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

Small Fiber Neuropathy Clinical Trial

Official title:

Intravenous Immunoglobulin (IVIG) in the Treatment of Small Fiber Neuropathy Due to TS-HDS, FGFR-3, or Plexin D1 Antibodies: a Double Blinded Placebo-controlled Phase II Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04153422
• Other study ID #: 212029
• Status: Recruiting
• Phase: Phase 2
• Start date: December 15, 2023
• Est. completion date: April 2027

Study information

• Verified date: June 2024
• Source: Henry Ford Health System
• Contact: Kelly Tundo, RN
• Phone: 313-916-1102
• Email: kciach1[@]hfhs.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 fibromyalgia. The prevalence is rising for SFN, and an immune etiology may underlie 19%-34% of cases. While there is no standard of care treatment, current treatment strategies for SFN include long-term steroid therapy which come with a host of side effects. 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, as well as improving validated questionnaire scores monitoring symptom burden and disability. However, neither IVIG nor any other immunosuppressant has been studied in a sufficiently powered and adequately dosed controlled, randomized clinical trial to demonstrate efficacy.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: April 2027
• Est. primary completion date: December 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Patients = age 18

2. 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, and using Corinthian Reference Laboratory (Benbrook, TX).

3. Patients must have elevated and/or abnormal titers of autoantibodies to TS-HDS-IgM or FGFR3-IgG or Plexin-D1, measured by the Washington University Neuromuscular Laboratory (St Louis) within 12 months of study enrollment.

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

8. Patients must be able to travel to Detroit, MI (USA) for the infusions, follow-up biopsy, and other clinical activities; these will not be performed elsewhere

Exclusion Criteria:

1. Any other known cause for small fiber neuropathy other than the presence of the elevated titers of the novel auto-antibodies.

2. Patients with generalized, severe musculoskeletal conditions other than SFN that prevent a sufficient assessment of the patient by the physician.

3. Electromyography/nerve conduction study (EMG/NCS) evidence of large fiber polyneuropathy, to be confirmed by study PI

4. Underlying severe heart, kidney, liver disease, or HIV infection, (Note: If there is no previous HIV test result documented, a test may be performed in order to confirm eligibility)

5. 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.

6. Known significant IgA deficiency with antibodies to IgA.

7. History of hypersensitivity, anaphylaxis or severe systemic response to immuno-globulin, blood or plasma derived products, or any component of IVIG 10%,

8. Known blood hyperviscosity, or other hypercoagulable states,

9. Use of IgG products within six months prior to enrollment,

10. Patients with a history of drug or alcohol abuse within the past five years prior to enrollment,

11. Patients unable or unwilling to understand or comply with the study protocol

Related Conditions & MeSH terms

• Autoimmune Small Fiber Neuropathy
• Immune-Mediated Neuropathy
• Inflammatory Polyneuropathy
• Peripheral Nervous System Diseases
• Polyneuropathies
• Small Fiber Neuropathy

Intervention

Drug:
• Panzyga IVIG
Immune Globulin Infusion 10% (Human)
• Placebo
0.9% NaCl prepared as the calculated dose equivalent volume to IVIG.

Locations

Country	Name	City	State
United States	Henry Ford Health	Detroit	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
Henry Ford Health System	Octapharma USA, Inc.

Country where clinical trial is conducted

United States, 

References & Publications (17)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	quantified change in intraepidermal nerve fiber density (IENFD)	3mm skin punch biopsy at 3 sites	Week 24
Secondary	Change in visual analogue pain scale responses	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	baseline and Week 28
Secondary	Change in Small Fiber Neuropathy-Rasch Overall Disability Scale (SFN-RODS) score	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	baseline and Week 28
Secondary	Change in Small Fiber Neuropathy-Symptom Inventory Questionnaire (SFN-SIQ) score	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.	baseline and Week 28
Secondary	Change in Utah Early Neuropathy Scale (UENS) examination scores	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.	baseline and Week 28