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

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ClinicalTrials.gov Identifier: NCT03401073
Recruitment Status : Recruiting
First Posted : January 17, 2018
Last Update Posted : December 12, 2019
Sponsor:
Collaborator:
Phoenix Neurological Associates, LTD
Information provided by (Responsible Party):
Christopher Gibbons, MD, Beth Israel Deaconess Medical Center

Tracking Information
First Submitted Date  ICMJE January 10, 2018
First Posted Date  ICMJE January 17, 2018
Last Update Posted Date December 12, 2019
Actual Study Start Date  ICMJE September 1, 2018
Estimated Primary Completion Date June 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 16, 2018)
The change in nerve fiber density between visits 1 and 8. [ Time Frame: 22-27 weeks after screening visit ]
Difference in intra-epidermal nerve fiber density between visits 1 and 8 will be measured
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03401073 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 16, 2018)
  • The change in neuropathic pain severity between visits 1 and 8. [ Time Frame: 22-27 weeks after screening visit ]
    The visual analog scale (VAS) of pain allows for quantification of neuropathic pain (line from 0: no pain to 10:worst pain)
  • 2) The difference in change between quantified Utah Early Neuropathy examination scores, between treatment and placebo groups between visits 1 and 8. [ Time Frame: 22-27 weeks after screening visit ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE IVIg for Small Fiber Neuropathy With Autoantibodies TS-HDS and FGFR3
Official Title  ICMJE A Double-Blind, Placebo Controlled Trial of Intravenous Immunoglobulin Therapy in Patient With Small Fiber Neuropathy Associated With Autoantibodies to TS-HDS and FGFR3
Brief Summary

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

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)

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Small Fiber Neuropathy
  • Idiopathic Peripheral Neuropathy
Intervention  ICMJE
  • Drug: Intravenous immunoglobulin
    Gamunex-C [immune globulin injection (human) 10% caprylate/chromatography purified] is a sterile solution of human immune globulin protein.
    Other Name: Gamunex-C Liquid
  • Drug: 0.9% Sodium Chloride
    Sodium Chloride (also known as saline) is a solution of sodium chloride, or salt, and sterile water.
    Other Name: Saline
Study Arms  ICMJE
  • Placebo Comparator: 0.9% Sodium Chloride
    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.
    Intervention: Drug: 0.9% Sodium Chloride
  • Experimental: Intravenous Immunoglobulin
    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
    Intervention: Drug: Intravenous immunoglobulin
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 16, 2018)
20
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 1, 2020
Estimated Primary Completion Date June 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. 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.
  2. Patients must have a baseline pain score on a VAS scale of Greater or equal to 4/10
  3. 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:

  1. 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.
  2. Patients with generalized, severe musculoskeletal conditions other than SFN that prevent a sufficient assessment of the patient by the physician
  3. Cardiac insufficiency (New York Heart Association III/IV), cardiomyopathy, significant cardiac dysrhythmia requiring treatment, unstable or advanced ischemic heart disease).
  4. Severe liver disease (ALAT 3x > normal value).
  5. Severe kidney disease (creatinine 1.5x > normal value).
  6. Known hepatitis B, hepatitis C or HIV infection.
  7. 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.
  8. Body mass index (BMI) ≥40 kg/m2.
  9. Medical conditions whose symptoms and effects could alter protein catabolism and/or IgG utilization (e.g. protein-losing enteropathies, nephrotic syndrome).
  10. Known IgA deficiency with antibodies to IgA.
  11. History of hypersensitivity, anaphylaxis or severe systemic response to immuno-globulin, blood or plasma derived products, or any component of Gamunex.
  12. Known blood hyperviscosity, or other hypercoagulable states.
  13. Use of IgG products within six months prior to enrolment.
  14. Use of other blood or plasma-derived products within three months prior to enrollment.
  15. Patients with a history of drug or alcohol abuse within the past five years prior to enrollment.
  16. Patients unable or unwilling to understand or comply with the study protocol
  17. Participating in another interventional clinical study with investigational treatment within three months prior to enrollment.
  18. 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Sharika Rajan, MD 617-632-8964 srajan@bidmc.harvard.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03401073
Other Study ID Numbers  ICMJE 2017P000592
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Christopher Gibbons, MD, Beth Israel Deaconess Medical Center
Study Sponsor  ICMJE Beth Israel Deaconess Medical Center
Collaborators  ICMJE Phoenix Neurological Associates, LTD
Investigators  ICMJE
Principal Investigator: Christopher Gibbons, MD Beth Israel Deaconess Medical Cednter
PRS Account Beth Israel Deaconess Medical Center
Verification Date December 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP