IVIG in Painful Sensory Neuropathy

Study Overview
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Brief Summary
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The goal of this clinical trial is to assess effect of Intravenous immunoglobulins (antibodies) as compared to Placebo, on pain intensity in patients from 18-65 years with painful sensory neuropathy without a known cause. Effect of the treatment will be recorded by the patient in a digital diary.

Detailed Description
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Patients suffering from idiopathic sensory neuropathies often report excruciating pain that interferes with daily function and leads to impaired quality of life. Current neuropathic pain treatment options are in general insufficient. Autoimmunity may play a role in some patients, and treatment with intravenous immunoglobulins (IVIG) may have a potential beneficial effect. Available scientific documentation on this topic is limited and disparate. The main purpose of this trial is to assess effect of IVIG as compared to placebo on pain intensity in patients >18 years with idiopathic painful small fiber neuropathy or sensory neuronopathy. Each patient will during the 30-week trial period get 3 IVIG courses and 3 placebo courses in a randomized order, given every 5 week on an outpatient basis for three consecutive days. Outcome measures will be recorded by the patient in a digital diary

Official Title
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Effect of Intravenous Immunoglobulins on Painful Sensory Neuropathy Evaluated by Aggregated N-of-one Trials

Conditions
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Sensory Neuropathy, Small Fiber Neuropathy

Intervention / Treatment
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* Drug: Intravenous immunoglobulin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Painful sensory neuropathy fulfilling diagnostic criteria for idiopathic small fiber neuropathy or sensory neuronopathy Idiopathic small fiber neuropathy (all of the following) Neuropathic pain (length-dependent/non-length dependent/focal) and at least two of the following clinical signs Hypoesthesia (tactile, pinprick, or thermal) Allodynia (tactile, dynamic, thermal, pressure) Hyperalgesia Aftersensation Normal nerve conduction studies: Reduced intra-epidermal nerve fiber density at the distal leg (IENFD) at the distal leg or Reduced thermal threshold assessed at the foot by QST Causal investigation according to clinical guidelines has not revealed a cause of the neuropathy Sensory neuronopathy (all of the following) Clinical pure sensory neuropathy A score >6.5 on the following Ataxia in the lower or upper limb: 3.1p Asymmetrical distribution of sensory loss: 1.7p IVIGSeN Protocol number 1.2 Sensory loss not restricted to the lower limb at full development: 2.0 p At least 1 sensory action potential absent or 3 sensory action potentials <30% of the lower limit of normal in the upper limbs not explained by entrapment neuropathy: 2.8p Less than two nerves with abnormal motor nerve conduction studies in the lower limbs: 3.1p Causal investigation according to clinical guidelines has not revealed a cause of the neuropathy Pain intensity > 5.0 on a pain score from 0-10, lasting at least 4 weeks Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply: Medical Conditions Previous allergic reaction to IVIG or other blood products) Selective IgA deficiency Cardiac insufficiency (NYHA III/IV ie marked or severe limitation in activity due to symptoms, even during less-than-ordinary activity) Cardiac dysrhythmia requiring treatment Unstable or advanced ischemic heart disease Severe hypertension (diastolic >120 or systolic > 170) Known hyperviscosity Renal insufficiency (GFR < 30 ml/min/1,73m2) or nephrotic syndrome Previous thromboembolic event Smoking Diabetes Prolonged immobilization Hypercoagulable state Prior/Concomitant Therapy Change of pain medication in the 30 days prior to inclusion (unchanged pain medication is allowed, provided dosages stay equal during the study) Treatment with IVIG the last 4 weeks or other ongoing immunomodulatory treatments Use of loop diuretics, Dinutuksimab beta, or Imlifidase Diagnostic assessments Predominant clinical or neurographic features of motor nerve fiber involvement Other Exclusions Females who are breastfeeding, pregnant or unwilling to practice contraception throughout the study Unable to give independent informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: N-of-one trial, individual randomized, double-blind, and multiple crossover comparisons of an interventional treatment and placebo
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravenous Immunoglobulin<br>3 courses Intravenous immunoglobulin, Infusion solution, 100mg/ml, 2g/kg over 3 days | Drug: Intravenous immunoglobulin<br>* Each patient will during the 30-week trial period get 3 IVIG courses (each total dose 2g/kg) for three consecutive days<br>* Other names: Privigen;|
| Placebo Comparator: Placebo<br>3 courses Saline infusion solution 0,9%, same volume as IVIG over 3 days | Drug: Placebo<br>* Each patient will during the 30-week trial period get 3 placebo courses (each 0.9% saline similar volume) for three consecutive days<br>* Other names: 0.9% saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain intensity the second week | Pain intensity after IVIG/Placebo infusions scored on a numeric rating scale (NRS) ranging from 0 to 10 | The second week after start of IVIG/Placebo infusions (mean of days 8, 10 and 13) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain intensity across 4 weeks | Pain intensity across 4 weeks after start of each infusion (mean of scoring three times per week from) | Day 8 to 34 after start of each infusion | 
| Disability and quality of life | Scored on: Polyneuropathy Patient-reported Index (CAPPRI) | At the end of the third week after infusion | 
| Anti-FGF3 antibodies | Blood samples will be tested for anti-FGF3 antibodies to evaluate their association with the observed clinical response in terms of pain relief to IVIG. | Before start of infusion of IVIG/Placebo week 1, 5, 11, 16, 21 and 26 | 
| Adverse events | Recording adverse events | From start to end of interventions week 1 - 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IVIG, nervous system diseases, neuromuscular diseases, peripheral nervous system diseases, small fiber neuropathy, sensory neuronopathy, sensory neuropathy, Intravenous immunoglobulin, n-of-1, Sørlandet sykehus, Sorlandet hospital, Kristiansand, polyneuropathy, Intravenous immune globulin