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

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ClinicalTrials.gov Identifier: NCT04153422
Recruitment Status : Suspended (Recruitment not started at Loyola, PI leaving Loyola, PI may resume at next affiliating instituation.)
First Posted : November 6, 2019
Last Update Posted : February 12, 2021
Sponsor:
Collaborator:
Takeda
Information provided by (Responsible Party):
Lawrence Zeidman, Loyola University

Brief Summary:

This study will enroll patients with small fiber neuropathy (SFN). The study will look at an intravenous immunoglobulin (IVIG) called Gammagard. Gammagard is approved by the FDA as a therapy for certain diseases that result from an impaired immune system and as a maintenance therapy to improve sensation and strength in patients with Chronic Immune Demyelinating Polyneuropathy (CIDP) and muscle strength in adults with Multifocal Motor Neuropathy (MMN). It has not been approved by the FDA for use in this condition.

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.


Condition or disease Intervention/treatment Phase
Small Fiber Neuropathy Autoimmune Small Fiber Neuropathy Inflammatory Polyneuropathy Immune-Mediated Neuropathy Drug: Gammagard IVIG Drug: Placebo Phase 2

Detailed Description:
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 even fibromyalgia. The prevalence is rising for SFN, and an immune etiology may underlie up to 20% of cases. 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. They would be spared the side effects of steroids. But neither IVIG nor any other immunosuppressant has been studied in a randomized clinical trial to demonstrate efficacy. Trisulfated disaccharide IdoA2S-GlcNS-6S (TS-HDS) and fibroblast growth factor receptor 3 (FGFR-3) serum antibodies are novel antibodies being discovered in large numbers of otherwise cryptogenic SFN cases. The hypothesis of this double-blinded placebo-controlled Phase II trial is that IVIG is effective in improving biopsies as a primary endpoint, and in improving pain, SFN symptom and disability scales, objective neuropathy physical exam scores, and antibody titers as secondary endpoints. Given the demonstrated prevalence of SFN and especially this novel autoimmune syndrome, this trial could have impact on thousands of patients.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This is a randomized, double-blind, placebo-controlled design with 10 patients in the treatment arm and 10 in the placebo arm. Patients in the treatment arm will receive 2g/kg Gammagard IVIG initially (1g/kg dose on Day 1 and 1g/kg dose on Day 2) and then 1g/kg maintenance infusions for 5 additional months (six months total). Patients in the placebo arm will receive 0.9% NaCl during the initial infusion and at maintenance infusions for 5 additional months (six months total).
Masking: Double (Participant, Investigator)
Masking Description: This is a double-blind trial. The participant and the investigator will be blinded.
Primary Purpose: Treatment
Official Title: Intravenous Immunoglobulin (IVIG) in the Treatment of Autoimmune Small Fiber Neuropathy Due to TS-HDS and FGFR-3 Antibodies: a Double Blinded Placebo-controlled Phase II Trial
Estimated Study Start Date : January 1, 2022
Estimated Primary Completion Date : September 1, 2023
Estimated Study Completion Date : September 1, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Dietary Fiber

Arm Intervention/treatment
Experimental: Treatment (IVIG)
Patients in the treatment arm will receive 2g/kg Gammagard IVIG initially (1g/kg dose on Day 1 and 1g/kg dose on Day 2) and then 1g/kg maintenance infusions for 5 additional months (six months total).
Drug: Gammagard IVIG
Immune Globulin Infusion 10% (Human)

Placebo Comparator: Placebo
Patients in the placebo arm will receive 0.9% NaCl during the initial infusion and at maintenance infusions for 5 additional months (six months total).
Drug: Placebo
0.9% NaCl prepared as the calculated dose equivalent volume to IVIG.




Primary Outcome Measures :
  1. quantified change in intraepidermal nerve fiber density (IENFD) [ Time Frame: Week 24 ]
    3mm skin punch biopsy


Secondary Outcome Measures :
  1. Change in visual analogue pain scale responses [ Time Frame: baseline and Week 28 ]
    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

  2. Change in Small Fiber Neuropathy-Rasch Overall Disability Scale (SFN-RODS) score [ Time Frame: baseline and Week 28 ]
    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

  3. Change in Small Fiber Neuropathy-Symptom Inventory Questionnaire (SFN-SIQ) score [ Time Frame: baseline and Week 28 ]
    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.

  4. Change in Small Fiber Neuropathy-Screening List (SFN-SL) score [ Time Frame: baseline and Week 28 ]
    The SFN-SL is a validated 21 item scale measuring frequency and severity of SFN and autonomic symptoms. Scores range from 0 - 84, with higher scores reflecting increased disease severity.

  5. Change in Utah Early Neuropathy Scale (UENS) examination scores [ Time Frame: baseline and Week 28 ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients ≥ age 18
  2. Patient with clinical and biopsy evidence of pure small fiber neuropathy 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.
  3. Patients must have elevated titers of autoantibodies to TS-HDS-IgM or FGFR3-IgG, measured by the Washington University Neuromuscular Laboratory (St Louis).
  4. Patients must have a baseline pain score on a visual analogue scale (VAS) of Greater or equal to 4/10
  5. Patients must have a baseline Utah Early Neuropathy Scale (UENS) score of Greater or equal to 4/10
  6. Small Fiber Neuropathy Screening List (SFNSL) score of 11/84 or greater
  7. Non-pregnant, non-lactating female

Exclusion Criteria:

  1. Any other known cause for small fiber neuropathy other than the presence of the elevated titers of auto-antibodies.
  2. Patients with generalized, severe musculoskeletal conditions other than SFN that prevent a sufficient assessment of the patient by the physician.
  3. Underlying severe heart, kidney, liver disease, or HIV infection,
  4. 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.
  5. Known IgA deficiency with antibodies to IgA,
  6. History of hypersensitivity, anaphylaxis or severe systemic response to immuno-globulin, blood or plasma derived products, or any component of Gammagard,
  7. Known blood hyperviscosity, or other hypercoagulable states,
  8. Use of IgG products within six months prior to enrollment,
  9. Patients with a history of drug or alcohol abuse within the past five years prior to enrollment,
  10. Patients unable or unwilling to understand or comply with the study protocol

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04153422


Locations
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United States, Illinois
Northwest Community Healthcare
Arlington Heights, Illinois, United States, 60005
Sponsors and Collaborators
Loyola University
Takeda
Investigators
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Principal Investigator: Lawrence Zeidman, MD, FAAN Loyola University Chicago
Publications:
Iodice V, et al. Ganglionic Antibody Mediated SFN. Neurology 2009;72:2002-6.
D'agostino, R. B., Chase, W., & Belanger, A. (1988). The appropriateness of some common procedures for testing the equality of two independent binomial populations. The American Statistician, 42(3), 198-202.
Fleiss, J. L., Levin, B., & Paik, M. C. (2013). Statistical methods for rates and proportions. John Wiley & Sons.

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Responsible Party: Lawrence Zeidman, Medical Director, Neuromuscular Medicine, Northwest Community Healthcare; Associate Professor, Loyola University
ClinicalTrials.gov Identifier: NCT04153422    
Other Study ID Numbers: 212029
First Posted: November 6, 2019    Key Record Dates
Last Update Posted: February 12, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Lawrence Zeidman, Loyola University:
Small Fiber Neuropathy
Neuropathy
Intravenous Immunoglobulin
IVIG
Gammagard
TS-HDS antibody
FGFR-3 antibody
FGFR3 antibody
Immune mediated small fiber neuropathy
Additional relevant MeSH terms:
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Peripheral Nervous System Diseases
Polyneuropathies
Small Fiber Neuropathy
Neuromuscular Diseases
Nervous System Diseases
Immunoglobulins, Intravenous
Immunologic Factors
Physiological Effects of Drugs