Study of PEMF to Evaluate VPT and Thermal Sensory in Subjects With Diabetic Peripheral Neuropathy

Study Overview
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Brief Summary
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A study to demonstrate the effectiveness of PEMF treatment compared to sham treatment in changing Vibration Perception Threshold (VPT) and Thermal Sensory (QST) in patients with diabetic peripheral neuropathy (DPN) when treatment is administered twice daily through 120-day period.

Detailed Description
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Multi-center, sham-controlled, double-blind, enriched enrollment, randomized withdrawal clinical trial conducted on subjects with bilateral symmetrical diabetic peripheral neuropathy. Eligible subjects will include those between 22 and 80 years of age with Type 1 or Type 2 diabetes having persistent pain, numbness, tingling, or burning in both feet despite treatment. Eligible subjects will receive two active treatment devices (one for each foot, to allow simultaneous treatment) and treat at home, twice daily for 60 days after which they will return to the clinic at Day 61 for a response assessment. Subjects that are determined to be responders at Day 61 (subjects that achieve a 1-point decrease in the average pain score over the last 24 hours using the Numeric Pain Rating Scale (NPRS)) will be randomized 1:1 to either active treatment or inactive sham devices and will continue treating through Day 120. Subjects that are determined to be non-responders at Day 61 will continue treating with the active devices given at enrollment and will return to the clinic at Day 75 and Day 91 for a response assessment. If a subject is determined to be a responder at Day 75, they will be randomized 1:1 to receive either active treatment or inactive sham and will continue treating through Day 120. If a subject is determined to be a responder at Day 91, they will be randomized 1:1 to receive either active treatment or sham and will continue to treat through Day 120. If a subject continues to be a non-responder at Day 91 they will be terminated from the study.

Official Title
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A Multi-Center, Sham-Controlled, Double-Blind Randomized Withdrawal Study of PEMF Therapy to Evaluate Vibration Perception Threshold and Thermal Sensory in Subjects With Diabetic Peripheral Neuropathy in the Lower Extremity

Conditions
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Diabetic Peripheral Neuropathy

Intervention / Treatment
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* Device: Active Provant Therapy System
* Device: Inactive (sham) Provant Therapy System


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject age is greater than or equal to 22 years and less than 80 years of age. Subject has documented Type 1 or Type 2 diabetes mellitus (receiving insulin, diet controlled, or taking parenteral hypoglycemic agents) Subject is on a stable antidiabetic regimen (medication and/or diet) to control their diabetes for at least 30 days prior to Screening. Subject has an HbA1c <10% at Screening or within 2 months of Screening. Subject has daily pain attributed to bilateral symmetrical Diabetic Peripheral Neuropathy with numbness, tingling, and/or burning based on clinical judgement for at least 6 months prior to screening. Subject's pain or discomfort from DPN is identifiable. Subject is in pain Phase 2, 3, or 4 as per the Phasing of Neuropathy Scale. Subjects average pain over the last 24 hours is ≥3 based on the 11-point Numeric Pain Rating Scale (NPRS) at the Screening Visit. Subject has adequate lower extremity pulse in both feet and no intermittent claudication. Subject is able to ambulate independently without assistive devices. Subject is willing and able to give written informed consent and to comply with all parts of the study protocol. Female subjects must be post-menopausal, surgically sterile, abstinent, or practicing (or agrees to practice) an effective method of birth control if they are sexually active for the duration of the study (Effective methods of birth control include prescription hormonal contraceptives, intrauterine devices, double-barrier methods, and/or male partner sterilization). Exclusion Criteria: Subject is in pain Phase 1 or 5 as per the Phasing of Neuropathy Scale. Subject has an active, open ulcer on the lower extremities. Subject has peripheral vascular disease defined as absence of more than one foot pulse per foot and/or ABI <0.8 and >1.4 and/or history of angioplasty or peripheral bypass surgery within 6 months of the Screening Visit. Subject has venous insufficiency as classified by the Venous Insufficiency Classification System of grade C6. Subject has undergone nerve decompression surgery on the lower extremities. Subject has a history of previous kidney, pancreas, cardiac transplantation, or severe renal disease. Subject has been diagnosed with non-diabetic chronic inflammatory neuropathic disease (e.g. end stage renal disease, hepatitis C, chemotherapy induced neuropathy, known connective tissue disease, systemic lupus). Subject has peripheral vascular disease requiring revascularization of lower limb or amputation or evidence of ulcer amputation. Subject has clinically significant cardiovascular disease within 6 months prior to screening (unstable or poorly controlled hypertension, transient ischemic attack, MI, unstable angina, arrhythmia, any heart surgery, stent placement, heart disease). Subject has a history of any uncontrolled medical illness that in the Investigators judgment places the subject at unacceptable risk for receipt of PEMF therapy. Subject requires or anticipates the need for surgery of any type or travel during the treatment period. Subject has a total foot depth (most inferior aspect of the medial malleolus to the plantar aspect of the foot when residing on a treatment pad) of >8 cm. Subject has received any investigational drug or device within 30 days prior to the Screening Visit or within 6 weeks prior to the Screening Visit for long acting lidocaine injection products. Subject has used systemic corticosteroids within 3 months of the Screening Visit. Subject has a history of malignancy within the past 5 years other than successfully treated non-metastatic basal cell or squamous cell carcinomas of the skin in the treatment area and/or localized in situ carcinoma of the cervix. Subject has a serious psychosocial co-morbidity. Subject has a history of drug or alcohol abuse, as confirmed by urine drug screen, within one year prior to the Screening Visit. Subject has an implanted pacemaker, defibrillator, neurostimulator, spinal cord stimulator, bone stimulator, cochlear implant, or other implanted device with an implanted metal lead(s). Subject is currently pregnant or planning on becoming pregnant prior to Day 121. Subject has previously treated with PROVANT® Therapy System within 60 days on the lower extremity. Subject is unwilling or unable to follow study instructions or comply with the treatment regimen, diary documentation, and study visits. Subject has pain from any other source that can confuse the assessment of the pain associated with DPN. Subject has a clinically significant foot deformity (Charcot's syndrome or club foot). Subject has received nerve blocks for neuropathic pain within 4 weeks of the Screening Visit. Subject has been diagnosed with mononeuropathy. Subject has a skin condition that could alter their sensation. Subject has had a previous surgery to the spine or lower extremity with residual symptoms of pain or difficulty with movement. Subject has moderate or severe arthropathy (RA, OA, Gout) that causes discomfort during casual walking or stair climbing.

Ages Eligible for Study
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Minimum Age: 22 Years
Maximum Age: 80 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
Interventional Model Description: Subjects deemed responders after active treatment will be randomized in a 1:1 ratio to either active treatment or a sham device.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active Group<br>Treatment with active Provant Therapy System | Device: Active Provant Therapy System<br>* Treatment with active Provant Therapy System<br>|
| Sham Comparator: Sham Group<br>Treatment with Inactive (sham) Provant Therapy System | Device: Inactive (sham) Provant Therapy System<br>* Treatment with Inactive (sham) Provant Therapy System<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vibration Perception Threshold (VPT) | A non-invasive test used in quantifying sensation/sensitivity to vibration in evaluating sensory dysfunction associated with diabetic neuropathy | Baseline to End of Treatment (Day 121) | 
| Quantitative Sensory Testing (QST) | QST is a noninvasive test used in peripheral nervous system disorders for thermal sensory testing. | Baseline to End of Treatment (Day 121) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nerve Conduction Velocity (NCV) - Velocity | NC-stat® DPNCheck® will be used to record NCV at Baseline and Day 121. Outcome Measure Data table displays change in NCV from Baseline to Day 121. | The sural nerve conduction velocity will be recorded at the Enrollment Visit and end of study visit (Day 121). | 
| Skin Perfusion Pressures (SPP) | The Vasamed Sensilase PAD-IQ will be used to record SPP. This machine measures pressure (in mm Hg) of microcirculation using a laser Doppler sensor. Outcome Measure Data Table below displays change from Baseline to Day 121. | SPP will be conducted at the Enrollment Visit, Day 61, and end of study visit (Day 121). | 
| Pain Intensity (PI) | Mean change from Baseline to Day 121, using a validated 11-point Numeric Pain Rating Scale (NPRS) with scores 0-10, where 0 = no pain and 10 = worst possible pain. | Collected as patient-reported outcomes on a paper diary and at the Enrollment visit to obtain a baseline value and on Days 61, 75, and 91 | 
| Brief Pain Inventory (BPI); Question on Pain Right Now. | The BPI long form will be administered at the Enrollment Visit, Day 30, 61, 91, and end of study visit (Day 121). Results for question #15 on Pain Right Now displayed below. Subject were asked to rate pain right now on a scale from 0 (no pain) to 10 (pain as bad as you can imagine). | Change in BPI, pain right now question, from Baseline to Day 121. | 
| Brief Fatigue Inventory (BFI) | A 4-question assessment that assesses the level of fatigue and the impact of the fatigue on daily function over the last 24 hours. BFI is patient reported and collected at the Enrollment Visit, Days 30, 61, 91, and end of study visit (Day 121). A global fatigue score was calculated by averaging all of the values on the questionnaire and results for the change from Baseline to Day 121 are displayed below. The scale ranged from 0 (no fatigue/does not interfere) to 10 (as bad as you can imagine/completely interferes). | Change from Baseline to Day 121 in BFI. | 
| Patient Global Impression of Change (PGIC) | A 7-choice validated categorical scale of overall change in status since initiation of treatment with the study device.PGIC was collected every 7 days in the paper diary, immediately following the morning treatment. Subjects were asked: Since the start of the study, my overall status is? Choices on the scale included: Very much worse, much worse, minimally worse, no change, minimally improved, much improved and very much improved. | PGIC results at Day 121 displayed below. | 
| Hospital Anxiety and Depression Scale (HADS) | A patient reported 14 question assessment that detects the status of depression and anxiety. Subjects completed the assessment at the Enrollment Visit, Days 30, 61, 91, and end of study visit (Day 121). The total score for anxiety and the total score for depression was calculated at Day 121. Low scores represent normal (0-7) while high scores represent abnormal (11-21). | Change in Depression and Anxiety from Baseline to Day 121. | 
| Neuro-QoL | A validated set of health-related quality of life measures that are domain specific.Subjects will completed 6 domains: (1) Pain, (2) Lost/Reduced Feeling, (3) Diffuse Sensory Motor Symptoms, (4) Restrictions in Activities of Daily Living, (5) Disruptions in Social Relationships, and (6) Emotional Distress.The short forms were completed by the subject at the Enrollment Visit and end of study visit (Day 121). Each question in the domain was rated on a symptom scale from 1 (never) to 5 (all the time) and a bothersome scale from 1 (none) to 3 (very much). The total score for the domain was calculated by multiplying the symptom score by the bothersome score. The scale range is from 1 to 15 where the minimum (best/least symptomatic) score is 1 and the maximum (worst/most symptomatic) score is 15. | Change in each domain from Baseline to Day 121 is displayed below. | 
| Nerve Conduction Velocity (NCV) - Amplitude | NC-stat® DPNCheck® will be used to record NCV at Baseline and Day 121. Outcome Measure Data table displays change in NCV from Baseline to Day 121. | The sural nerve conduction amplitude will be recorded at the Enrollment Visit and end of study visit (Day 121). |