RELIEF: Dual Field PEMF Therapy in Lower Extremity Painful Diabetic Distal Symmetric Peripheral Neuropathy

• Sponsor: Regenesis Biomedical, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03455543
• Collaborator: (none)
• Enrollment: 182
• Locations: 18
• Arms: 2
• Actual Duration (Months): 15.7
• Patients Per Site: 10.1
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

Part A of this trial is a multi-center, prospective, double-blinded, sham-controlled, randomized clinical trial. Part A will evaluate PEMF treatment compared to sham treatment in patients with painful diabetic distal symmetric peripheral neuropathy (DSPN) when treatment is administered 30 minutes twice daily through a 120-day period (4 months). Part B is a 8-month open-label active treatment extension period designed to collect longer-term data on pain, medication use, quality of life and safety (Part B).Part B of this trial is a an extension period upon completion of Part A.

Condition or Disease	Intervention/Treatment	Phase
Diabetic Neuropathy Peripheral	Device: Active Provant Therapy System; Device: Inactive (sham) Provant Therapy System	N/A

Detailed Description

Eligible subjects will be entered into a 14-day ePRO diary run-in period to collect average baseline pain scores related to their diabetic neuropathy in the lower extremities, diary compliance, and analgesic consumption (maintenance and prn prescribed peripheral neuropathic pain medication pill counts). Subjects will collect electronic patient-reported outcome (ePRO) data each morning around the same time during the run-in period.

Subjects will return to the clinic at Baseline (Day 0) for review of eligibility, diary compliance, average baseline diabetic neuropathic pain score of ≥4 and <9, and review of stable analgesic pain consumption profile during the 14-day run-in period. Qualified subjects based on diary compliance and average pain score will be randomized 1:1 (active: sham) and will be instructed to self-treat twice daily for 120 days. Subjects will record electronic patient-reported outcome (ePRO) data following each morning treatment for 120 days. Subjects consenting to distal thigh and distal leg skin biopsies during the Screening visit will have biopsies collected and sent to the central laboratory for assessment. All subjects will have baseline assessments conducted.

Subjects will receive a telephone call at Day 7 to ensure compliance to treatment and diary completion, provide follow-up information on the biopsy sites (if applicable), complete a blinding assessment as well as be assessed for safety and concomitant medication changes.

At Month 1 subjects will return to the clinic for evaluation of safety, concomitant medication changes, review device usage and ePRO diary completion, and Patient Global Impression (PGI). Treatment satisfaction will also be assessed.

At Month 2 subjects will return to the clinic for evaluation of safety, concomitant medication changes, treatment satisfaction, review of device usage (reports will be supplied to the site) and ePRO diary completion, quality of life outcomes (WPAIQ and NeuroQoL), Patient Global Impression (PGI), and interim visit measurements of SPP.

At Month 3, subjects will return to the clinic for evaluation of safety, concomitant medication changes, review device usage (reports will be supplied to the site) and ePRO diary completion, and Patient Global Impression (PGI). Treatment satisfaction will also be assessed.

At Month 4 (end of Part A / start of Part B), subjects will return to the clinic for evaluation of safety, treatment satisfaction, review of device usage (reports will be supplied to the site), HbA1c, concomitant medication changes, weight, quality of life outcomes (WPAIQ and NeuroQoL), PGI, final measurements of SPP, NCS, QST and be assessed to determine their Toronto Clinical Neuropathy Score. Those subjects who consented and had biopsies collected at the Enrollment visit, will have their end of study biopsies during this visit and samples sent directly to the central laboratory for assessment. Subjects will return the study device and complete a blinding assessment.

Subjects that complete Part A will continue into the open-label extension period (Part B). All subjects will be reconsented if not completed at a prior visit and given an open-label active device. Subjects will record ePRO data for one week prior to the Month 6, 8, 10, and 12 visits following each morning treatment. Subjects will be reminded of the150-day (Month 5) phone call.

At Month 5, subjects will receive a telephone call to ensure compliance to treatment, and to be assessed for safety and concomitant medication changes.

At Month 6, subjects will receive a telephone call to ensure treatment compliance and collection of diary data, and to assess safety and concomitant medication changes.

At Month 7, subjects will receive a telephone call to ensure treatment compliance, and to assess safety and concomitant medication changes.

At Month 8, subjects will return to the clinic for evaluation of safety, measure QST, treatment satisfaction, review of device usage and collection of diary data, concomitant medication changes, quality of life outcomes (NeuroQoL), and PGI.

At Month 9, subjects will receive a telephone call to ensure treatment compliance, and to assess safety and concomitant medication changes.

At Month 10, subjects will receive a telephone call to ensure treatment compliance and collection of diary data, and to assess safety and concomitant medication changes.

At Month 11, subjects will receive a telephone call to ensure treatment compliance, and to assess safety and concomitant medication changes.

At Month 12 (end of open-label treatment extension), subjects will return to the clinic for evaluation of safety, weight, QST, NCS, TCNSS, PGI, treatment satisfaction, review of device usage and collection of diary data, concomitant medication changes, quality of life outcomes (NeuroQoL), and will return the study device. Subjects who consented and had biopsies collected at the 4 Month visit, will have their end of study biopsies performed during this visit.

Study Design

• Study Type: Interventional
• Actual Enrollment: 182 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Two parallel groups, active device group versus sham device group. Subjects will be randomized 1:1 at baseline and treat with active PEMF or sham for 4 months.Two parallel groups, active device group versus sham device group. Subjects will be randomized 1:1 at baseline and treat with active PEMF or sham for 4 months.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Active and sham devices will look identical. Participants and site staff will be blind to the randomization.
• Primary Purpose: Treatment
• Official Title: A Multi-Center, Double-Blind, Sham-Controlled, Randomized Trial of Dual Field PEMF Therapy [Provant® Therapy System] in Lower Extremity Painful Diabetic Distal Symmetric Peripheral Neuropathy (DSPN) (The RELIEF Trial)
• Actual Study Start Date: Mar 26, 2018
• Actual Primary Completion Date: Nov 14, 2018
• Actual Study Completion Date: Jul 18, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Active Group Treatment with active Provant Therapy System	Device: Active Provant Therapy System; Treatment with active Provant Therapy System
Sham Comparator: Sham Group Treatment with in-active (sham) Provant Therapy System	Device: Inactive (sham) Provant Therapy System; Treatment with inactive Provant Therapy System

Outcome Measures

Primary Outcome Measures

1. Change in Pain Intensity [Baseline through 4 months]

   Absolute change in pain intensity as measured by the 11-point, numerical pain rating scale (NPRS) (0-10; where 0=no pain, to 10=worst possible pain).

Secondary Outcome Measures

1. Patients With 2 Point or 30% Reduction in Pain at 4 Months [Baseline to 4 months]

   Percentage of patients who have either a 2 point or 30% reduction in (pain) NPRS at 4 Months. Absolute change in pain intensity as measured by the 11-point, numerical pain rating scale (NPRS) (0-10; where 0=no pain, to 10=worst possible pain).

2. Patient Global Impression at 4 Months [Baseline through 4 months.]

   Patient Global Impression at 4 Months. The question assesses change since the start of the study on a 7-point scale ("Since the start of the study, how has your diabetic neuropathy in your legs changed?"), and to score it as either very much worse, much worse, minimally worse, no change, minimally improved, much improved or very much improved.

3. Time to 30% or 2-point Reduction in NPRS, Whichever Comes First, Through 4 Months [Through 4 months]

   Absolute change in pain intensity as measured by the 11-point, numerical pain rating scale (NPRS) (0-10; where 0=no pain, to 10=worst possible pain). Number of participants achieving a 30% or 2-point reduction at or prior to weeks 1, 4, 8, 12 and 17 are displayed below.

4. Change in Neuropathy Related Quality of Life (NeuroQoL) Between Baseline and End of Treatment at 4 Months. [Baseline to 4 months]

   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. The mean change from Baseline to month 4 is displayed below.

5. Change is Skin Perfusion Pressure (SPP) for Baseline to End of Treatment at 4 Months [Baseline to 4 months]

   SPP was measured at two locations on each foot (dorsal right and left and plantar right and left). Mean change displayed from Baseline to 4-months displayed below. SPP measures pressure in mmHg; an increase in pressure is favorable. Normal SPP: 50 mmHg to 100 mmHg Marginal Ischemia SPP: 30 mmHg to 50 mmHg Critical Limb Ischemia / PAD SPP: < 30 mmHg

6. Changes in Nerve Conduction Studies of Velocity Between Baseline and End of Treatment at 4 Months. [Baseline to 4 Months]

   Using the NC-stat DPNCheck, the sural nerve conduction velocity was recorded on the right and left legs. An increase in velocity would suggest DPN improvement. The mean change from Baseline to 4-months is displayed below.

7. Changes in Quantitative Sensory Testing (QST) Between Baseline and End of Treatment at 4 Months. [Baseline to 4 months]

   Contact thermal stimulation will be delivered using the Medoc Ltd. Q-Sense system to assess cool sensation threshold, warm sensation threshold and heat pain threshold modalities using the method of limits. Within the cool and warm sensation modalities, the trial is repeated 4 times on each foot and 3 times on each foot for heat pain threshold modality. The cool thermal testing will be conducted prior to the warm and heat pain thermal testing. Mean change from baseline to 4-months displayed below.

8. Changes in Nerve Conduction Studies of Amplitude Between Baseline and End of Treatment at 4 Months. [Baseline to 4 Months]

   Using the NC-stat DPNCheck, the sural nerve conduction amplitude was recorded on the right and left legs. An increase in amplitude would suggest DPN improvement. The mean change from Baseline to 4-months is displayed below.

Other Outcome Measures

1. Exploratory Endpoint: Changes in the Work Productivity and Activity Impairment Questionnaire (WPAIQ) (Questions 2-4) [Baseline to 4 Months]

   The Work Productivity and Activity Impairment Questionnaire (WPAIQ) is a validated 6 question assessment tool that measures time missed from work, impairment of work and regular activities due to their health problem. Subjects are asked if they are working (Question 1), and if answer is yes, subjects are asked about the effect their diabetic neuropathy (DN) has on their ability to work and perform regular activities in the past 7 days. Mean change from Baseline to 4-months are displayed below (Questions 2-4) for subjects that responded "Yes" to working in Question 1. Questions 2-4 are answered in number of hours.

2. Exploratory Endpoint: Changes in Intraepidermal Nerve Fiber Density (IENFD) at the Distal Thigh and Distal Leg - Part A [Baseline to Month 4]

   Optional two 3 mm punch skin biopsies will be performed at baseline and end of treatment to assess IENFD. At the Enrollment Visit, one biopsy will be obtained at the distal leg, 10 cm above the lateral malleolus on the right leg and a second biopsy will be obtained at the distal thigh, 10 cm above the superior margin of the patella on the lateral right leg. At the end of Part A study visit Month 4 (Day 121), a second set of biopsies will be obtained lateral to the baseline biopsies and shipped overnight to the central lab. For Active Group and Sham Group displayed below, result are the change in nerve fiber density from Baseline to Month 4.

3. Exploratory Endpoint: Change in Pain Intensity During Part B [Baseline through 12 months]

   Absolute change in pain intensity as measured by the 11-point, numerical pain rating scale (NPRS) (0-10; where 0=no pain, to 10=worst possible pain). Results below display the change from Baseline to Month 12 for subjects that participated in the open-label extension (Part B), stratified by their original randomization in Part A.

4. Exploratory Endpoint: Changes in Nerve Conduction Studies of Velocity During Part B [Baseline to Month 12]

   Using the NC-stat DPNCheck, the sural nerve conduction velocity was recorded on the right and left legs. An increase in velocity would suggest DPN improvement. Results below display the mean change in velocity and from Baseline to Month 12 for subjects that participated in the open-label extension (Part B), stratified by their original randomization in Part A.

5. Exploratory Endpoint: Change in Neuropathy Related Quality of Life (NeuroQoL) During Part B [Baseline to Month 12]

   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, end of study visit (Day 121) and at 12 months. 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. Results below display the change from Baseline to Month 12 for subjects that participated in the open-label extension (Part B), stratified by their original randomization in Part

6. Exploratory Endpoint: Changes in Nerve Conduction Studies of Amplitude During Part B [Baseline to Month 12]

   Using the NC-stat DPNCheck, the sural nerve conduction amplitude was recorded on the right and left legs. An increase in amplitude would suggest DPN improvement. Results below display the mean change in amplitude from Baseline to Month 12 for subjects that participated in the open-label extension (Part B), stratified by their original randomization in Part A.

7. Exploratory Endpoint: Changes in the Work Productivity and Activity Impairment Questionnaire (WPAIQ) (Questions 5-6) [Baseline to 4 Months]

   The Work Productivity and Activity Impairment Questionnaire (WPAIQ) is a validated 6 question assessment tool that measures time missed from work, impairment of work and regular activities due to their health problem. Subjects are asked if they are working (Question 1), and if answer is yes, subjects are asked about the effect their diabetic neuropathy (DN) has on their ability to work and perform regular activities in the past 7 days. Mean change from Baseline to 4-months displayed below (Questions 5-6) for subjects that responded "Yes" to working in Question 1. Questions 5 and 6 use a 0-10 scale where 0 = no effect on work and/or daily activities and 10 =DN completely prevented me from working and/or doing daily activities.

8. Exploratory Endpoint: Changes in Intraepidermal Nerve Fiber Density (IENFD) at the Distal Thigh and Distal Leg - Part B [Baseline to Month 12]

   Optional two 3 mm punch skin biopsies will be performed at baseline and end of treatment to assess IENFD. At the Enrollment Visit, one biopsy will be obtained at the distal leg, 10 cm above the lateral malleolus on the right leg and a second biopsy will be obtained at the distal thigh, 10 cm above the superior margin of the patella on the lateral right leg. At the end of Part A study visit Month 4 (Day 121), a second set of biopsies will be obtained lateral to the baseline biopsies and shipped overnight to the central lab. At the end of Part B study visit Month 12 (Day 361), a final set of biopsies will be obtained lateral to the Month 4 biopsies. Results displayed are the change in nerve fiber density from Baseline to Month 12 for subjects that participated in the open-label extension (Part B), stratified by their original randomization in Part A.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 22 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Type 1 or Type 2 diabetes

• Pain attributed to symmetrical lower extremity diabetic peripheral neuropathy for at least 6 months

• DPN pain over the preceding 24 hours is ≥4 and <9 based on the 11-point NPRS (0-10)

• 22 to 80 years of age

• On stable diabetes treatment

• HbA1c less than or equal to 10%

• No recent changes to analgesic prescriptions

• ABI of ≥0.8 to ≤1.3

• Walks independently

• Willing and able to give consent

• If female, must be post-menopausal, surgically sterile, abstinent or practicing an effective method of birth control

• Can access an internet browser or smart phone

To be randomized after the 14-day run-in period, average pain (NPRS) must be ≥ 4 and < 9 over preceding 7 days and subject must be 70% compliant with ePRO assessments (electronic diary)

Exclusion Criteria:

• Active, open ulcer on either extremity

• Significant peripheral vascular disease

• Venous insufficiency

• History of solid organ transplant or severe renal disease

• Diagnosed with a non-diabetic cause of chronic neuropathy

• Previous or current history of primary or tertiary hyperparathyroidism, hypercalcemia, psychiatric disorder, alcohol dependency, Hepatitis B or C, or HIV infection

• Significant cardiovascular disease

• Uncontrolled medical illness

• Requires or anticipates the need for surgery during the study

• Total foot depth of >8 cm

• Has received any investigational drug or device within 30 days

• Has used systemic corticosteroids within 3 months

• History of malignancy within 5 years in treatment area

• A psychiatric disorder of sufficient severity

• Receiving prn narcotic medications

• History of drug or alcohol abuse within 1 year

• Implanted pacemaker, defibrillator, neurostimulator, spinal cord stimulator, bone stimulator, cochlear implant, or other implanted device with an implanted metal lead(s0

• Pregnant or planning to become pregnant

• Previous treatment with Provant Therapy

• Unwilling to follow instructions or comply with study instructions

• Pain from any other source that could confuse DPN pain assessment

• Clinically significant foot deformity

• Skin condition that could alter peripheral sensations

• Previous surgery to the spine or lower extremity with residual symptoms of pain or difficulty with movement.

• Clinically significant arthropathy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Physician's Research Group	Mesa	Arizona	United States	85206
2	Valley Clinical Research	Northridge	California	United States	91325
3	Northern California Research	Sacramento	California	United States	95821
4	Diabetes Research Center	Tustin	California	United States	92780
5	Mountain View Clinical Research	Denver	Colorado	United States	80209
6	Lake Internal Medicine Associates	Eustis	Florida	United States	32726
7	Clinical Physiology Associates	Fort Myers	Florida	United States	33912
8	Spotlight Research Center	Miami	Florida	United States	33176
9	Clinical Research of Central Florida	Winter Haven	Florida	United States	33880
10	River Birch Research Alliance, LLC	Blue Ridge	Georgia	United States	30514
11	MediSphere Medical Research Center, LLC	Evansville	Indiana	United States	47714
12	Heartland Research Associate, LLC	Wichita	Kansas	United States	67207
13	Healthcare Research Network	Hazelwood	Missouri	United States	63042
14	The Center for Pharmaceutical Research, LLC	Kansas City	Missouri	United States	64114
15	Palm Research Center	Las Vegas	Nevada	United States	89128
16	Great Lakes Medical Resarch	Westfield	New York	United States	14787
17	Wake Family Medicine, PC	Cary	North Carolina	United States	27513
18	Rainier Clinical Research	Renton	Washington	United States	98057

Sponsors and Collaborators

• Regenesis Biomedical, Inc.

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jul 17, 2018
• Statistical Analysis Plan - Nov 7, 2018

More Information

Publications

None provided.

• Responsible Party: Regenesis Biomedical, Inc.
• ClinicalTrials.gov Identifier: NCT03455543
• Other Study ID Numbers: RBI.2017.002
• First Posted: Mar 6, 2018
• Last Update Posted: Jul 15, 2020
• Last Verified: Jul 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: Yes
• Additional relevant MeSH terms: Peripheral Nervous System Diseases; Diabetic Neuropathies

Study Results

Participant Flow

Pre-assignment Detail	Protocol Sample Size was anticipated at 170 subjects. The original enrollment target of 170 subjects was exceeded to grant study entry to qualified subjects that completed the 14-day run-in period.

Arm/Group Title	Active Group	Sham Group	Open-label Extension Group (Part B)
Arm/Group Description	Treatment with active Provant Therapy System Active Provant Therapy System: Treatment with active Provant Therapy System	Treatment with in-active (sham) Provant Therapy System Inactive (sham) Provant Therapy System: Treatment with inactive Provant Therapy System	Subjects receiving open-label active PEMF therapy in Part B after 17 weeks of randomized treatment in Part A.
Period Title: Part A: Randomized Treatment (17 Weeks)
STARTED	92	90	0
COMPLETED	81	83	0
NOT COMPLETED	11	7	0
Period Title: Part A: Randomized Treatment (17 Weeks)
STARTED	0	0	152
COMPLETED	0	0	115
NOT COMPLETED	0	0	37

Baseline Characteristics

Arm/Group Title	Active Group	Sham Group	Total
Arm/Group Description	Treatment with active Provant Therapy System Active Provant Therapy System: Treatment with active Provant Therapy System	Treatment with in-active (sham) Provant Therapy System Inactive (sham) Provant Therapy System: Treatment with inactive Provant Therapy System	Total of all reporting groups
Overall Participants	92	90	182
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.27 (10.21)	62.17 (9.33)	62.22 (9.76)
Sex: Female, Male (Count of Participants)
Female	50 54.3%	42 46.7%	92 50.5%
Male	42 45.7%	48 53.3%	90 49.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	12 13%	15 16.7%	27 14.8%
Not Hispanic or Latino	80 87%	75 83.3%	155 85.2%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 1.1%	1 0.5%
Asian	3 3.3%	1 1.1%	4 2.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	15 16.3%	14 15.6%	29 15.9%
White	74 80.4%	73 81.1%	147 80.8%
More than one race	0 0%	1 1.1%	1 0.5%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	92 100%	90 100%	182 100%

Outcome Measures

1. Primary Outcome

Title	Change in Pain Intensity
Description	Absolute change in pain intensity as measured by the 11-point, numerical pain rating scale (NPRS) (0-10; where 0=no pain, to 10=worst possible pain).
Time Frame	Baseline through 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Group	Sham Group
Arm/Group Description	Treatment with active Provant Therapy System Active Provant Therapy System: Treatment with active Provant Therapy System	Treatment with in-active (sham) Provant Therapy System Inactive (sham) Provant Therapy System: Treatment with inactive Provant Therapy System
Measure Participants	92	90
Mean (Standard Deviation) [units on a scale]	-1.47 (1.845)	-1.25 (2.018)

2. Secondary Outcome

Title	Patients With 2 Point or 30% Reduction in Pain at 4 Months
Description	Percentage of patients who have either a 2 point or 30% reduction in (pain) NPRS at 4 Months. Absolute change in pain intensity as measured by the 11-point, numerical pain rating scale (NPRS) (0-10; where 0=no pain, to 10=worst possible pain).
Time Frame	Baseline to 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Group	Sham Group
Arm/Group Description	Treatment with active Provant Therapy System Active Provant Therapy System: Treatment with active Provant Therapy System	Treatment with in-active (sham) Provant Therapy System Inactive (sham) Provant Therapy System: Treatment with inactive Provant Therapy System
Measure Participants	92	90
Count of Participants [Participants]	28 30.4%	26 28.9%

3. Secondary Outcome

Title	Patient Global Impression at 4 Months
Description	Patient Global Impression at 4 Months. The question assesses change since the start of the study on a 7-point scale ("Since the start of the study, how has your diabetic neuropathy in your legs changed?"), and to score it as either very much worse, much worse, minimally worse, no change, minimally improved, much improved or very much improved.
Time Frame	Baseline through 4 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Group	Sham Group
Arm/Group Description	Treatment with active Provant Therapy System Active Provant Therapy System: Treatment with active Provant Therapy System	Treatment with in-active (sham) Provant Therapy System Inactive (sham) Provant Therapy System: Treatment with inactive Provant Therapy System
Measure Participants	92	90
Much Worse	1 1.1%	2 2.2%
Minimally Worse	3 3.3%	11 12.2%
No Change	24 26.1%	28 31.1%
Minimally Improved	37 40.2%	23 25.6%
Much Improved	16 17.4%	20 22.2%
Very Much Improved	3 3.3%	3 3.3%
Not reported	8 8.7%	3 3.3%

4. Secondary Outcome

Title	Time to 30% or 2-point Reduction in NPRS, Whichever Comes First, Through 4 Months
Description	Absolute change in pain intensity as measured by the 11-point, numerical pain rating scale (NPRS) (0-10; where 0=no pain, to 10=worst possible pain). Number of participants achieving a 30% or 2-point reduction at or prior to weeks 1, 4, 8, 12 and 17 are displayed below.
Time Frame	Through 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Group	Sham Group
Arm/Group Description	Treatment with active Provant Therapy System Active Provant Therapy System: Treatment with active Provant Therapy System	Treatment with in-active (sham) Provant Therapy System Inactive (sham) Provant Therapy System: Treatment with inactive Provant Therapy System
Measure Participants	92	90
Week 1	4 4.3%	3 3.3%
Week 4	18 19.6%	18 20%
Week 8	32 34.8%	27 30%
Week 12	43 46.7%	34 37.8%
Week 17	45 48.9%	40 44.4%

5. Secondary Outcome

Title	Change in Neuropathy Related Quality of Life (NeuroQoL) Between Baseline and End of Treatment at 4 Months.
Description	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. The mean change from Baseline to month 4 is displayed below.
Time Frame	Baseline to 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Group	Sham Group
Arm/Group Description	Treatment with active Provant Therapy System Active Provant Therapy System: Treatment with active Provant Therapy System	Treatment with in-active (sham) Provant Therapy System Inactive (sham) Provant Therapy System: Treatment with inactive Provant Therapy System
Measure Participants	92	90
(1) Pain	-1.66	-1.52
(2) Lost/Reduced Feeling	-1.03	-1.42
(3) Diffuse Sensory Motor Symptoms	-0.92	-0.79
(4) Restrictions in Activities of Daily Living	-1.66	-2.38
(5) Disruptions in Social Relationships	-1.31	-1.99
(6) Emotional Distress	-1.12	-1.63

6. Secondary Outcome

Title	Change is Skin Perfusion Pressure (SPP) for Baseline to End of Treatment at 4 Months
Description	SPP was measured at two locations on each foot (dorsal right and left and plantar right and left). Mean change displayed from Baseline to 4-months displayed below. SPP measures pressure in mmHg; an increase in pressure is favorable. Normal SPP: 50 mmHg to 100 mmHg Marginal Ischemia SPP: 30 mmHg to 50 mmHg Critical Limb Ischemia / PAD SPP: < 30 mmHg
Time Frame	Baseline to 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Group	Sham Group
Arm/Group Description	Treatment with active Provant Therapy System Active Provant Therapy System: Treatment with active Provant Therapy System	Treatment with in-active (sham) Provant Therapy System Inactive (sham) Provant Therapy System: Treatment with inactive Provant Therapy System
Measure Participants	92	90
Dorsal - Left	-0.25 (34.22)	3.27 (33.82)
Dorsal - Right	-0.74 (35.18)	2.93 (25.83)
Plantar - Left	6.37 (27.72)	-1.84 (28.87)
Plantar - Right	2.12 (21.05)	-2.51 (23.66)

7. Secondary Outcome

Title	Changes in Nerve Conduction Studies of Velocity Between Baseline and End of Treatment at 4 Months.
Description	Using the NC-stat DPNCheck, the sural nerve conduction velocity was recorded on the right and left legs. An increase in velocity would suggest DPN improvement. The mean change from Baseline to 4-months is displayed below.
Time Frame	Baseline to 4 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Group	Sham Group
Arm/Group Description	Treatment with active Provant Therapy System Active Provant Therapy System: Treatment with active Provant Therapy System	Treatment with in-active (sham) Provant Therapy System Inactive (sham) Provant Therapy System: Treatment with inactive Provant Therapy System
Measure Participants	92	90
Velocity (uv) - Left	-4.15 (20.45)	-5.12 (22.25)
Velocity (uv) - Right	-1.11 (18.18)	-5.06 (20.94)

8. Secondary Outcome

Title	Changes in Quantitative Sensory Testing (QST) Between Baseline and End of Treatment at 4 Months.
Description	Contact thermal stimulation will be delivered using the Medoc Ltd. Q-Sense system to assess cool sensation threshold, warm sensation threshold and heat pain threshold modalities using the method of limits. Within the cool and warm sensation modalities, the trial is repeated 4 times on each foot and 3 times on each foot for heat pain threshold modality. The cool thermal testing will be conducted prior to the warm and heat pain thermal testing. Mean change from baseline to 4-months displayed below.
Time Frame	Baseline to 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Group	Sham Group
Arm/Group Description	Treatment with active Provant Therapy System Active Provant Therapy System: Treatment with active Provant Therapy System	Treatment with in-active (sham) Provant Therapy System Inactive (sham) Provant Therapy System: Treatment with inactive Provant Therapy System
Measure Participants	92	90
Cold - Right	0.57 (3.32)	-0.21 (3.07)
Cold - Left	0.08 (3.25)	0.02 (2.85)
Warm - Right	-0.58 (3.70)	-0.54 (4.07)
Warm - Left	-0.53 (4.25)	0.01 (4.41)
Pain - Right	-0.29 (3.21)	-0.75 (3.10)
Pain - Left	-0.62 (3.23)	-0.23 (2.97)

9. Other Pre-specified Outcome

Title	Exploratory Endpoint: Changes in the Work Productivity and Activity Impairment Questionnaire (WPAIQ) (Questions 2-4)
Description	The Work Productivity and Activity Impairment Questionnaire (WPAIQ) is a validated 6 question assessment tool that measures time missed from work, impairment of work and regular activities due to their health problem. Subjects are asked if they are working (Question 1), and if answer is yes, subjects are asked about the effect their diabetic neuropathy (DN) has on their ability to work and perform regular activities in the past 7 days. Mean change from Baseline to 4-months are displayed below (Questions 2-4) for subjects that responded "Yes" to working in Question 1. Questions 2-4 are answered in number of hours.
Time Frame	Baseline to 4 Months

Outcome Measure Data

Analysis Population Description

Includes only subjects that indicated they were working at the Enrollment Visit (Question 1).

Arm/Group Title	Active Group	Sham Group
Arm/Group Description	Treatment with active Provant Therapy System Active Provant Therapy System: Treatment with active Provant Therapy System	Treatment with in-active (sham) Provant Therapy System Inactive (sham) Provant Therapy System: Treatment with inactive Provant Therapy System
Measure Participants	29	18
Work hours missed in past 7 days due to DN	0.12 (2.96)	0.33 (1.89)
Work hours missed in past 7 days not due to DN	0.60 (9.17)	2.61 (9.38)
Hours worked in past 7 days	-0.48 (10.62)	-2.11 (20.80)

10. Other Pre-specified Outcome

Title	Exploratory Endpoint: Changes in Intraepidermal Nerve Fiber Density (IENFD) at the Distal Thigh and Distal Leg - Part A
Description	Optional two 3 mm punch skin biopsies will be performed at baseline and end of treatment to assess IENFD. At the Enrollment Visit, one biopsy will be obtained at the distal leg, 10 cm above the lateral malleolus on the right leg and a second biopsy will be obtained at the distal thigh, 10 cm above the superior margin of the patella on the lateral right leg. At the end of Part A study visit Month 4 (Day 121), a second set of biopsies will be obtained lateral to the baseline biopsies and shipped overnight to the central lab. For Active Group and Sham Group displayed below, result are the change in nerve fiber density from Baseline to Month 4.
Time Frame	Baseline to Month 4

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Group	Sham Group
Arm/Group Description	Treatment with active Provant Therapy System Active Provant Therapy System: Treatment with active Provant Therapy System	Treatment with in-active (sham) Provant Therapy System Inactive (sham) Provant Therapy System: Treatment with inactive Provant Therapy System
Measure Participants	32	38
Right Distal Leg	-0.12 (1.60)	0.73 (2.33)
Right Distal Thigh	0.64 (2.93)	1.68 (2.63)

11. Other Pre-specified Outcome

Title	Exploratory Endpoint: Change in Pain Intensity During Part B
Description	Absolute change in pain intensity as measured by the 11-point, numerical pain rating scale (NPRS) (0-10; where 0=no pain, to 10=worst possible pain). Results below display the change from Baseline to Month 12 for subjects that participated in the open-label extension (Part B), stratified by their original randomization in Part A.
Time Frame	Baseline through 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Group	Sham Group
Arm/Group Description	Treatment with active Provant Therapy System Active Provant Therapy System: Treatment with active Provant Therapy System	Treatment with in-active (sham) Provant Therapy System Inactive (sham) Provant Therapy System: Treatment with inactive Provant Therapy System
Measure Participants	72	80
Mean (Standard Deviation) [units on a scale]	-2.96 (2.38)	2.49 (2.38)

12. Other Pre-specified Outcome

Title	Exploratory Endpoint: Changes in Nerve Conduction Studies of Velocity During Part B
Description	Using the NC-stat DPNCheck, the sural nerve conduction velocity was recorded on the right and left legs. An increase in velocity would suggest DPN improvement. Results below display the mean change in velocity and from Baseline to Month 12 for subjects that participated in the open-label extension (Part B), stratified by their original randomization in Part A.
Time Frame	Baseline to Month 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Group	Sham Group
Arm/Group Description	Treatment with active Provant Therapy System Active Provant Therapy System: Treatment with active Provant Therapy System	Treatment with in-active (sham) Provant Therapy System Inactive (sham) Provant Therapy System: Treatment with inactive Provant Therapy System
Measure Participants	72	80
Velocity (m/s) - Left	-11.9 (26.0)	-8.64 (24.7)
Velocity (m/s) - Right	-9.48 (19.5)	-6.31 (22.9)

13. Other Pre-specified Outcome

Title	Exploratory Endpoint: Change in Neuropathy Related Quality of Life (NeuroQoL) During Part B
Description	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, end of study visit (Day 121) and at 12 months. 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. Results below display the change from Baseline to Month 12 for subjects that participated in the open-label extension (Part B), stratified by their original randomization in Part
Time Frame	Baseline to Month 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Group	Sham Group
Arm/Group Description	Treatment with active Provant Therapy System Active Provant Therapy System: Treatment with active Provant Therapy System	Treatment with in-active (sham) Provant Therapy System Inactive (sham) Provant Therapy System: Treatment with inactive Provant Therapy System
Measure Participants	72	80
(1) Pain	-3.14 (2.33)	-2.88 (3.19)
(2) Lost/Reduced Feeling	-2.42 (2.99)	-1.96 (4.07)
(3) Diffuse Sensory Motor	-1.58 (2.78)	-1.04 (3.41)
(4) Restrictions in Activities	-2.67 (3.61)	-2.14 (4.85)
(5) Distruptions in Social Relationships	-2.25 (3.73)	-1.73 (3.96)
(6) Emotional Distress	-1.60 (3.81)	-1.79 (3.58)

14. Secondary Outcome

Title	Changes in Nerve Conduction Studies of Amplitude Between Baseline and End of Treatment at 4 Months.
Description	Using the NC-stat DPNCheck, the sural nerve conduction amplitude was recorded on the right and left legs. An increase in amplitude would suggest DPN improvement. The mean change from Baseline to 4-months is displayed below.
Time Frame	Baseline to 4 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Group	Sham Group
Arm/Group Description	Treatment with active Provant Therapy System Active Provant Therapy System: Treatment with active Provant Therapy System	Treatment with in-active (sham) Provant Therapy System Inactive (sham) Provant Therapy System: Treatment with inactive Provant Therapy System
Measure Participants	92	90
Amplitude (m/s) - Left	1.27 (9.96)	1.36 (11.63)
Amplitude (m/s) - Right	1.95 (10.27)	1.03 (9.91)

15. Other Pre-specified Outcome

Title	Exploratory Endpoint: Changes in Nerve Conduction Studies of Amplitude During Part B
Description	Using the NC-stat DPNCheck, the sural nerve conduction amplitude was recorded on the right and left legs. An increase in amplitude would suggest DPN improvement. Results below display the mean change in amplitude from Baseline to Month 12 for subjects that participated in the open-label extension (Part B), stratified by their original randomization in Part A.
Time Frame	Baseline to Month 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Group	Sham Group
Arm/Group Description	Treatment with active Provant Therapy System Active Provant Therapy System: Treatment with active Provant Therapy System	Treatment with in-active (sham) Provant Therapy System Inactive (sham) Provant Therapy System: Treatment with inactive Provant Therapy System
Measure Participants	72	80
Amplitude (uv) - Left	5.28 (14.4)	4.42 (14.6)
Amplitude (uv) - Right	6.0 (15.3)	4.28 (14.2)

16. Other Pre-specified Outcome

Title	Exploratory Endpoint: Changes in the Work Productivity and Activity Impairment Questionnaire (WPAIQ) (Questions 5-6)
Description	The Work Productivity and Activity Impairment Questionnaire (WPAIQ) is a validated 6 question assessment tool that measures time missed from work, impairment of work and regular activities due to their health problem. Subjects are asked if they are working (Question 1), and if answer is yes, subjects are asked about the effect their diabetic neuropathy (DN) has on their ability to work and perform regular activities in the past 7 days. Mean change from Baseline to 4-months displayed below (Questions 5-6) for subjects that responded "Yes" to working in Question 1. Questions 5 and 6 use a 0-10 scale where 0 = no effect on work and/or daily activities and 10 =DN completely prevented me from working and/or doing daily activities.
Time Frame	Baseline to 4 Months

Outcome Measure Data

Analysis Population Description

Includes only subjects that indicated they were working at the Enrollment Visit (Question 1).

Arm/Group Title	Active Group	Sham Group
Arm/Group Description	Treatment with active Provant Therapy System Active Provant Therapy System: Treatment with active Provant Therapy System	Treatment with in-active (sham) Provant Therapy System Inactive (sham) Provant Therapy System: Treatment with inactive Provant Therapy System
Measure Participants	29	18
Effect of DN on work in past 7 days	-0.40 (1.89)	-0.61 (3.01)
Effect on daily activities in past 7 days	-0.67 (2.19)	-0.59 (2.70)

17. Other Pre-specified Outcome

Title	Exploratory Endpoint: Changes in Intraepidermal Nerve Fiber Density (IENFD) at the Distal Thigh and Distal Leg - Part B
Description	Optional two 3 mm punch skin biopsies will be performed at baseline and end of treatment to assess IENFD. At the Enrollment Visit, one biopsy will be obtained at the distal leg, 10 cm above the lateral malleolus on the right leg and a second biopsy will be obtained at the distal thigh, 10 cm above the superior margin of the patella on the lateral right leg. At the end of Part A study visit Month 4 (Day 121), a second set of biopsies will be obtained lateral to the baseline biopsies and shipped overnight to the central lab. At the end of Part B study visit Month 12 (Day 361), a final set of biopsies will be obtained lateral to the Month 4 biopsies. Results displayed are the change in nerve fiber density from Baseline to Month 12 for subjects that participated in the open-label extension (Part B), stratified by their original randomization in Part A.
Time Frame	Baseline to Month 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Open-label Extension Group (Part B)
Arm/Group Description	Subjects receiving open-label active PEMF therapy in Part B after 17 weeks of randomized treatment in Part A.
Measure Participants	57
Right Distal Leg	.22 (2.17)
Right Distal Thigh	1.09 (2.94)

Adverse Events

Time Frame	Part A: 4 months (Baseline to Month 4); Part B: 8 months (Month 4 to Month 12)
Arm/Group Title	Active Group (Part A)		Sham Group (Part A)		Open-label Extension Group (Part B)
Arm/Group Description	Treatment with active Provant Therapy System Active Provant Therapy System: Treatment with active Provant Therapy System		Treatment with in-active (sham) Provant Therapy System Inactive (sham) Provant Therapy System: Treatment with inactive Provant Therapy System		Treatment with open-label active Provant Therapy System during Part B (months 4-12)
All Cause Mortality
	Active Group (Part A)		Sham Group (Part A)		Open-label Extension Group (Part B)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/92 (0%)		0/90 (0%)		57/152 (37.5%)
Serious Adverse Events
	Active Group (Part A)		Sham Group (Part A)		Open-label Extension Group (Part B)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/92 (5.4%)		6/90 (6.7%)		5/152 (3.3%)
Cardiac disorders
Cardiac failure congestive	1/92 (1.1%)	1	0/90 (0%)	0	0/152 (0%)	0
Endocrine disorders
Goitre	0/92 (0%)	0	0/90 (0%)	0	1/152 (0.7%)	1
Gastrointestinal disorders
Pancreatitis	1/92 (1.1%)	1	0/90 (0%)	0	0/152 (0%)	0
abdominal pain upper	0/92 (0%)	0	1/90 (1.1%)	1	0/152 (0%)	0
Diverticulum	0/92 (0%)	0	0/90 (0%)	0	1/152 (0.7%)	1
Small intestinal obstruction	0/92 (0%)	0	0/90 (0%)	0	1/152 (0.7%)	1
General disorders
Chest pain	0/92 (0%)	0	0/90 (0%)	0	1/152 (0.7%)	1
Infections and infestations
Sepsis	0/92 (0%)	0	1/90 (1.1%)	1	0/152 (0%)	0
pneumonia	0/92 (0%)	0	1/90 (1.1%)	1	0/152 (0%)	0
Injury, poisoning and procedural complications
Subdural heamatoma	0/92 (0%)	0	1/90 (1.1%)	1	0/152 (0%)	0
Infusion related reaction	0/92 (0%)	0	1/90 (1.1%)	1	0/152 (0%)	0
rib fracture	0/92 (0%)	0	1/90 (1.1%)	1	0/152 (0%)	0
Metabolism and nutrition disorders
Dehydration	1/92 (1.1%)	1	0/90 (0%)	0	0/152 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma gastric	0/92 (0%)	0	1/90 (1.1%)	1	0/152 (0%)	0
Malignant melanoma in situ	0/92 (0%)	0	0/90 (0%)	0	1/152 (0.7%)	1
Nervous system disorders
seizure	0/92 (0%)	0	1/90 (1.1%)	1	0/152 (0%)	0
Ischaemic stroke	0/92 (0%)	0	0/90 (0%)	0	1/152 (0.7%)	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/92 (1.1%)	1	1/90 (1.1%)	1	0/152 (0%)	0
Vascular disorders
Peripheral vascular disorder	1/92 (1.1%)	1	0/90 (0%)	0	0/152 (0%)	0
Other (Not Including Serious) Adverse Events
	Active Group (Part A)		Sham Group (Part A)		Open-label Extension Group (Part B)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/92 (0%)		0/90 (0%)		0/152 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Publication Rights. Independent analysis and/or publication of data generated or arising from the performance of this Agreement is not permitted without the prior written consent of Regenesis. Such consent may be contingent on Regenesis' review and approval of any proposed analysis and manuscript. Institution will retain the right to review and analyze the database created from this study for its own scientific purposes so long as such scientific purposes are non-commercial in nature.