Clinical trial NCT03401073
Conditions: Small Fiber Neuropathy Idiopathic Peripheral Neuropathy
Keywords: small Fiber Neuropathy Idiopathic Peripheral Neuropathy IVIg Gamunex-C
Sponsor: Beth Israel Deaconess Medical Center
Start date: 2018-09-01; Completion date: 2022-02-01
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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)

Arms: arm 1: 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. arm 2: 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
Interventions: intervention 1: Intravenous immunoglobulin intervention 2: 0.9% Sodium Chloride
Intervention descriptions: intervention 1: Gamunex-C \[immune globulin injection (human) 10% caprylate/chromatography purified\] is a sterile solution of human immune globulin protein. intervention 2: Sodium Chloride (also known as saline) is a solution of sodium chloride, or salt, and sterile water.

Protocol documents:
Prot_SAP_000.pdf: 
Study Title “IVIg for Small Fiber Neuropathy With AutoanƟbodies to TS-
HDS and FGFR3” 
NCT number: NCT03401073 
Document Date: 11/29/2022 
 
 


Protocol: 
Study Design: This was a prospecƟve 6-month double-blind placebo-controlled pilot study of IVIG for 
treatment of suspected immune mediated SFN associated with TS-HDS or FGFR-3.  The trial was 
registered with ClinicalTrials.gov (NCT03401073).   
Subjects:  PotenƟal research subjects were recruited from the panel of paƟents seen by 
neuromuscular/peripheral nerve groups at Beth Israel Deaconess Medical Center (BIDMC) (Boston, MA) 
and HonorHealth Neurology (Phoenix, AZ) and by paƟents seen at neighboring insƟtuƟons in the Boston 
and Phoenix areas.  AddiƟonal referrals were obtained through ClinicalTrials.gov. All recruited subjects 
provided signed informed consent as approved by the InsƟtuƟonal Review Boards of BIDMC and 
HonorHealth.  
Inclusion Criteria: PaƟents were potenƟally eligible if they had clinically evident SFN in a length 
dependent or non-length dependent patern as conﬁrmed by history of symptoms that included burning, 
shooƟng, or prickling pain or dysesthesia for at least 6 months and examinaƟon ﬁndings demonstraƟng 
loss of pain sensaƟon and/or loss of temperature detecƟon in the distribuƟon of pain.  Subjects also 
required evidence of reduced intra-epidermal nerve ﬁber density (IENFD) seen on skin biopsy in the 
region corresponding to examinaƟon abnormaliƟes, based on age and sex-matched normaƟve values, 
using PGP 9.5 as the immunostain .15 Subjects required a baseline daily pain score on a visual analogue 
scale (VAS) of greater than or equal to 4/10.  PaƟents also required elevated Ɵters of autoanƟbodies to 
TS-HDS or FGFR-3 as measured by the Neuromuscular Clinical Laboratory at Washington University in St 
Louis using standard enzyme linked immunoassay (ELISA) assays as previously published. 14, 16  AnƟbody 
Ɵters were measured at the Ɵme of screening and abnormal values measured at the Washington 
University laboratory within the 6 months prior to screening were accepted.  NormaƟve values re 
<10,000 for TS-HDS and <3,000 for FGFR3 .   
Exclusion Criteria: Individuals were excluded if they had evidence of large ﬁber neuropathy such as 
abnormal nerve conducƟon studies, motor weakness, absent vibraƟon, propriocepƟon or deep tendon 
reﬂexes.  Individuals were also excluded if they were found to have other known causes for small ﬁber 
neuropathy: diabetes, prediabetes, HIV, Sjogren's syndrome, vitamin deﬁciency, toxin exposure, or 
monoclonal gammopathy.  PaƟents were also excluded for generalized, severe musculoskeletal 
condiƟons other than SFN that would have prevented accurate assessment by the physician, or for an 
underlying condiƟon that would put them at risk of complicaƟon from a biopsy such as anƟcoagulant use 


or high risk of infecƟon. Other exclusions were a contraindicaƟon to IVIG because of renal dysfuncƟon 
with creaƟnine >1.5 mg/dl, prior thromboƟc event or a hypersensiƟvity reacƟon to IVIG in the past. 
Screening: Study subjects underwent a detailed history, physical examinaƟon, laboratory studies, pain 
VAS scores, the Short-From 36 quesƟon health survey (SF-36), anƟbody measurement of TS-HDS and 
FGFR-3 and skin biopsy evaluaƟon of nerve ﬁber density at the distal leg and proximal thigh using 
standard methodology. 
Randomization and Blinding: Subjects who were eligible for study inclusion were block randomized into 
2 groups (IVIG or placebo) by a blinded staƟsƟcian.  All study personnel, study subjects and support staﬀ 
were blinded to treatment assignment.  Only the single research pharmacist who mixed the 
IVIG/placebo was aware of the treatment assignment and was not in communicaƟon with any study 
staﬀ.  IVIG and placebo were placed in opaque infusion bags that covered the enƟre treatment product 
and infusion line to prevent unblinding.   
Study Medication and Treatment Allocation: Subjects received either IVIG or placebo.  IVIG treatment 
involved an iniƟal dose of 1 gm/kg (Gamunex, Grifols, Los Angeles, CA) daily for 2 days followed by 1 
gm/kg in a single dose every 3 weeks for 21 weeks (for a total of 8 doses) with a maximum of 80 gm IVIG 
infusion.  Normal saline was used as placebo and included in a volume equivalent to that of IVIG.   
Study Procedures: The outline of the study protocol is seen in Supplemental Figure 1.  At all study visits 
parƟcipants underwent review of inclusion and exclusion criteria, medical history, medicaƟon review, 
adverse eﬀect review, and pain VAS scores (0-10 scale – reported as pain on the day of visit). At the 
screening and ﬁnal study visits all subjects also completed skin biopsies at the distal leg,17 the Utah Early 
Neuropathy Scale (UENS),18 and the SF-36.19 
Physical Examination: Detailed neurologic examinations were performed at baseline and at 
the final visit.  The physical examination was quantified via the UENS.18  In brief, the UENS is a 
42-point system that grades neuropathy from 0 (no neuropathy) to 42 (absent ankle reflexes, 
weakness at the toes, absent sensation to multiple modalities in the legs).   
Pain Scores: Subjects rated their pain on an 11-point visual analogue Likert scale at every visit 
(where 0 = no pain and 10 = maximal pain). The location, exacerbating factors and character of 
pain were recorded at each visit. Subjects were treated with medications to reduce neuropathic 
pain at the discretion of the treating physician, including anti-convulsants, anti-depressants and 
opioids, typically in combination. Pain scores were measured while on medication. Subjects 


were asked not to change doses of daily neuropathy pain medications while participating in the 
clinical trial.  Subject use of pain medications was monitored at each study visit. 
Skin Biopsy Evaluation of Intra-Epidermal Nerve Fiber Density (IENFD):  All study 
participants underwent 3-mm punch skin biopsies 10 cm above the lateral malleolus at their 
baseline visit.  Follow-up biopsies were taken 21-25 weeks later on the same leg adjacent to the 
original biopsy sites using standard techniques.  Specimens were fixed and stained with PGP 
9.5 (ubiquitin hydrolase, Chemicon).20  All patients underwent IENFD counting by a blinded 
physician and results were expressed as a linear density for IENFD (number of fibers per 
millimeter).21  
 
 
StaƟsƟcal Analysis Plan:   
Primary Outcome: The primary eﬃcacy endpoint for this study was the change in IENFD between 
visits 1 and 8. We deﬁned a clinically relevant change in disease endpoint as a >2.0 ﬁber/millimeter 
increase in IENFD between screening and ﬁnal visit. We anƟcipated no change in IENFD between visits 1 
and 8 in the placebo treatment arm. The change in IENFD was based on prior studies of lifestyle 
modiﬁcaƟon in diabeƟc neuropathy where increases in IENFD of >2 ﬁbers/mm over 1 year were seen in 
25% of paƟents associated with an improvement in neuropathic pain.22   Pain was not selected as a 
primary outcome measure because a separate ongoing clinical trial using IVIG in small ﬁber neuropathy 
was already invesƟgaƟng pain as an endpoint,2 and also because of our speciﬁc interest was in evaluaƟng 
IVIG for potenƟal impact on disease modiﬁcaƟon.   
Secondary Outcomes: Two secondary outcome measures are included in this study: 
1) The change in neuropathic pain severity between visits 1 and 8.       
We expected that individuals with immune mediated small ﬁber neuropathy treated with IVIG 
would have a >2-point reducƟon in neuropathic pain VAS score between screening and ﬁnal visit.  
We anƟcipated a <1.5-point reducƟon in neuropathic pain VAS score between screening and 
ﬁnal visit in the placebo group. 
2) The change in quanƟﬁed UENS scores, between screening and ﬁnal visit.   


We expected that individuals with immune mediated SFN treated with IVIG would have a 
have a >1 point reduction in the UENS score between screening and final visit.  We 
expected that the placebo treated group would have no change in UENS score between 
screening and final visits. 
Exploratory Outcomes: Safety in response to IVIG infusion and changes in distribuƟon or character 
of pain associated with SFN in paƟents treated with IVIG.   
This pilot study was being conducted in order to obtain adequate preliminary data for a larger clinical 
trial but was powered to answer the primary endpoint analysis.  Secondary endpoints and exploratory 
endpoints are not included in the power analysis.  The sample size of 10 parƟcipants per group was 
determined with an assumed change in IENFD rate of 0 ﬁbers/millimeter in the placebo group and >2.0 
ﬁbers/millimeter in the IVIG group, a 1-sided α of 5%, and 80% power between the 2 groups, including 
the assumpƟon of a dropout rate of 10% (2 paƟents). Therefore, the aim was to include in total 20 
paƟents in the study. 
The results were analyzed according to the intenƟon-to-treat (ITT) protocol. For the primary ITT analysis, 
missing values were imputed as no change from baseline. ParƟcipants were analyzed for eﬃcacy 
according to randomized treatment. For the SF-36 Health Survey, biopsy results, and UENS examinaƟon 
ﬁndings, the diﬀerence between baseline (screening period) and the end of the ﬁnal visit was calculated. 
For the primary outcome measure, the proporƟon of paƟents with a decrease of at least 2.0 
ﬁbers/millimeter was compared between the IVIG and placebo groups with a χ2 test, with mean and 
standard deviaƟons reported. For secondary outcome measure, mean change in values between groups 
was compared using a student’s T-test (2 tailed, 2 sample, homoscedasƟc variance).  For pain VAS scores, 
ANOVA was used to measure diﬀerences in pain scores between IVIG and placebo groups.