effects could alter protein catabolism and/or IgG utilization (e.g. protein-losing enteropathies, nephrotic syndrome). Known 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 Gamunex. Known blood hyperviscosity, or other hypercoagulable states. Use of IgG products within six months prior to enrolment. Use of other blood or plasma-derived products within three 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 Participating in another interventional clinical study with investigational treatment within three months prior to enrollment. Women who are breast feeding, pregnant, or planning to become pregnant, or are unwilling to use an effective birth control method (such as implants, injectable, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomized partner) while on study.
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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: 0.9% Sodium Chloride<br>The study will include a total 20 individuals. Subjects will be randomized equally to treatment or placebo. The placebo will consist of 0.9% Sodium Chloride per day over 2 days. Followed by 0.9% Sodium Chloride over 1 day every 3 weeks for a total of 6 treatments. Participants who are randomized to placebo will receive the same volume as they would if they were randomized to IVIG (i.e.: as if receiving IVIG at 2gm/kg) through a peripheral IV line. | Drug: 0.9% Sodium Chloride<br>* Sodium Chloride (also known as saline) is a solution of sodium chloride, or salt, and sterile water.<br>* Other names: Saline;|
| Experimental: Intravenous Immunoglobulin<br>The study will include a total 20 individuals. Subjects will be randomized equally to treatment or placebo. Treatment will consist of IVIG administered at an initial dose of 2 grams/kg over 2 days followed by 1 gram/kg over 1 day every 3 weeks for a total of 6 treatments | Drug: Intravenous immunoglobulin<br>* Gamunex-C [immune globulin injection (human) 10% caprylate/chromatography purified] is a sterile solution of human immune globulin protein.<br>* Other names: Gamunex-C Liquid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Change in Nerve Fiber Density Between Visits 1 and 8. | Difference in intra-epidermal nerve fiber density between visits 1 and 8 will be measured. Intra-epidermal nerve fiber density is a quantitative measure of the number of nerve fibers per millimeter. The outcome is the number of nerve fibers measured at visit 8 minus the number of nerve fibers measured at visit 1. A positive value indicates that nerve fiber density has increased (a better outcome), a negative value indicates that the nerve fiber density has decreased (a worse outcome). | Visit 1 (time zero) and visit 8 (range of visit time 22-27 weeks after visit 1), thus a total of 22-27 weeks for the study (the range is provided to ensure final follow up is completed despite any conflicts with travel or holidays). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Change in Neuropathic Pain Severity Between Visits 1 and 8. | The visual analog scale (VAS) of pain allows for quantification of neuropathic pain. The VAS pain scale depicts a line ranging from 0 (no pain) to 10 (worst possible pain). The scale is ordinal ranging from 0-10. The difference in pain between visit 1 and visit 8 (pain measured at visit 8 subtracted from the score at visit 1) is the range. Positive values indicate an increase in pain (worse outcome), negative values indicate an improvement in pain (better outcome). | Visit 1 (time zero) and visit 8 (range of visit time 22-27 weeks after visit 1), thus a total of 22-27 weeks for the study (the range is provided to ensure final follow up is completed despite any conflicts with travel or holidays). | 
| 2) The Difference in Change Between Quantified Utah Early Neuropathy Examination Scores, Between Treatment and Placebo Groups Between Visits 1 and 8. | The Utah Early Neuropathy Scale (UENS) was developed specifically to detect and quantify early small-fiber sensory neuropathy and to recognize modest changes in sensory severity and distribution. The UENS scale ranges from 0 (no neuropathy) to 42 (severe small fiber neuropathy). The outcome measure is the UENS score from Visit 8 minus the UENS score at visit 1. The difference in the two scores indicates the change in neuropathy severity. A positive value indicates that neuropathy has worsened over the course of the study, a negative value indicates that neuropathy has improved over the course of the study. | Visit 1 (time zero) and visit 8 (range of visit time 22-27 weeks after visit 1), thus a total of 22-27 weeks for the study (the range is provided to ensure final follow up is completed despite any conflicts with travel or holidays). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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small Fiber Neuropathy, Idiopathic Peripheral Neuropathy, IVIg, Gamunex-C