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

NCT03401073 | Completed Phase 2 Results FDA Drug

• 1 other identifier: 2017P000592
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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.

Conditions

Small Fiber Neuropathy; Idiopathic Peripheral Neuropathy

Keywords

small Fiber Neuropathy; Idiopathic Peripheral Neuropathy; IVIg; Gamunex-C

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• The Change in Neuropathic Pain Severity Between Visits 1 and 8.

  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.

  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).

Study Arms (2)

0.9% Sodium Chloride

PLACEBO COMPARATOR

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

Intravenous Immunoglobulin

EXPERIMENTAL

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

Interventions

Intravenous immunoglobulin DRUG

Gamunex-C \[immune globulin injection (human) 10% caprylate/chromatography purified\] is a sterile solution of human immune globulin protein.

Also known as: Gamunex-C Liquid

Intravenous Immunoglobulin

0.9% Sodium Chloride DRUG

Sodium Chloride (also known as saline) is a solution of sodium chloride, or salt, and sterile water.

Also known as: Saline

0.9% Sodium Chloride

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Beth Israel Deaconess Medical Center: lead
• Phoenix Neurological Associates, LTD: collaborator

Study Sites (1)

Beth Israel Deaconness Medical Center

Boston, Massachusetts, 02215, United States

Location

Related Publications (15)

• Gibbons CH. Small fiber neuropathies. Continuum (Minneap Minn). 2014 Oct;20(5 Peripheral Nervous System Disorders):1398-412. doi: 10.1212/01.CON.0000455874.68556.02.

  PMID: 25299289 BACKGROUND

• Cortez M, Singleton JR, Smith AG. Glucose intolerance, metabolic syndrome, and neuropathy. Handb Clin Neurol. 2014;126:109-22. doi: 10.1016/B978-0-444-53480-4.00009-6.

  PMID: 25410218 BACKGROUND

• Peltier A, Goutman SA, Callaghan BC. Painful diabetic neuropathy. BMJ. 2014 May 6;348:g1799. doi: 10.1136/bmj.g1799.

  PMID: 24803311 BACKGROUND

• Kass-Iliyya L, Javed S, Gosal D, Kobylecki C, Marshall A, Petropoulos IN, Ponirakis G, Tavakoli M, Ferdousi M, Chaudhuri KR, Jeziorska M, Malik RA, Silverdale MA. Small fiber neuropathy in Parkinson's disease: A clinical, pathological and corneal confocal microscopy study. Parkinsonism Relat Disord. 2015 Dec;21(12):1454-60. doi: 10.1016/j.parkreldis.2015.10.019. Epub 2015 Nov 3.

  PMID: 26578039 BACKGROUND

• Lefaucheur JP, Wahab A, Plante-Bordeneuve V, Sene D, Menard-Lefaucheur I, Rouie D, Tebbal D, Salhi H, Creange A, Zouari H, Ng Wing Tin S. Diagnosis of small fiber neuropathy: A comparative study of five neurophysiological tests. Neurophysiol Clin. 2015 Dec;45(6):445-55. doi: 10.1016/j.neucli.2015.09.012. Epub 2015 Nov 17.

  PMID: 26596193 BACKGROUND

• Kafaie J, Al Balushi A, Kim M, Pestronk A. Clinical and Laboratory Profiles of Idiopathic Small Fiber Neuropathy in Children: Case Series. J Clin Neuromuscul Dis. 2017 Sep;19(1):31-37. doi: 10.1097/CND.0000000000000178.

  PMID: 28827487 BACKGROUND

• Pestronk A, Schmidt RE, Choksi RM, Sommerville RB, Al-Lozi MT. Clinical and laboratory features of neuropathies with serum IgM binding to TS-HDS. Muscle Nerve. 2012 Jun;45(6):866-72. doi: 10.1002/mus.23256.

  PMID: 22581541 BACKGROUND

• Antoine JC, Boutahar N, Lassabliere F, Reynaud E, Ferraud K, Rogemond V, Paul S, Honnorat J, Camdessanche JP. Antifibroblast growth factor receptor 3 antibodies identify a subgroup of patients with sensory neuropathy. J Neurol Neurosurg Psychiatry. 2015 Dec;86(12):1347-55. doi: 10.1136/jnnp-2014-309730. Epub 2015 Jan 27.

  PMID: 25628376 BACKGROUND

• Hahn AF, Bolton CF, Zochodne D, Feasby TE. Intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy. A double-blind, placebo-controlled, cross-over study. Brain. 1996 Aug;119 ( Pt 4):1067-77. doi: 10.1093/brain/119.4.1067.

  PMID: 8813271 BACKGROUND

• Mendell JR, Barohn RJ, Freimer ML, Kissel JT, King W, Nagaraja HN, Rice R, Campbell WW, Donofrio PD, Jackson CE, Lewis RA, Shy M, Simpson DM, Parry GJ, Rivner MH, Thornton CA, Bromberg MB, Tandan R, Harati Y, Giuliani MJ; Working Group on Peripheral Neuropathy. Randomized controlled trial of IVIg in untreated chronic inflammatory demyelinating polyradiculoneuropathy. Neurology. 2001 Feb 27;56(4):445-9. doi: 10.1212/wnl.56.4.445.

  PMID: 11222785 BACKGROUND

• Cocito D, Ciaramitaro P, Isoardo G, Barbero P, Migliaretti G, Pipieri A, Proto G, Quadri R, Bergamasco B, Durelli L. Intravenous immunoglobulin as first treatment in diabetics with concomitant distal symmetric axonal polyneuropathy and CIDP. J Neurol. 2002 Jun;249(6):719-22. doi: 10.1007/s00415-002-0698-0.

  PMID: 12111305 BACKGROUND

• Eftimov F, Winer JB, Vermeulen M, de Haan R, van Schaik IN. Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev. 2013 Dec 30;(12):CD001797. doi: 10.1002/14651858.CD001797.pub3.

  PMID: 24379104 BACKGROUND

• Singleton JR, Bixby B, Russell JW, Feldman EL, Peltier A, Goldstein J, Howard J, Smith AG. The Utah Early Neuropathy Scale: a sensitive clinical scale for early sensory predominant neuropathy. J Peripher Nerv Syst. 2008 Sep;13(3):218-27. doi: 10.1111/j.1529-8027.2008.00180.x.

  PMID: 18844788 BACKGROUND

• Lauria G, Hsieh ST, Johansson O, Kennedy WR, Leger JM, Mellgren SI, Nolano M, Merkies IS, Polydefkis M, Smith AG, Sommer C, Valls-Sole J; European Federation of Neurological Societies; Peripheral Nerve Society. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol. 2010 Jul;17(7):903-12, e44-9. doi: 10.1111/j.1468-1331.2010.03023.x.

  PMID: 20642627 BACKGROUND

• Nolano M, Biasiotta A, Lombardi R, Provitera V, Stancanelli A, Caporaso G, Santoro L, Merkies IS, Truini A, Porretta-Serapiglia C, Cazzato D, Dacci P, Vitale DF, Lauria G. Epidermal innervation morphometry by immunofluorescence and bright-field microscopy. J Peripher Nerv Syst. 2015 Dec;20(4):387-91. doi: 10.1111/jns.12146.

  PMID: 26309146 BACKGROUND

MeSH Terms

Conditions

Small Fiber Neuropathy

Interventions

Immunoglobulins, Intravenous; Sodium Chloride

Condition Hierarchy (Ancestors)

Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Immunoglobulin G; Immunoglobulin Isotypes; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Limitations and Caveats

This was a small pilot study that was underpowered to detect changes to secondary endpoints. There was a 15% dropout. Despite several publications that note an association between TS-HDS and FGFR-3 autoantibodies in neuropathy, we do not have evidence for pathogenicity (supported by a non-insignificant number of patients excluded from the study with autoantibodies but without evidence of neuropathy). This too may have limited the potential treatment effect of immune globulin.

Results Point of Contact

• Title: Christopher Gibbons MD
• Organization: BIDMC

cgibbons@bidmc.harvard.edu

617-632-8454

Study Officials

• Christopher Gibbons, MD

  Beth Israel Deaconess Medical Cednter

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Neurology

Study Record Dates

• First Submitted: January 10, 2018
• First Posted: January 17, 2018
• Study Start: September 1, 2018
• Primary Completion: February 1, 2022
• Study Completion: February 1, 2022
• Last Updated: September 13, 2023
• Results First Posted: September 13, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)