Noninvasive Brain Stimulation for Diabetic Neuropathic Pain

Optimization of ESStim for the Diabetic Neuropathic Pain Treatment Phase II Study

This is an investigator-initiated study that is in the funding range for a grant from the NIH. This study is testing the possibility that non-invasive brain stimulation (ESSTim) would be superior to sham in the treatment of pain secondary to diabetic neuropathy.

Study Overview

• Status: Recruiting
• Conditions: Diabetic Neuropathies; Chronic Pain
• Intervention / Treatment: Device: Active tDCS + Active TUS; Device: Device: Sham

Detailed Description

The investigators hypothesize that Active ESStim will have a significantly improved and lasting effect compared to SHAM ESStim assessed in 40 DNP patients, 20 per group, given now for 5 consecutive days, 20 min/day, followed by 2 weeks of bi-weekly stimulation given 20 min/day (total stimulations n=11) and follow-ups at 2, 4, 6, & 8 weeks post-stim): 13 visits plus screening/ baseline (total 14 visits).

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Megan O'Neill O'Neill Miller; Phone Number: 216-844-4720; Email: megan.miller3@uhhospitals.org
• Study Contact Backup: Name: Terrah Morrison; Phone Number: 216.844.2685; Email: Terrah.Morrison@UHhospitals.org

Study Locations

• United States
  • Illinois
    • Hinsdale, Illinois, United States, 60612
      • Recruiting
      • University of Illinois Health/ University of Illinois at Chicago
      • Contact: Ciro Ramos Estebanez MD, PhD, MBA, FNCS; Email: cramoses@icloud.com
      • Principal Investigator: Ciro RamosEstebanez, MD., Ph.D.
    • Hinsdale, Illinois, United States, 60521-4902
      • Recruiting
      • University of Illinois Health/ University of Illinois at Chicago
      • Contact: Elizabeth Villagrana; Phone Number: 312-355-1528; Email: nevilla@uic.edu
      • Contact: Ciro Ramos Estebanez MD, PhD, MBA, FNCS; Email: cramoses@icloud.com
  • Ohio
    • Cleveland, Ohio, United States, 44106-1716
      • Recruiting
      • University Hospitals Cleveland Medical Center/ Dahms Clinical Research Unit
      • Contact: Salim Hayek, MD, PhD; Phone Number: 216.844.2685; Email: Salim.Hayek@UHhospitals.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Providing informed consent to participate in the study.
2. Having diabetic neuropathic pain, involving at least 1 foot, as defined by International Association for the Study of Pain and meeting criteria detailed by the Toronto Diabetic Neuropathy Expert Group - existing pain for at least 6 months and having pain on at least half the days in the past 6 months with an average of at least a 4 on a 0-10 VAS scale.
3. Pain resistant to common analgesics and medications for first line therapy of chronic pain such as Tylenol, Aspirin, Ibuprofen, Soma, Parafon Forte DCS, Zanaflex, Codeine, etc.
4. Must have the ability to feel pain as self-reported.

Exclusion Criteria:

1. Subject is pregnant.
2. Contraindications to Electrosonic Stimulation (ESStim): metal in the head, or implanted brain medical devices.
3. History of alcohol or drug abuse within the past 6 months as self-reported.
4. Use of carbamazepine within the past 6 months as self-reported.
5. Suffering from major depression (with a PHQ-9 score of ≥10).
6. History of neurological disorders involving stroke, brain tumors, or epilepsy as self-reported (note patients will also be evaluated via EEG at baseline 1 week prior to stimulation and any patient showing abnormal EEG activity will be removed))
7. History of unexplained fainting spells as self-reported.
8. History of head injury resulting in more than a momentary loss of consciousness as self-reported.
9. History of neurosurgical procedures as self-reported.
10. Unstable pain (defined as pain intensities that vary by more than 4 points on 0-10 VAS scale over the 1-week period of trial run-in.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Active tDCS + Active TUS; Subjects in the experimental group will undergo 20 minutes of active transcranial direct current stimulation (tDCS) and active transcranial ultrasound (TUS).	Device: Active tDCS + Active TUS; Device: Active comparator device: Active transcranial Direct Current Stimulation (tDCS). Subjects will receive 20 minutes of active tDCS. During each Active stimulation session, stimulation will be applied for the full 20 minutes. Device: Active comparator device: Active Transcranial Ultrasound (TUS). Subjects will receive 20 minutes of active Transcranial Ultrasound (TUS). During active stimulation the (TUS) will be active for the full 20 minutes.
SHAM_COMPARATOR: Sham; Subjects in the sham group will undergo 20 minutes of sham transcranial direct current stimulation (tDCS) and sham transcranial ultrasound (TUS).	Device: Device: Sham; Device: SHAM Comparator Device: transcranial Direct Current Stimulation (tDCS) Subjects will receive 20 minutes of sham tDCS. In the sham group, the tDCS device will not be active for the full 20 minutes. Device: Transcranial Ultrasound (TUS) Subjects will receive 20 minutes of sham TUS. During sham stimulation the ultrasound will not be active for the full 20 minutes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in pain as measured by the Visual Analog Scale	The Visual Analog Scale will assess a patient's pain intensity on a scale from 0 (no pain) to 10 (worst pain imaginable). Changes in VAS for Pain will be measured to determine whether anodal transcranial direct current stimulation in conjunction with transcranial ultrasound (applied in a diagnostic mode) is effective in reducing pain of subjects with diabetic neuropathic pain.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in the Verbal Rating Scale for Pain	The Verbal Rating Scale for Pain is a categorical scale of pain with categories: none, mild, moderate, severe pain intensity. Changes in VRS for Pain will be measured in order to determine whether anodal transcranial direct current stimulation in conjunction. with transcranial ultrasound (applied in a diagnostic mode) is effective in reducing pain of subjects with diabetic neuropathic pain.	3 months
Changes in Conditional Pain Modulation	Changes in Conditional Pain Modulation will be measured in order to determine whether anodal transcranial direct current stimulation in conjunction with transcranial ultrasound (applied in a diagnostic mode) is effective in increasing the pain pressure threshold (e.g., pounds per square inch) in subjects with diabetic neuropathic pain where a higher number is better and a lower number is worse.	3 months
Changes in Visual Analog Scale for Mood - Anxiety	The Visual Analog Scale for Mood will investigate Anxiety. The Subscales is as follows: The anxiety scale will assess a patient's anxiety on a scale from 0 (not anxious) to 10 (very anxious).	3 months
Montreal Cognitive Assessment	The investigators will monitor the safety of transcranial direct current stimulation and transcranial ultrasound in subjects by measuring any changes in cognition. Scores range from lowest being 0 to highest being 30.	3 months
4-choice reaction time	This is an attentional task that measures the time for a subject response to stimuli (in seconds) with shorter times being better.	3 months
N-back tests	This instrument has been used in our past brain stimulation studies and will be used to assess working memory. This is a computer-assisted test.	3 months
Electroencephalography	Investigators will measure electroencephalogram electrical activity (amplitude) as function of time.	3 months
Electroencephalography	Investigators will measure electroencephalogram electrical activity (frequency) as function of time.	3 months
Walking test	The investigators will measure if there are changes in the walking speed of the subject from the beginning of the study to the end	3 months
Walking test	The investigators will measure if there are changes in the gait asymmetry of the subject from the beginning of the study to the end	3 months
Walking test	The investigators will measure if there are changes in the stride length, and walking smoothness of the subject from the beginning of the study to the end	3 months
Walking test	The investigators will measure if there are changes in the stride length of the subject from the beginning of the study to the end	3 months
Walking test	The investigators will measure if there are changes in the walking smoothness of the subject from the beginning of the study to the end	3 months
Functional reach test	The investigators will measure changes in subjects ability to complete the functional reach test across the duration of study.	3 months
Study 36-Item Short Form	This is a health survey using a scale from 0 (worst) to 100 (best)	3 months
Patient Health Questionnaire	This questionnaire screens for depression with a score of 0 (best) to 27 (worst)	3 months
American Pain Foundation Pain and Medication Diary	The pain sub-scale measures pain intensity from 0 (best) to 10 (worst)	3 months
Multidimensional Pain Inventory	This pain scale measures aspects of pain from 0 (best) to 6 (worst)	3 months
Brief Pain Inventory	This pain scale measures aspects of pain from 0 (no pain) to 10 (worst)	3 months
Adverse events	At each session after stimulation begins, subjects will complete a questionnaire to evaluate potential adverse effects of stimulation (headache, neck pain, mood alterations, and seizures) on a 5-point scale (0 being best and 5 worst). The scale will also be administered at the follow-up.	3 months
The Visual Analog Scale for Mood - Depression	The Visual Analog Scale for Mood will investigate Depression. The Subscales is as follows: The depression scale will assess a patient's depression on a scale from 0 (not depressed) to 10 (very depressed).	3 months
The Visual Analog Scale for Mood - Stress	The Visual Analog Scale for Mood will investigate Stress. The Subscales is as follows: The stress scale will assess a patient's stress on a scale from 0 (not stressed) to 10 (very stressed).	3 months
The Visual Analog Scale for Mood - Sleep	The Visual Analog Scale for Mood will investigate Sleepiness. The Subscales is as follows: The sleepiness scale will assess a patient's depression on a scale from 0 (not sleepy) to 10 (very sleepy).	3 months

Collaborators and Investigators

• Sponsor: Case Western Reserve University
• Collaborators: Highland Instruments, Inc.

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 25, 2022
• Primary Completion (ANTICIPATED): August 1, 2023
• Study Completion (ANTICIPATED): August 1, 2024

Study Registration Dates

• First Submitted: March 14, 2022
• First Submitted That Met QC Criteria: July 19, 2022
• First Posted (ACTUAL): July 21, 2022

Study Record Updates

• Last Update Posted (ACTUAL): July 22, 2022
• Last Update Submitted That Met QC Criteria: July 20, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Pain; Neurologic Manifestations; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Neuromuscular Diseases; Peripheral Nervous System Diseases; Chronic Pain; Neuralgia; Diabetic Neuropathies
• Other Study ID Numbers: STUDY20201584

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes