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

NCT04153422 | Recruiting Phase 2 FDA Drug

• 1 other identifier: 2025-0046
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Small Fiber Neuropathy; Autoimmune Small Fiber Neuropathy; Inflammatory Polyneuropathy; Immune-Mediated Neuropathy

Keywords

Small Fiber Neuropathy; Neuropathy; Intravenous Immunoglobulin; IVIG; TS-HDS antibody; FGFR-3 antibody; FGFR3 antibody; Immune mediated small fiber neuropathy; Panzyga; Plexin D1 antibody

Outcome Measures

Primary Outcomes (1)

• quantified change in intraepidermal nerve fiber density (IENFD)

  3mm skin punch biopsy at 3 sites

  Week 24

Secondary Outcomes (4)

• Change in visual analogue pain scale responses

  baseline and Week 28

• Change in Small Fiber Neuropathy-Rasch Overall Disability Scale (SFN-RODS) score

  baseline and Week 28

• Change in Small Fiber Neuropathy-Symptom Inventory Questionnaire (SFN-SIQ) score

  baseline and Week 28

• Change in Utah Early Neuropathy Scale (UENS) examination scores

  baseline and Week 28

Study Arms (2)

Treatment (IVIG)

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

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

Interventions

Panzyga IVIG DRUG

Immune Globulin Infusion 10% (Human)

Treatment (IVIG)

Placebo DRUG

0.9% NaCl prepared as the calculated dose equivalent volume to IVIG.

Placebo

Eligibility Criteria

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

You may qualify if:

• 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. If biopsies were not done at CRL, they will be repeated and done at 3 sites (upper and lower thigh, lower calf), to have consistent and equivalent biopsy data with the follow up biopsy done after 6 mos of treatment
• Patients must have elevated and/or abnormal titers of autoantibodies to TS-HDS-IgM, FGFR3-IgG, or Plexin-D1 measured by the Washington University Neuromuscular Laboratory (St Louis) within 12 mos of 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. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during treatment

You may not qualify if:

• Any other known cause for small fiber neuropathy other than the presence of the elevated titers of TS-HDS-IgM, FGFR3-IgG, or Plexin-D1 autoantibodies
• 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 within the last 5 years, 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 to understand or unwilling or unable to comply with the study protocol

Sponsors & Collaborators

• Endeavor Health: lead
• Octapharma USA, Inc.: collaborator

Study Sites (1)

Endeavor Health

Glenview, Illinois, 60026, United States

RECRUITING

Related Publications (18)

• Peters MJ, Bakkers M, Merkies IS, Hoeijmakers JG, van Raak EP, Faber CG. Incidence and prevalence of small-fiber neuropathy: a survey in the Netherlands. Neurology. 2013 Oct 8;81(15):1356-60. doi: 10.1212/WNL.0b013e3182a8236e. Epub 2013 Aug 30.

  PMID: 23997150 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

• Darabi K, Abdel-Wahab O, Dzik WH. Current usage of intravenous immune globulin and the rationale behind it: the Massachusetts General Hospital data and a review of the literature. Transfusion. 2006 May;46(5):741-53. doi: 10.1111/j.1537-2995.2006.00792.x.

  PMID: 16686841 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

• Souayah N, Chin RL, Brannagan TH, Latov N, Green PH, Kokoszka A, Sander HW. Effect of intravenous immunoglobulin on cerebellar ataxia and neuropathic pain associated with celiac disease. Eur J Neurol. 2008 Dec;15(12):1300-3. doi: 10.1111/j.1468-1331.2008.02305.x.

  PMID: 19049545 BACKGROUND

• Levine TD, Kafaie J, Zeidman LA, Saperstein DS, Massaquoi R, Bland RJ, Pestronk A. Cryptogenic small-fiber neuropathies: Serum autoantibody binding to trisulfated heparan disaccharide and fibroblast growth factor receptor-3. Muscle Nerve. 2020 Apr;61(4):512-515. doi: 10.1002/mus.26748. Epub 2019 Nov 6.

  PMID: 31650561 BACKGROUND

• Bitzi LM, Lehnick D, Wilder-Smith EP. Small fiber neuropathy: Swiss cohort characterization. Muscle Nerve. 2021 Sep;64(3):293-300. doi: 10.1002/mus.27340. Epub 2021 Jun 16.

  PMID: 34075618 BACKGROUND

• de Greef BTA, Hoeijmakers JGJ, Gorissen-Brouwers CML, Geerts M, Faber CG, Merkies ISJ. Associated conditions in small fiber neuropathy - a large cohort study and review of the literature. Eur J Neurol. 2018 Feb;25(2):348-355. doi: 10.1111/ene.13508. Epub 2017 Dec 18.

  PMID: 29112785 BACKGROUND

• Fujii T, Yamasaki R, Iinuma K, Tsuchimoto D, Hayashi Y, Saitoh BY, Matsushita T, Kido MA, Aishima S, Nakanishi H, Nakabeppu Y, Kira JI. A Novel Autoantibody against Plexin D1 in Patients with Neuropathic Pain. Ann Neurol. 2018 Aug;84(2):208-224. doi: 10.1002/ana.25279. Epub 2018 Sep 3.

  PMID: 30014510 BACKGROUND

• Gaillet A, Champion K, Lefaucheur JP, Trout H, Bergmann JF, Sene D. Intravenous immunoglobulin efficacy for primary Sjogren's Syndrome associated small fiber neuropathy. Autoimmun Rev. 2019 Nov;18(11):102387. doi: 10.1016/j.autrev.2019.102387. Epub 2019 Sep 11. No abstract available.

  PMID: 31520801 BACKGROUND

• Goodman BP. Immunoresponsive Autonomic Neuropathy in Sjogren Syndrome-Case Series and Literature Review. Am J Ther. 2019 Jan/Feb;26(1):e66-e71. doi: 10.1097/MJT.0000000000000583.

  PMID: 28379880 BACKGROUND

• Kovvuru S, Cardenas YC, Huttner A, Nowak RJ, Roy B. Clinical characteristics of fibroblast growth factor receptor 3 antibody-related polyneuropathy: a retrospective study. Eur J Neurol. 2020 Jul;27(7):1310-1318. doi: 10.1111/ene.14180. Epub 2020 Mar 20.

  PMID: 32068339 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

• Tavee JO, Karwa K, Ahmed Z, Thompson N, Parambil J, Culver DA. Sarcoidosis-associated small fiber neuropathy in a large cohort: Clinical aspects and response to IVIG and anti-TNF alpha treatment. Respir Med. 2017 May;126:135-138. doi: 10.1016/j.rmed.2017.03.011. Epub 2017 Mar 9.

  PMID: 28318820 BACKGROUND

• Zeidman LA. Advances in the Management of Small Fiber Neuropathy. Neurol Clin. 2021 Feb;39(1):113-131. doi: 10.1016/j.ncl.2020.09.006. Epub 2020 Nov 7.

  PMID: 33223078 BACKGROUND

• Zeidman LA, Kubicki K. Clinical Features and Treatment Response in Immune-Mediated Small Fiber Neuropathy with Trisulfated Heparin Disaccharide or Fibroblast Growth Factor Receptor 3 Antibodies. J Clin Neuromuscul Dis. 2021 Jun 1;22(4):192-199. doi: 10.1097/CND.0000000000000355.

  PMID: 34019003 BACKGROUND

• Zeidman LA, Saini P, Mai P. Immune-Mediated Small Fiber Neuropathy With Trisulfated Heparin Disaccharide, Fibroblast Growth Factor Receptor 3, or Plexin D1 Antibodies: Presentation and Treatment With Intravenous Immunoglobulin. J Clin Neuromuscul Dis. 2022 Sep 1;24(1):26-37. doi: 10.1097/CND.0000000000000423.

  PMID: 36005471 BACKGROUND

• Zeidman LA. Effectiveness of IVIG on Non-Length-Dependent Skin Biopsies in Small Fiber Neuropathy With Plexin D1, Trisulfated Heparin Disaccharide, and Fibroblast Growth Factor Receptor 3 Autoantibodies. J Clin Neuromuscul Dis. 2024 Jun 1;25(4):184-196. doi: 10.1097/CND.0000000000000485.

  PMID: 38771228 BACKGROUND

MeSH Terms

Conditions

Small Fiber Neuropathy; Neuritis

Condition Hierarchy (Ancestors)

Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases

Study Officials

• Lawrence Zeidman, MD, FAAN

  Endeavor Health

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Anna Pham

CONTACT

8475034344; anna.pham@endeavorhealth.org

May Aunaetitrakul

CONTACT

8475702570

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: This is a double-blind trial. The participant and the investigator will be masked to the treatment assignment.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Neuromuscular and Autonomic Division, Endeavor Health

Model Details: 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)). All study visits will take place at Endeavor Health.

Study Record Dates

• First Submitted: November 4, 2019
• First Posted: November 6, 2019
• Study Start: December 15, 2023
• Primary Completion (Estimated): August 27, 2027
• Study Completion (Estimated): February 28, 2028
• Last Updated: January 9, 2026

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)