A Physiologic Comparison of Two Approaches to Treating Peripheral Neuropathy

Study Overview
=================
Brief Summary
-----------------
Diabetic peripheral neuropathy is one of the most common and costly microvascular complications of diabetes impacting more than 50% of patients and costing more than 10.1 billion dollars annually. Intraneural facilitation™ (INF) is a non-invasive technique that has shown to improve balance and pain in patients with Type 2 Diabetic Peripheral Neuropathy (T2DPN); however, the underlying physiological mechanisms need further understanding. The purpose of this study is to investigate the physiological mechanisms behind two approaches to treating T2DPN, INF and standard physical therapy. Eligible subjects presenting with diabetic neuropathy symptoms will be recruited and referred to the Loma Linda University Health's Neuropathic Therapy Center. Forty patients will be evenly randomized into two groups: an INF™ treatment group and standard physical therapy treatment group. Subjects will participate in 11 study visits over a period of 6 weeks. Non-invasive assessments will measure neuropathy pain, heart rate variability, neuropathy severity, blood oxygen levels, and blood flow under the skin. Lab draws will measure inflammation levels in the blood and how well blood sugar levels have been maintained over a period of about 3 months. Descriptive statistics and repeated measures ANOVA will be used to analyze data and answer the research questions. The findings of this study will provide a better understanding of how INF™ and standard physical therapy work, subsequently improving non-invasive treatment methods for T2DPN patients.

Detailed Description
-----------------
Study participants will be assessed on the first, second, fifth, tenth and eleventh sessions. During the participants first and eleventh sessions participants will complete the Pain Quality Assessment Scale (PQAS), the Lower Extremity Neuropathy Scale (LENS), a vascular analysis of the Neurovascular Index (NVI) using a Philips Affinity 50 Ultrasound, and Neuropad® testing. The first session will also include completion of the Background Information form. Patients will be asked to wear loose fitting clothing and to arrive 15 minutes early to complete the informed consent documents on the first session. Welltory App measurements to assess heart rate variability will be taken in the morning and evening the day before, the day of, and the day after each treatment session. On the second session the patient will have: Electrocardiogram testing (ECG) for assessment of heart rate variability (HRV) using PowerLab+LabChart and BioAmp (AD Instruments, Colorado Springs, CO). Near-infrared Spectroscopy (NIRS) measurement using a Foresight Elite monitor (Edwards LifeSciences, Irvine, CA Laser Doppler flowmetry (LDF) measurement using a skin surface Laser Doppler add-on for Chart/Powerlab (AD Instruments, Colorado Springs, CO). Welltory App measurements will be taken before and after treatment to assess for heart rate variability (HRV). A blood draw will be completed by a licensed lab technician to measure blood cytokine and HbA1C levels. A total of 1 1/3 teaspoons of blood will collected at this time point. The blood draw will be performed prior to treatment. The patient will then receive a 60 minute INF™ or standard physical therapy session. The aforementioned tests will then be repeated including ECG, NIRS, and LDF to measure post treatment values. During the third, fourth, sixth, seventh, eighth, and ninth sessions, the patient will have a 60 minute INF™ or standard physical therapy session. Welltory App measurements will be taken before and after treatment to assess for heart rate variability (HRV). On the fifth session the patient will have a 60 minute INF™ or standard physical therapy session. Welltory App measurements will be taken before and after treatment to assess for heart rate variability (HRV). Followed by: • A blood draw by a licensed lab technician to measure blood cytokine levels. A total of 1 ¼ teaspoons will be collected at this time point. On the tenth session the patient will have a 60 minute INF™ or standard physical therapy session. Welltory App measurements will be taken before and after treatment to assess for heart rate variability (HRV). Followed by: Electrocardiogram testing (ECG) for assessment of heart rate variability (HRV) using PowerLab+LabChart and BioAmp (AD Instruments, Colorado Springs, CO). Near-infrared Spectroscopy (NIRS) using a Foresight Elite monitor (Edwards LifeSciences, Irvine, CA Laser Doppler flowmetry (LDF) measurement using a skin surface Laser Doppler add-on for Chart/PowerLab (AD Instruments, Colorado Springs, CO). A blood draw will be completed by licensed lab technician to measure blood cytokine levels and HbA1C. A total of 1 1/3 teaspoons will be collected at this time point.

Official Title
-----------------
A Physiologic Comparison of Two Approaches to Treating Peripheral Neuropathy

Conditions
-----------------
Peripheral Neuropathy With Type 2 Diabetes

Intervention / Treatment
-----------------
* Other: Intraneural Facilitation Treatment™
* Other: Standard Physical Therapy Treatment


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Between the ages of 45 and 85 Moderate to severe type II diabetic neuropathy with one or more symptoms including: numbness, tingling, burning, sharp pain, and/or increased sensitivity. Diagnosis confirmed by a physician. Cellphone access with Android 5.0 and up or iOS 14.0 or later. Exclusion Criteria: Subjects with a medical condition predisposing them to medical decline during the next 6 months will be excluded from the study. Examples include: Chemotherapy Radiation Lower extremity amputations Open wounds Documented active drug and or alcohol misuse Chronic liver disease Active inflammations Other types of neuropathies not associated with diabetes including B12 deficiency and Charcot Marie Tooth Morbid obesity Pregnancy. Taking beta blockers Unable to maintain steady fingers or operate a cellphone Smoking or ingesting marijuana Having a pacemaker Allergies to cobalt, chrome, or nickel

Ages Eligible for Study
-----------------
Minimum Age: 45 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Two arms: One INF™ treatment group and One standard physical therapy treatment group
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intraneural Facilitation™ Treatment Group<br>Subjects will receive nine 60-minute Intraneural Facilitation™ treatments during sessions 2 through 10. Intraneural facilitation™ is a non-invasive treatment that helps eliminate pain, tingling, numbness, and other symptoms that come with neuropathy. | Other: Intraneural Facilitation Treatment™<br>* Intraneural facilitation™ uses three manual holds to bias blood flow to closed endoneurial capillaries. The first is the facilitation hold, which is thought to pressurize the nervous system and bias circulation from the artery into the epineurium. This hold stretches the nerve further than the artery, increasing the amount of elastin in the artery and enlarging the opening of the arterial junction increasing blood into the epineurium. The secondary hold then increases epineurial blood into the transperineurial vessels increasing pressure into the endoneurial capillaries of the site being treated. The third hold, known as the sub hold, encourages blood flow through ischemic endoneurial capillaries that have increased resistance/pressure through the application of Bernoulli's principle. The series of stretches will be repeated on the affected side for the treatment duration.<br>|
| Experimental: Standard Physical Therapy Treatment Group<br>Subjects will receive nine 60-minute standard physical therapy treatments during sessions 2 through 10. | Other: Standard Physical Therapy Treatment<br>* The standard physical therapy treatment includes muscle stretching, balance, and strengthening exercises known to improve neuropathy symptoms.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Impact of INF™ and Standard Physical Therapy on Heart Rate Variability | This is a composite measurement combining electrocardiogram and Welltory App measurements. Heart rate variability (HRV) is the variation in the time interval between consecutive heartbeats and can be used to assess the current state of the nervous system. HRV measures will include LF, HF, LF/HF ratio, SDNN, SDANN, RMSSD, and NN50. The calculation of these variables allows HRV to be quantified. A normal result is between 25 to 50 milliseconds while an abnormal result is less than or greater than that range. | Through study completion, an average of 6 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The impact of INF™ and Standard Physical Therapy on neuropathy severity | This will be measured by using ultrasound testing with Neurovascular Index assessment. This is a composite measure of blood flow in the limb. Anterograde and retrograde pulsatility index and volume flow measures are combined to form a mathematical descriptor of the waveform followed by a statistical analysis of variation and then a general score is obtained. A normal result is scored at 250 or less. | Through study completion, an average of 6 weeks. | 
| The impact of INF™ and Standard Physical Therapy on blood flow | This will be measured by laser doppler flow. Laser Doppler Flowmetry (LDF) is a non-invasive method for measuring changes in microvascular blood perfusion (blood flow) in a variety of tissues. The frequency distribution of the backscattered light is then calculated based on the illumination of the tissue sample. A normal result is relative to the non-affected limb and will be quantified in each patient and compared between visit 2 and 10. An abnormal result would be a 20% or greater reduction in flow in the affected limb. | Through study completion, an average of 6 weeks. | 
| The impact of INF™and Standard Physical Therapy on inflammation | This will be measured through cytokine levels taken by lab collection. Cytokine levels can vary widely and depend upon current inflammatory state in the patient. C-reactive protein (CRP) is an inflammatory protein that increases with inflammation or infection and can be used as a clinical marker for inflammation. A normal result is < 3mg/L for c-reactive protein. Abnormal result would be levels greater than normal for c-reactive protein. | Through study completion, an average of 6 weeks. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Type 2 Diabetes, Neuropathy, Heart rate variability, Intraneural Facilitation