CompletedNCT03401073Updated Sep 13, 2023Results posted

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

A Phase 2 interventional study of Intravenous immunoglobulin and 0.9% Sodium Chloride in Small Fiber Neuropathy and Idiopathic Peripheral Neuropathy, sponsored by Beth Israel Deaconess Medical Center. Completed at 1 site in United States. Per ClinicalTrials.gov, last updated 2023-09-13.

Sponsored by Beth Israel Deaconess Medical Center · Phase 2, Interventional, and Treatment

Phase: Phase 2
Study type: Interventional
Enrollment: 20
Allocation: Randomized
Sex: All

Study 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.

Read the 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)

Conditions studied

Small Fiber Neuropathy
Idiopathic Peripheral Neuropathy

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Keywords

small Fiber Neuropathy
Idiopathic Peripheral Neuropathy
IVIg
Gamunex-C

Who can participate

Ages eligible: Child (0–17), Adult (18–64), Older adult (65+)
Sexes eligible: All
Accepts healthy volunteers: No

Inclusion criteria

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.

Exclusion criteria

Exclusion Criteria:

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.
Patients unable or unwilling to understand or comply with the study protocol
Participating in another interventional clinical study with investigational treatment within three months prior to enrollment.
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.

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment: 20 participants (actual)

Study arms

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.
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
Drug: Intravenous immunoglobulin

Interventions

DrugIntravenous immunoglobulin
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
Drug0.9% Sodium Chloride
Sodium Chloride (also known as saline) is a solution of sodium chloride, or salt, and sterile water.
Also known as: Saline

What researchers measure

Primary outcomes

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).
Time frame: 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

The Change in Neuropathic Pain Severity Between Visits 1 and 8.
The visual analog scale (VAS) of pain allows for quantification of neuropathic pain. The VAS pain scale depicts a line ranging from 0 (no pain) to 10 (worst possible pain). The scale is ordinal ranging from 0-10. The difference in pain between visit 1 and visit 8 (pain measured at visit 8 subtracted from the score at visit 1) is the range. Positive values indicate an increase in pain (worse outcome), negative values indicate an improvement in pain (better outcome).
Time frame: 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.
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. The UENS scale ranges from 0 (no neuropathy) to 42 (severe small fiber neuropathy). The outcome measure is the UENS score from Visit 8 minus the UENS score at visit 1. The difference in the two scores indicates the change in neuropathy severity. A positive value indicates that neuropathy has worsened over the course of the study, a negative value indicates that neuropathy has improved over the course of the study.
Time frame: 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).

Results

Posted Sep 13, 2023

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.

Participant flow

Potential research subjects were recruited from Beth Israel Deaconess Medical Center (BIDMC) (Boston, MA) and HonorHealth Neurology (Phoenix, AZ). All recruited subjects signed a consent form approved by the Institutional Review Boards of BIDMC and HonorHealth.

Participant flow — Overall Study
Milestone	0.9% Sodium Chloride	Intravenous Immunoglobulin
Started	10	10
Completed	9	8
Not completed	1	2
Withdrew: Lost to follow-up	1	2

Outcome measures

PrimaryThe 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).

Time frame:: 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).
Reported as:: Mean · fibers/mm

The Change in Nerve Fiber Density Between Visits 1 and 8.
fibers/mm	0.9% Sodium Chloride	Intravenous Immunoglobulin
The Change in Nerve Fiber Density Between Visits 1 and 8.	0.5 ± 0.8	0.6 ± 0.6

SecondaryThe Change in Neuropathic Pain Severity Between Visits 1 and 8.

The visual analog scale (VAS) of pain allows for quantification of neuropathic pain. The VAS pain scale depicts a line ranging from 0 (no pain) to 10 (worst possible pain). The scale is ordinal ranging from 0-10. The difference in pain between visit 1 and visit 8 (pain measured at visit 8 subtracted from the score at visit 1) is the range. Positive values indicate an increase in pain (worse outcome), negative values indicate an improvement in pain (better outcome).

Time frame:: 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).
Reported as:: Mean · units on a scale

The Change in Neuropathic Pain Severity Between Visits 1 and 8.
units on a scale	0.9% Sodium Chloride	Intravenous Immunoglobulin
The Change in Neuropathic Pain Severity Between Visits 1 and 8.	-1.7 ± 0.9	-1.9 ± 2.6

Secondary2) The Difference in Change Between Quantified Utah Early Neuropathy Examination Scores, Between Treatment and Placebo Groups Between Visits 1 and 8.

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. The UENS scale ranges from 0 (no neuropathy) to 42 (severe small fiber neuropathy). The outcome measure is the UENS score from Visit 8 minus the UENS score at visit 1. The difference in the two scores indicates the change in neuropathy severity. A positive value indicates that neuropathy has worsened over the course of the study, a negative value indicates that neuropathy has improved over the course of the study.

Time frame:: 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).
Reported as:: Mean · units on a scale

2) The Difference in Change Between Quantified Utah Early Neuropathy Examination Scores, Between Treatment and Placebo Groups Between Visits 1 and 8.
units on a scale	0.9% Sodium Chloride	Intravenous Immunoglobulin
2) The Difference in Change Between Quantified Utah Early Neuropathy Examination Scores, Between Treatment and Placebo Groups Between Visits 1 and 8.	-3.0 ± 5.8	-1.8 ± 3.9

Adverse events

Collected over 6 months. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
0.9% Sodium Chloride	0/10 (0%)	0/10 (0%)	9/10 (90%)
Intravenous Immunoglobulin	0/10 (0%)	0/10 (0%)	8/10 (80%)

Most frequent other events

Most frequent other events
Event	0.9% Sodium Chloride	Intravenous Immunoglobulin
Infusion reactionProduct Issues	9/10	8/10

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)	0.9% Sodium Chloride	Intravenous Immunoglobulin	Total
<=18 years	0	0	0
Between 18 and 65 years	9	10	19
>=65 years	1	0	1

Age, Continuous
Age, Continuous(Years)	0.9% Sodium Chloride	Intravenous Immunoglobulin	Total
Mean	51.3 ± 9.4	51.5 ± 7.8	51.4 ± 8.4

Sex: Female, Male
Sex: Female, Male(Participants)	0.9% Sodium Chloride	Intravenous Immunoglobulin	Total
Female	5	6	11
Male	5	4	9

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	0.9% Sodium Chloride	Intravenous Immunoglobulin	Total
Hispanic or Latino	1	2	3
Not Hispanic or Latino	9	8	17
Unknown or Not Reported	0	0	0

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	0.9% Sodium Chloride	Intravenous Immunoglobulin	Total
American Indian or Alaska Native	0	0	0
Asian	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	1	1	2
White	9	9	18
More than one race	0	0	0
Unknown or Not Reported	0	0	0

Region of Enrollment
Region of Enrollment(participants)	0.9% Sodium Chloride	Intravenous Immunoglobulin	Total
United States	10	10	20

Intra-epidermal nerve fiber density
Intra-epidermal nerve fiber density(Fibers/mm)	0.9% Sodium Chloride	Intravenous Immunoglobulin	Total
Mean	2.02 ± 1.49	2.47 ± 1.83	2.25 ± 1.66

Pain score
Pain score(units on a scale)	0.9% Sodium Chloride	Intravenous Immunoglobulin	Total
Mean	5.5 ± 1.2	6.9 ± 1.8	6.2 ± 1.6

Study locations

1 site

Beth Israel Deaconness Medical Center
Boston, Massachusetts 02215, United States

References and documents

Publications

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. PubMed 25299289 ↗
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. PubMed 25410218 ↗
Peltier A, Goutman SA, Callaghan BC. Painful diabetic neuropathy. BMJ. 2014 May 6;348:g1799. doi: 10.1136/bmj.g1799. Erratum In: BMJ. 2014;348:g3440. PubMed 24803311 ↗
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. PubMed 26578039 ↗
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. PubMed 26596193 ↗
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. PubMed 28827487 ↗
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. PubMed 22581541 ↗
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. PubMed 25628376 ↗
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. PubMed 8813271 ↗
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. PubMed 11222785 ↗
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. PubMed 12111305 ↗
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. PubMed 24379104 ↗
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. PubMed 18844788 ↗
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. PubMed 20642627 ↗
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. PubMed 26309146 ↗

Study documents

Protocol and statistical analysis plan · Nov 29, 2022

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

Registry details

Key details

Study ID: NCT03401073
Lead sponsor: Beth Israel Deaconess Medical Center
Collaborators: Phoenix Neurological Associates, LTD
Responsible party: Christopher Gibbons, MD (Associate Professor of Neurology, Beth Israel Deaconess Medical Center) — Principal investigator
First posted: Jan 17, 2018
Start date: Sep 1, 2018
Primary completion: Feb 1, 2022
Completion: Feb 1, 2022
Results posted: Sep 13, 2023
Last update: Sep 13, 2023

Study contacts

Christopher Gibbons, MD

principal investigator · Beth Israel Deaconess Medical Cednter

Oversight

Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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