Chronic Inflammatory Demyelinating Polyneuropathy
Conditions
Keywords
Pediatrics, Vagus nerve stimulation
Brief summary
Participants will be requested to deliver non-invasive vagus nerve stimulation (nVNS) two times per day, at least five days per week. Participants will be followed for two years with nVNS as an adjunctive therapy to the standard of care therapy for chronic inflammatory demyelinating polyneuropathy (CIDP).
Detailed description
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronic immune-mediated disease of the peripheral sensory motor nerves characterized by motor weakness, sensory loss, muscle wasting and loss of motor ability. The majority of CIDP cases are idiopathic with insidious onset, relapsing remitting course, and a prolonged clinical course (over years). CIDP incidence is unknown in pediatric population, however, it is a rare treatable cause of neuromuscular weakness in children. Treatment of CIDP involves chronic use of steroids, intravenous immunoglobulin (IVIG) and, rarely, plasma exchange (PLEX). Despite above mentioned treatments the majority of patients continue to have tremendous disease burden. There is a need for alternative or adjunctive therapies that can decrease chronic inflammation effectively and safely in pediatric CIDP patients. Vagus nerve stimulation has received significant scientific and clinical attention and has been shown to effectively reduce systemic inflammation. Results from early clinical trials for treatment of Rheumatoid Arthritis (RA) have demonstrated significant lifestyle benefits and reduced symptoms in RA patients. Similar benefits of VNS have been observed in Crohn's disease patients. In these studies, patients are surgically implanted with a stimulator and electrodes directly on the nerve. Preliminary results have demonstrated safety and efficacy in patients that previously were unresponsive to traditional pharmacological therapies. Unfortunately, surgical implantation of a device is difficult and costly. Recent investigations have significantly increased the understanding of non-invasive vagus nerve stimulation (nVNS). Compared to traditional implanted vagus nerve stimulation devices, nVNS uses electrodes placed on the skin surface to stimulate the vagus nerve. nVNS has shown promise in animal and human models to reduce chronic inflammation in multiple disease states. By delivering electrical pulses at the skin surface above the vagus nerve, neural pathways involved in regulating systemic inflammation are activated. Using a handheld device, patients apply brief durations of stimulation multiple times per day to achieve therapeutic benefit. nVNS is currently FDA approved for clinical use in the treatment of migraines and cluster headaches, with on-going clinical studies on epilepsy and systemic inflammation. Preliminary published results have demonstrated significant therapeutic benefit to the patients with minimal side-effects such as a feeling of paresthesia at the site of the electrodes which subsides after turning the stimulation off. Study participants will administer non-invasive vagus nerve stimulation (nVNS) two times per day, at least five days per week, as an adjunctive therapy to their standard of care treatment for CIDP. Participants will be followed for two years to understand the impact of nVNS on CIDP symptoms and the compliance with nVNS therapies in pediatric patients.
Interventions
The nVNS study intervention will be delivered using a handheld electrical neuromuscular stimulator device (VitalStim 400). Participants will deliver nVNS twice per day for 60 minutes each time at least 5 days per week. The two electrodes for the device will be placed on the subjects left cervical (neck) region. Parents will be trained on where to place electrodes, how to ensure that the electrodes make a good contact with the skin, and how to set the stimulation parameters. The stimulation frequency (number of pulses) and amplitude (amount of current) will be set during the initial baseline session in the clinic at a level that prevents discomfort and does not impact cardiorespiratory parameters. The stimulator will be placed in a comfortable position, such as next to the pillow. The stimulators are battery-powered and allow configuration of the stimulation parameters to the comfort of the patient.
OTHERStandard of care treatment
Patients will be asked to continue their standard medication regimens which include in most cases will involve 3 weekly infusions of intravenous immunoglobulin (IVIG) (1 gm/kg) and rarely plasma exchange (PLEX).
Sponsors
Georgia Institute of Technology
Emory University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to 21 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of CIDP based upon clinical/electrophysiological criteria * On treatment for CIDP including IVIG and/ or steroids/plasma exchange
Exclusion criteria
* Inherited polyneuropathy, such as Charcot Tooth Marie disease * Abnormal baseline EKG, heart disease, epilepsy, pregnancy, multiple sclerosis and diabetes mellitus
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rasch-built Overall Disability Scale (R-ODS) for CIDP Score | Baseline, Month 6, Month 12, Month 18, Month 24 | The Rasch-built Overall Disability Scale (R-ODS) used for those with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and gammopathy-related polyneuropathy (MGUSP) is a 24-item scale asking respondents to rate how greatly polyneuropathy impacts activities. Responses are given on a scale of 0 to 2 where 0 indicates it is not possible for the respondent to perform the task and 2 means that the task can be performed without difficulty. Total scores range from 0 to 48 and higher scores indicate greater ability to perform daily and social tasks. |
| Nerve Conduction Study - Conduction Amplitude | Baseline, Month 12, Month 24 | Motor nerve conduction studies are used to examine conduction of electrical impulses along nerves. Electrodes are placed on the skin in specific areas to evaluate peripheral nerves. An electrode stimulates a nerve while the receiving site records how well electrical impulses are being conducted along the nerve. Conduction amplitude is the size of the response to electrical stimulation, measured in millivolts (mV). Reduced amplitude indicates axon loss. |
| Hand Grip Strength | Baseline, Month 6, Month 12, Month 18, Month 24 | Hand grip strength is assessed with a Jamar Handheld Dynamometer for children ages 5-18 years and measures strength in kilograms (kg). Both right and left hand grip strength were measured and the best of three attempts were used for each hand. Increased hand strength is an indicator of effective treatment. |
| Nerve Conduction Study - Distal Latency | Baseline, Month 12, Month 24 | Motor nerve conduction studies are used to examine conduction of electrical impulses along nerves. Electrodes are placed on the skin in specific areas to evaluate peripheral nerves. An electrode stimulates a nerve while the receiving site records how well electrical impulses are being conducted along the nerve. Latency is the time it takes in milliseconds (ms) for the electrical impulse to travel to the site receiving the stimulation. |
| Nerve Conduction Study - F Wave Latency | Baseline, Month 12, Month 24 | Motor nerve conduction studies are used to examine conduction of electrical impulses along nerves. Electrodes are placed on the skin in specific areas to evaluate peripheral nerves. An electrode stimulates a nerve while the receiving site records how well electrical impulses are being conducted along the nerve. F wave latency is the time it takes in milliseconds (ms) for an electrical signal to travel from the stimulating electrode to the distal muscle and back to the stimulating site. F waves are used to assess polyneuropathy and F wave latency can be extended or even absent in persons with CIDP. |
| Nerve Conduction Study - Conduction Velocity | Baseline, Month 12, Month 24 | Motor nerve conduction studies are used to examine conduction of electrical impulses along nerves. Electrodes are placed on the skin in specific areas to evaluate peripheral nerves. An electrode stimulates a nerve while the receiving site records how well electrical impulses are being conducted along the nerve. Conduction velocity measures the rate of impulse conduction in meters per second (m/s) and is often decreased in patients with CIDP as myelination is affected. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Interleukin (IL)-1β | Baseline, Month 6, Month 12, Month 18, Month 24 | The impact of treatment on serum cytokine profiles will be assessed by measuring IL-1β. Serum cytokine levels will be statistically analyzed on a per patient basis, with each patient's baseline measurements used for comparison. IL-1β is elevated in CIDP patients and a decrease in IL-1β values is an indication of effective treatment. |
| Tumor Necrosis Factor (TNF)-α | Baseline, Month 6, Month 12, Month 18, Month 24 | The impact of treatment on serum cytokine profiles will be assessed by measuring TNF-α. Serum cytokine levels will be statistically analyzed on a per patient basis, with each patient's baseline measurements used for comparison. TNF-α is elevated in CIDP patients and a decrease in serum TNF-α is an indication of effective treatment. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from Children's Healthcare of Atlanta in Atlanta, Georgia, USA. Participant enrollment began February 22, 2022 and the study was terminated June 30, 2022, prior to any participant reaching the first follow-up visit at Month 6.
Participants by arm
| Arm | Count |
|---|---|
| Non-invasive Vagus Nerve Stimulation (nVNS) Participants with CIDP used the electrical neuromuscular stimulator device, VitalStim 400, while continuing to take their standard of care medication. | 2 |
| Total | 2 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Non-invasive Vagus Nerve Stimulation (nVNS) |
|---|---|
| Age, Categorical <=18 years | 2 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 1 Participants |
| Region of Enrollment United States | 2 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 2 |
| other Total, other adverse events | 0 / 2 |
| serious Total, serious adverse events | 1 / 2 |
Outcome results
Primary
Hand Grip Strength
Hand grip strength is assessed with a Jamar Handheld Dynamometer for children ages 5-18 years and measures strength in kilograms (kg). Both right and left hand grip strength were measured and the best of three attempts were used for each hand. Increased hand strength is an indicator of effective treatment.
Time frame: Baseline, Month 6, Month 12, Month 18, Month 24
Population: Participants withdrew from the study prior to completing any follow-up study visits.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Non-invasive Vagus Nerve Stimulation (nVNS) | Hand Grip Strength | Baseline - Right Hand | 19.1 kg | Standard Deviation 2.97 |
| Non-invasive Vagus Nerve Stimulation (nVNS) | Hand Grip Strength | Baseline - Left Hand | 18.55 kg | Standard Deviation 2.62 |
Primary
Nerve Conduction Study - Conduction Amplitude
Motor nerve conduction studies are used to examine conduction of electrical impulses along nerves. Electrodes are placed on the skin in specific areas to evaluate peripheral nerves. An electrode stimulates a nerve while the receiving site records how well electrical impulses are being conducted along the nerve. Conduction amplitude is the size of the response to electrical stimulation, measured in millivolts (mV). Reduced amplitude indicates axon loss.
Time frame: Baseline, Month 12, Month 24
Population: Participants withdrew from the study prior to completing any follow-up study visits.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Non-invasive Vagus Nerve Stimulation (nVNS) | Nerve Conduction Study - Conduction Amplitude | Baseline | 4.15 mV | Standard Deviation 1.2 |
Primary
Nerve Conduction Study - Conduction Velocity
Motor nerve conduction studies are used to examine conduction of electrical impulses along nerves. Electrodes are placed on the skin in specific areas to evaluate peripheral nerves. An electrode stimulates a nerve while the receiving site records how well electrical impulses are being conducted along the nerve. Conduction velocity measures the rate of impulse conduction in meters per second (m/s) and is often decreased in patients with CIDP as myelination is affected.
Time frame: Baseline, Month 12, Month 24
Population: Participants withdrew from the study prior to completing any follow-up study visits.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Non-invasive Vagus Nerve Stimulation (nVNS) | Nerve Conduction Study - Conduction Velocity | Baseline | 37.5 m/s | Standard Deviation 10.61 |
Primary
Nerve Conduction Study - Distal Latency
Motor nerve conduction studies are used to examine conduction of electrical impulses along nerves. Electrodes are placed on the skin in specific areas to evaluate peripheral nerves. An electrode stimulates a nerve while the receiving site records how well electrical impulses are being conducted along the nerve. Latency is the time it takes in milliseconds (ms) for the electrical impulse to travel to the site receiving the stimulation.
Time frame: Baseline, Month 12, Month 24
Population: Participants withdrew from the study prior to completing any follow-up study visits.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Non-invasive Vagus Nerve Stimulation (nVNS) | Nerve Conduction Study - Distal Latency | Baseline | 4.8 ms | Standard Deviation 0.28 |
Primary
Nerve Conduction Study - F Wave Latency
Motor nerve conduction studies are used to examine conduction of electrical impulses along nerves. Electrodes are placed on the skin in specific areas to evaluate peripheral nerves. An electrode stimulates a nerve while the receiving site records how well electrical impulses are being conducted along the nerve. F wave latency is the time it takes in milliseconds (ms) for an electrical signal to travel from the stimulating electrode to the distal muscle and back to the stimulating site. F waves are used to assess polyneuropathy and F wave latency can be extended or even absent in persons with CIDP.
Time frame: Baseline, Month 12, Month 24
Population: F wave latency was not performed for one participant at the baseline visit. Participants withdrew from the study prior to completing any follow-up study visits.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Non-invasive Vagus Nerve Stimulation (nVNS) | Nerve Conduction Study - F Wave Latency | Baseline | 20.12 ms |
Primary
Rasch-built Overall Disability Scale (R-ODS) for CIDP Score
The Rasch-built Overall Disability Scale (R-ODS) used for those with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and gammopathy-related polyneuropathy (MGUSP) is a 24-item scale asking respondents to rate how greatly polyneuropathy impacts activities. Responses are given on a scale of 0 to 2 where 0 indicates it is not possible for the respondent to perform the task and 2 means that the task can be performed without difficulty. Total scores range from 0 to 48 and higher scores indicate greater ability to perform daily and social tasks.
Time frame: Baseline, Month 6, Month 12, Month 18, Month 24
Population: Participants withdrew from the study prior to completing any follow-up study visits.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Non-invasive Vagus Nerve Stimulation (nVNS) | Rasch-built Overall Disability Scale (R-ODS) for CIDP Score | Baseline | 45.5 score on a scale | Standard Deviation 2.12 |
Secondary
Interleukin (IL)-1β
The impact of treatment on serum cytokine profiles will be assessed by measuring IL-1β. Serum cytokine levels will be statistically analyzed on a per patient basis, with each patient's baseline measurements used for comparison. IL-1β is elevated in CIDP patients and a decrease in IL-1β values is an indication of effective treatment.
Time frame: Baseline, Month 6, Month 12, Month 18, Month 24
Population: One participant had a IL-1β value at baseline that was below the limit of detection (\<6.5 pg/mL) so the observation for this participant is not included as a summary score cannot be calculated. Participants withdrew from the study prior to completing any follow-up study visits.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Non-invasive Vagus Nerve Stimulation (nVNS) | Interleukin (IL)-1β | Baseline | 13.4 pg/mL |
Secondary
Tumor Necrosis Factor (TNF)-α
The impact of treatment on serum cytokine profiles will be assessed by measuring TNF-α. Serum cytokine levels will be statistically analyzed on a per patient basis, with each patient's baseline measurements used for comparison. TNF-α is elevated in CIDP patients and a decrease in serum TNF-α is an indication of effective treatment.
Time frame: Baseline, Month 6, Month 12, Month 18, Month 24
Population: One participant had TNF-α value at baseline that was below the limit of detection (\<1.7 pg/mL) so the observation for this participant is not included as a summary score cannot be calculated. Participants withdrew from the study prior to completing any follow-up study visits.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Non-invasive Vagus Nerve Stimulation (nVNS) | Tumor Necrosis Factor (TNF)-α | Baseline | 2.9 picograms per milliliter (pg/mL) |