IVIG in Painful Sensory Neuropathy

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Small Fiber Neuropathy; Sensory Neuropathy
• Intervention / Treatment: Drug: Intravenous immunoglobulin; Drug: Placebo

Detailed Description

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

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Ørnes; Phone Number: +47 38125396; Email: Jon-Marius.Rognhaug.Ornes@sshf.no
• Study Contact Backup: Name: Unn Ljøstad; Phone Number: +47 38073908; Email: Unn.Ljostad@sshf.no

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Painful sensory neuropathy fulfilling diagnostic criteria for idiopathic small fiber neuropathy or sensory neuronopathy

• Idiopathic small fiber neuropathy (all of the following)

  1. Neuropathic pain (length-dependent/non-length dependent/focal) and at least two of the following clinical signs

     1. Hypoesthesia (tactile, pinprick, or thermal)
     2. Allodynia (tactile, dynamic, thermal, pressure)
     3. Hyperalgesia
     4. Aftersensation
  2. Normal nerve conduction studies:
  3. 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
  4. Causal investigation according to clinical guidelines has not revealed a cause of the neuropathy

• Sensory neuronopathy (all of the following)

  1. Clinical pure sensory neuropathy

  2. A score >6.5 on the following

     1. Ataxia in the lower or upper limb: 3.1p
     2. Asymmetrical distribution of sensory loss: 1.7p IVIGSeN Protocol number 1.2
     3. Sensory loss not restricted to the lower limb at full development: 2.0 p
     4. 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
     5. Less than two nerves with abnormal motor nerve conduction studies in the lower limbs: 3.1p
  3. 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

1. Previous allergic reaction to IVIG or other blood products)
2. Selective IgA deficiency
3. Cardiac insufficiency (NYHA III/IV ie marked or severe limitation in activity due to symptoms, even during less-than-ordinary activity)
4. Cardiac dysrhythmia requiring treatment
5. Unstable or advanced ischemic heart disease
6. Severe hypertension (diastolic >120 or systolic > 170)
7. Known hyperviscosity
8. Renal insufficiency (GFR < 30 ml/min/1,73m2) or nephrotic syndrome
9. Previous thromboembolic event
10. Smoking
11. Diabetes
12. Prolonged immobilization

13. Hypercoagulable state

    Prior/Concomitant Therapy

14. Change of pain medication in the 30 days prior to inclusion (unchanged pain medication is allowed, provided dosages stay equal during the study)
15. Treatment with IVIG the last 4 weeks or other ongoing immunomodulatory treatments
16. Use of loop diuretics, Dinutuksimab beta, or Imlifidase Diagnostic assessments
17. Predominant clinical or neurographic features of motor nerve fiber involvement Other Exclusions
18. Females who are breastfeeding, pregnant or unwilling to practice contraception throughout the study
19. Unable to give independent informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Sorlandet Hospital HF
• Collaborators: Oslo University Hospital; University Hospital of North Norway; University Hospital of Saint-Etienne
• Investigators: Principal Investigator: Jon-Marius Ørnes, Cand.med, Sorlandet Hospital HF, Department of Neurology; Study Director: Unn Ljøstad, Cand.med PhD, Sorlandet Hospital HF, Department of Neurology; Study Director: Åse Mygland, Cand.med PhD, Sorlandet Hospital HF, Department of Neurology

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2024
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: December 13, 2023
• First Submitted That Met QC Criteria: December 13, 2023
• First Posted (Estimated): December 27, 2023

Study Record Updates

• Last Update Posted (Estimated): December 27, 2023
• Last Update Submitted That Met QC Criteria: December 13, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: IVIG; nervous system diseases; peripheral nervous system diseases; Intravenous immunoglobulin; polyneuropathy; neuromuscular diseases; small fiber neuropathy; n-of-1; sensory neuropathy; sensory neuronopathy; Sørlandet sykehus; Sorlandet hospital; Kristiansand; Intravenous immune globulin
• Additional Relevant MeSH Terms: Nervous System Diseases; Neuromuscular Diseases; Peripheral Nervous System Diseases; Small Fiber Neuropathy; Physiological Effects of Drugs; Immunologic Factors; Antibodies; Immunoglobulins; Immunoglobulins, Intravenous; gamma-Globulins; Rho(D) Immune Globulin
• Other Study ID Numbers: IVIGSeN

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No