Scrambler Trial for Pain in NMOSD

Study Overview
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Brief Summary
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A novel technology called Scrambler Therapy is a non-invasive pain modifying technique that utilizes transcutaneous electrical stimulation of C fibers with the intent of re-organizing maladaptive signaling pathways. This neuromodulatory therapy has been investigated for treatment of chronic neuropathic pain in several conditions including chemotherapy-induced peripheral neuropathy, post-herpetic neuralgia and post-surgical neuropathic pain with promising results. Patients report sustained relief after undergoing daily treatment sessions for 10 consecutive weekdays. This study is a randomized single blinded, sham-controlled trial of patients with Neuromyelitis Optica Spectrum Disorder who have central neuropathic pain using Scrambler Therapy added to standardized empiric medications using patient reported outcomes to determine if Scrambler Therapy is a feasible and effective add-on treatment of chronic neuropathic pain. This trial will recruit twenty-two adult patients diagnosed with NMOSD who have chronic neuropathic pain despite empiric treatment with an anti-epileptic, antidepressant, opioid and/or an NSAID medication. Patients will be randomized 1:1 to undergo Scrambler Therapy or blinded sham daily for 10 days. The primary outcomes will be acceptability and feasibility. The secondary outcome will be efficacy measured as a change in pain scores of more than two points recorded daily by the patient using an 11-point visual analog scale; quality of life (QoL), neurologic function, anxiety, depression, sleep disturbance and pain will also be evaluated at baseline, at the end of therapy, and at 4 & 8 weeks following completion of treatment. Investigators hypothesize that Scrambler Therapy will be an acceptable, feasible and efficacious intervention that significantly reduces pain in patients with neuromyelitis optica spectrum disorder.

Detailed Description
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Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease of the central nervous system that disproportionately affects non-Caucasians and females,1,2 and has a worldwide prevalence estimated to be 0.52 to 4.4/100,000.3 NMOSD preferentially causes recurrent inflammatory attacks in the optic nerves and spinal cord, leading to blindness, paralysis and death. Despite these devastating consequences of the disease, patients have reported that pain is among the most prevalent and debilitating symptom, and impacts mood, mobility and quality of life (QoL). In particular, central neuropathic pain (CNP) is pervasive, severe, intractable to treatment, and affects 62-91% of patients with NMOSD. CNP is described as agonizing burning, stabbing, shooting, tingling or squeezing sensation that is distressing, persistent and incapacitating.13,14 The presence of CNP in NMOSD is a direct consequence of targeted immune-mediated destruction of the spinal cord and may be influenced by lesion span and location: NMOSD lesions are generally transverse, involving both the central gray matter and dorsal horns. The dorsal horns are innervated by primary ascending fibers that convey sensory information to the brain. Damage to the central gray matter in NMOSD leads to astrocytic damage and tissue necrosis, thus disrupting sensory pain tracts going to and from the brain. As a consequence of ongoing spontaneous activity arising in the periphery, surviving neurons develop increased background activity and increased responses to ascending nerve impulses, including normally harmless tactile stimulation. An additional mechanism of CNP involves peripheral sensitization of non-myelinated ascending C fibers interpreted by the brain as persistent pain, a characteristic sign of an inflammatory process in the spinal cord. Spinal CNP typically presents weeks to months after the cord damage has occurred, long after the acute injury, and may be the result of secondary changes due to reorganization of damaged circuits of the somatosensory system. CNP occurs at and below the spinal cord lesion level, and can persist for years, decades or throughout the patient's life. As with neuropathic pain from other etiologies, the most frequently-used medications for its treatment in NMOSD are anti-epileptics, antidepressants and non-steroidal anti-inflammatory agents. Descriptive studies in NMOSD recognized the inadequate effect of these medications, resulting in frequent breakthrough opioid use. Furthermore, side effects from these medications, particularly at higher doses, are independently associated with fatigue. Scrambler is a type of transcutaneous electrostimulation (TENS) that uses peripheral nerve stimulation to modify ascending sensory responses in the spinal cord. Electrical impulses are transmitted via surface electrodes placed surrounding the pain area. Traditional TENS units take advantage of the Gate Control Theory in which stimulation of surrounding A-delta fibers dampens incoming pain signals. Scrambler therapy provides additional stimulation of ascending sensory C fibers that imitate normal nerve action potentials with the intent of re-organizing maladaptive signaling pathways. The theory behind Scrambler treatment is that scrambled waveforms - instead of repetitive identical waveforms in traditional TENS - are dynamically assembled into strings of information that are interpreted by the brain to replace pain with no-pain information. In contrast to traditional TENS therapy that provides only short term pain relief, studies with Scrambler therapy in peripheral neuropathy suggest that patients can have significantly reduced pain or be pain-free for up to 3 months following a series of treatments, and that follow-up treatments may require fewer sessions for continued relief. This study is a randomized single blinded, sham-controlled trial of patients with Neuromyelitis Optica Spectrum Disorder who have central neuropathic pain using Scrambler Therapy added to standardized empiric medications using patient reported outcomes to determine if Scrambler Therapy is a feasible and effective add-on treatment of chronic neuropathic pain. This trial will recruit twenty-two adult patients diagnosed with NMOSD who have chronic neuropathic pain despite empiric treatment with an anti-epileptic, antidepressant, opioid and/or an NSAID medication. Patients will be randomized 1:1 to undergo Scrambler Therapy or blinded sham daily for 10 days. The primary outcomes will be acceptability and feasibility. The secondary outcome will be efficacy measured as a change in pain scores of more than two points recorded daily by the patient using an 11-point visual analog scale; quality of life (QoL), neurologic function, anxiety, depression, sleep disturbance and pain will also be evaluated at baseline, at the end of therapy, and at 4 & 8 weeks following completion of treatment. Investigators hypothesize that Scrambler Therapy will be an acceptable, feasible and efficacious intervention that significantly reduces pain in patients with neuromyelitis optica spectrum disorder.

Official Title
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Phase II, Randomized, Single Blind Sham Controlled Trial Investigating Scrambler Therapy for Neuropathic Pain Caused by Neuromyelitis Optica Spectrum Disorder

Conditions
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Neuromyelitis Optica

Intervention / Treatment
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* Device: Scrambler
* Device: Scrambler Sham Control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be 18 years of age or older Have the presence of persistent CNP rated at a level of 4 or higher on an 11-point numeric rating scale (NRS); persistent pain is defined as presence for >3 months Patients must be stable in their disease, such that they have had no spinal cord relapses with the last 6 months Patients may use any combination of standard of care medications for pain treatment, to include anti-epileptic, antidepressant, opioid or non-steroidal anti-inflammatory medications, with no adjustments to the regimen within 30 days of enrollment. Aquaporin-4 (AQP4)-antibody positive or negative, or untested, but otherwise meeting criteria for diagnosis of NMOSD. Exclusion Criteria: A concomitant diagnosis of peripheral neuropathy An ongoing concomitant central neurologic disorder Pain that is referable to a spinal cord lesion that starts above the 4th vertebral disc of the cervical spinal cord because FDA device clearance allows for treatment below the neck Use of an investigational agent for pain control within 30 days of enrollment Pregnant or breastfeeding women Those with cognitive or mental incompetency Patients with implantable devices

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Scrambler<br>This arm will receive the Scrambler intervention for 1 hour daily x10 days. | Device: Scrambler<br>* Scrambler is a non-invasive pain modifying technique that utilizes transcutaneous electrical stimulation of nociceptive fibers with the intent of re-organizing maladaptive signaling pathways which has been investigated for treatment of peripheral neuropathy.<br>* Other names: CALMARE;|
| Sham Comparator: Sham-Control<br>This arm will receive the Sham-Control intervention for 1 hour daily x10 days. | Device: Scrambler Sham Control<br>* Sham control should be indistinguishable to the participants from experimental Scrambler therapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acceptability as Assessed by the Number of Participants Responding Yes to a Question | Will be determined by how many participants say yes to the following question, Would you want to continue the treatment if it were available? | 10 days | 
| Feasibility as Assessed by Number of Participants That Completed Treatment Visits | Adherence to visit schedule will be determined by the number of participants that completed the 10 treatment visits. | 10 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Pain Level | Change in NRS pain score (score ranges from 1 to 10 with 1 being No pain and 10 being Worst pain) will be calculated by subtracting the patient's Day 10 pain score (end of treatment) from his or her baseline value. | Baseline, 10 days | 
| Change in Pain Level | Change in NRS pain score (score ranges from 1 to 10 with 1 being No pain and 10 being Worst pain) will be calculated by subtracting the patient's Day 10 pain score (end of treatment) from his or her baseline value. | Baseline, 30 days | 
| Change in Pain Level | Change in NRS pain score (score ranges from 1 to 10 with 1 being No pain and 10 being Worst pain) will be calculated by subtracting the patient's Day 10 pain score (end of treatment) from his or her baseline value. | Baseline, 60 days |