A Physiologic Comparison of Two Approaches to Treating Peripheral Neuropathy (INF)

November 17, 2025 updated by: Loma Linda University
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 Therapy (INF® Therapy) 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® Therapy 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® Therapy 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® Therapy and standard physical therapy work, subsequently improving non-invasive treatment methods for T2DPN patients.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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® Therapy 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® Therapy 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® Therapy 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® Therapy 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.

Study Type

Interventional

Enrollment (Estimated)

40

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • California
      • Loma Linda, California, United States, 92350
        • Recruiting
        • Loma Linda University Health Neuropathic Therapy Center
        • Contact:
        • Principal Investigator:
          • Mark Bussell, DPT, OCS

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

45 years to 85 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Standard Physical Therapy Treatment Group
Subjects will receive nine 60-minute standard physical therapy treatments during sessions 2 through 10.
Other: Standard Physical Therapy Treatment
The standard physical therapy treatment includes muscle stretching, balance, and strengthening exercises known to improve neuropathy symptoms.
Experimental: Intraneural Facilitation Therapy Treatment Group
Subjects will receive nine 60-minute INF® Therapy Treatments during sessions 2 through 10. INF® Therapy is a non-invasive treatment that helps eliminate pain, tingling, numbness, and other symptoms that come with neuropathy.
Other: Intraneural Facilitation Therapy Treatment
Intraneural Facilitation Therapy 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The Impact of INF® Therapy and Standard Physical Therapy on Heart Rate Variability
Time Frame: Through study completion, an average of 6 weeks.
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® Therapy and Standard Physical Therapy on neuropathy severity
Time Frame: Through study completion, an average of 6 weeks.
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® Therapy and Standard Physical Therapy on blood flow
Time Frame: Through study completion, an average of 6 weeks.
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® Therapy and Standard Physical Therapy on inflammation
Time Frame: Through study completion, an average of 6 weeks.
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.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Loma Linda University

Investigators

  • Principal Investigator: Mark Bussell, DPT, OCS, Loma Linda University Health

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 8, 2024

Primary Completion (Estimated)

August 1, 2027

Study Completion (Estimated)

August 1, 2027

Study Registration Dates

First Submitted

September 27, 2022

First Submitted That Met QC Criteria

October 10, 2022

First Posted (Actual)

October 13, 2022

Study Record Updates

Last Update Posted (Estimated)

November 19, 2025

Last Update Submitted That Met QC Criteria

November 17, 2025

Last Verified

November 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 5220363

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

All de-identified results and locally developed analysis software will be made available via our laboratory GitHub repository (https://github.com/drcgw/BASS) upon publication of manuscripts from this project. Individual data will be de-identified and combined in a master spreadsheet with subject I.D. numbers. As described in the research protocol, metrics will include data from ultrasound assessments, HRV summary data for each subject, Pulse-doppler, and NIRS data, as well as relevant subject notes that do not include PHI.

IPD Sharing Time Frame

The data will be available indefinitely from six months post-manuscript publication.

IPD Sharing Access Criteria

Data stored on our GitHub repository will be made available to clinicians and researchers after reaching out to the project leaders for access to the data repository.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • ANALYTIC_CODE
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Subscribe