INF: Investigation Into Physiologic Mechanism of Intraneural Facilitation™
Study Details
Study Description
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 the success of INF™ in treating T2DPN. Eligible subjects presenting with diabetic neuropathy symptoms will be recruited and referred to the Loma Linda University Health's Neuropathic Therapy Center. Four cohorts of ten subjects (total of 40) will be evenly randomized into two groups: an INF™ treatment group and Sham control group. Subjects will participate in 11 study visits over a period of 3 months. 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™ works, subsequently improving non-invasive treatment methods for T2DPN patients.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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N/A |
Detailed Description
Subjects will be assessed on the first, second, fifth, tenth and eleventh sessions.
During the subject's first and eleventh sessions, subjects will be asked to complete the Pain Quality Assessment Scale (PQAS) and the Lower Extremity Neuropathy Scale (LENS), followed by a vascular analysis of the Neurovascular Index (NVI) using a Philips Affinity 50 Ultrasound, and Neuropad® testing. The first session will also include collection of a routine medical intake questionnaire. The eleventh session will also include a debriefing session at the completion of the study.
Welltory App measurements to assess heart rate variability will be taken in the morning and evening the day before, the day of, and after each treatment session.
On the second session the subject will have:
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Electrocardiogram testing (ECG) for assessment of heart rate variability (HRV) using PowerLab+LabChart and BioAmp (AD Instruments, Colorado Springs, CO).
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Near-infrared Spectroscopy (NIRS) measurement using a Foresight Elite monitor (Edwards LifeSciences, Irvine, CA).
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Laser Doppler flowmetry (LDF) measurement using a skin surface Laser Doppler add-on for Chart/Powerlab (AD Instruments, Colorado Springs, CO).
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Welltory App measurements will be taken before and after treatment to assess for heart rate variability (HRV).
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A blood draw will be completed by a licensed lab technician to measure blood cytokine and HbA1C levels. The blood draw will be performed prior to treatment.
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The subject will then have a 60 minute INF™ session or 60 minutes of Sham Treatment (anodyne infrared with machine turned off).
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The aforementioned test 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 subject will have a 60 minute INF™ session or 60 minutes of Sham treatment (anodyne infrared with machine turned off). Welltory App measurements will be taken before and after treatment to assess for heart rate variability (HRV).
On the fifth session the subject will then have a 60 minute INF™ session or 60 minutes of Sham treatment (anodyne infrared with machine turned off). 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.
On the tenth session the subject will then have a 60 minute INF™ session or 60 minutes of Sham Treatment (anodyne infrared with machine turned off). Welltory App measurements will be taken before and after treatment to assess for heart rate variability (HRV). Followed by:
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Electrocardiogram testing (ECG) for assessment of heart rate variability (HRV) using PowerLab+LabChart and BioAmp (AD Instruments, Colorado Springs, CO).
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Near-infrared Spectroscopy (NIRS) using a Foresight Elite monitor (Edwards LifeSciences, Irvine, CA).
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Laser Doppler flowmetry (LDF) measurement using a skin surface Laser Doppler add-on for Chart/PowerLab (AD Instruments, Colorado Springs, CO).
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A blood draw will be completed by licensed lab technician to measure blood cytokine levels and HbA1C.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Intraneural Facilitation™ Treatment Group Subjects will receive nine 60-minute Intraneural Facilitation™ treatments during sessions 2 through 10. |
Other: Intraneural Facilitation Treatment™
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.
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| Sham Comparator: Sham Control Treatment Group Subjects will receive nine 60-minute Sham treatments during sessions 2 through 10. |
Other: Sham Treatment
The sham treatment uses an anodyne therapy system for the duration of the treatment time; however, the machine is turned off.
Other Names:
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Outcome Measures
Primary Outcome Measures
- The Impact of INF™ on Heart Rate Variability [Through study completion, an average of 3 months.]
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.
Secondary Outcome Measures
- The impact of INF™ on neuropathy severity [Through study completion, an average of 3 months.]
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.
- The impact of INF™ on blood flow [Through study completion, an average of 3 months.]
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.
- The impact of INF™ on inflammation [Through study completion, an average of 3 months.]
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.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Between the ages of 45 and 85
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Moderate to severe type II diabetic neuropathy with one or more symptoms including: numbness, tingling, burning, sharp pain, and/or increased sensitivity.
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Diagnosis confirmed by a physician.
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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:
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Chemotherapy
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Radiation
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Lower extremity amputations
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Open wounds
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Documented active drug and or alcohol misuse
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Chronic liver disease
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Active inflammations
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Other types of neuropathies not associated with diabetes including B12 deficiency and Charcot Marie Tooth
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Morbid obesity
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Pregnancy.
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Taking beta blockers
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Unable to maintain steady fingers or operate a cellphone
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Smoking or ingesting marijuana
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Having a pacemaker
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Allergies to cobalt, chrome, or nickel
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Loma Linda University Health Neuropathic Therapy Center | Loma Linda | California | United States | 92350 |
Sponsors and Collaborators
- Loma Linda University
Investigators
- Principal Investigator: Mark Bussell, DPT, OCS, Loma Linda University Health
Study Documents (Full-Text)
None provided.More Information
Publications
- Alshahrani A, Bussell M, Johnson E, Tsao B, Bahjri K. Effects of a Novel Therapeutic Intervention in Patients With Diabetic Peripheral Neuropathy. Arch Phys Med Rehabil. 2016 May;97(5):733-8. doi: 10.1016/j.apmr.2015.12.026. Epub 2016 Jan 22.
- Brown CD, Davis HT, Ediger MN, Fleming CM, Hull EL, Rohrscheib M. Clinical assessment of near-infrared spectroscopy for noninvasive diabetes screening. Diabetes Technol Ther. 2005 Jun;7(3):456-66. doi: 10.1089/dia.2005.7.456.
- Callaghan BC, Gallagher G, Fridman V, Feldman EL. Diabetic neuropathy: what does the future hold? Diabetologia. 2020 May;63(5):891-897. doi: 10.1007/s00125-020-05085-9. Epub 2020 Jan 23.
- Feldman EL, Callaghan BC, Pop-Busui R, Zochodne DW, Wright DE, Bennett DL, Bril V, Russell JW, Viswanathan V. Diabetic neuropathy. Nat Rev Dis Primers. 2019 Jun 13;5(1):41. doi: 10.1038/s41572-019-0092-1.
- Gordois A, Scuffham P, Shearer A, Oglesby A, Tobian JA. The health care costs of diabetic peripheral neuropathy in the US. Diabetes Care. 2003 Jun;26(6):1790-5. doi: 10.2337/diacare.26.6.1790.
- Gore M, Brandenburg NA, Dukes E, Hoffman DL, Tai KS, Stacey B. Pain severity in diabetic peripheral neuropathy is associated with patient functioning, symptom levels of anxiety and depression, and sleep. J Pain Symptom Manage. 2005 Oct;30(4):374-85. doi: 10.1016/j.jpainsymman.2005.04.009.
- Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Eur Heart J. 1996 Mar;17(3):354-81. No abstract available.
- Hicks CW, Selvin E. Epidemiology of Peripheral Neuropathy and Lower Extremity Disease in Diabetes. Curr Diab Rep. 2019 Aug 27;19(10):86. doi: 10.1007/s11892-019-1212-8.
- Iannetta D, Inglis EC, Soares RN, McLay KM, Pogliaghi S, Murias JM; CAPES scholarship holder. Reliability of microvascular responsiveness measures derived from near-infrared spectroscopy across a variety of ischemic periods in young and older individuals. Microvasc Res. 2019 Mar;122:117-124. doi: 10.1016/j.mvr.2018.10.001. Epub 2018 Oct 4.
- Lockhart CJ, McCann AJ, Pinnock RA, Hamilton PK, Harbinson MT, McVeigh GE. Multimodal functional and anatomic imaging identifies preclinical microvascular abnormalities in type 1 diabetes mellitus. Am J Physiol Heart Circ Physiol. 2014 Dec 15;307(12):H1729-36. doi: 10.1152/ajpheart.00372.2014. Epub 2014 Oct 3.
- McVeigh GE, Morgan DR, Allen P, Trimble M, Hamilton P, Dixon LJ, Silke B, Hayes JR. Early vascular abnormalities and de novo nitrate tolerance in diabetes mellitus. Diabetes Obes Metab. 2002 Sep;4(5):336-41. doi: 10.1046/j.1463-1326.2002.00220.x.
- Pop-Busui R, Backlund JC, Bebu I, Braffett BH, Lorenzi G, White NH, Lachin JM, Soliman EZ; DCCT/EDIC Research Group. Utility of using electrocardiogram measures of heart rate variability as a measure of cardiovascular autonomic neuropathy in type 1 diabetes patients. J Diabetes Investig. 2022 Jan;13(1):125-133. doi: 10.1111/jdi.13635. Epub 2021 Aug 14.
- Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, Colagiuri S, Guariguata L, Motala AA, Ogurtsova K, Shaw JE, Bright D, Williams R; IDF Diabetes Atlas Committee. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019 Nov;157:107843. doi: 10.1016/j.diabres.2019.107843. Epub 2019 Sep 10.
- Selvarajah D, Wilkinson ID, Fang F, Sankar A, Davies J, Boland E, Harding J, Rao G, Gandhi R, Tracey I, Tesfaye S. Structural and Functional Abnormalities of the Primary Somatosensory Cortex in Diabetic Peripheral Neuropathy: A Multimodal MRI Study. Diabetes. 2019 Apr;68(4):796-806. doi: 10.2337/db18-0509. Epub 2019 Jan 7.
- Sun PC, Kuo CD, Chi LY, Lin HD, Wei SH, Chen CS. Microcirculatory vasomotor changes are associated with severity of peripheral neuropathy in patients with type 2 diabetes. Diab Vasc Dis Res. 2013 May;10(3):270-6. doi: 10.1177/1479164112465443. Epub 2012 Dec 14.
- Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care. 2003 May;26(5):1553-79. doi: 10.2337/diacare.26.5.1553.
- Zheng H, Sun W, Zhang Q, Zhang Y, Ji L, Liu X, Zhu X, Ye H, Xiong Q, Li Y, Lu B, Zhang S. Proinflammatory cytokines predict the incidence of diabetic peripheral neuropathy over 5 years in Chinese type 2 diabetes patients: A prospective cohort study. EClinicalMedicine. 2020 Dec 23;31:100649. doi: 10.1016/j.eclinm.2020.100649. eCollection 2021 Jan.
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