Neural and Immune Correlates of CIPN and Possible Analgesic Effect of Non-invasive Motor Cortex Stimulation (NIBS4CIPN)

Neural and Immune Correlates of Painful Chemotherapy-Induced Neuropathy, Feasibility and Preliminary Efficacy of a Motor Cortex Non-Invasive Brain Stimulation Intervention

Over half of cancer patients receiving common chemotherapy treatments experience painful nerve damage called chemotherapy-induced peripheral neuropathy (CIPN). Non-Hispanic Black (NHB) patients are more likely to suffer from this condition and more often need to reduce their chemotherapy doses compared to Non-Hispanic White (NHW) patients.

Currently, only one medication, duloxetine, is approved for treating CIPN, but it doesn't work for everyone. A new approach, transcranial direct current stimulation (tDCS), shows promise as a safe and effective treatment. tDCS can be done at home and reduces the need for hospital visits.

Research indicates that tDCS can improve pain responses in the brain's pain control network. There are differences in pain sensitivity and brain activity related to pain between NHB and NHW individuals, which may influence the effectiveness of treatments.

This research aims to conduct a study to:

1. Test if tDCS is a helpful treatment for painful CIPN.
2. Investigate how CIPN affects brain function in NHB and NHW patients.
3. Examine the role of inflammation in CIPN and its connection to pain severity and brain function.

The investigators expect that NHB patients will benefit more from tDCS due to differences in their brain's pain response system. This project aims to address health disparities and improve outcomes for urban communities, particularly in Baltimore.

Study Overview

• Status: Not yet recruiting
• Conditions: Chemotherapy-induced Peripheral Neuropathy
• Intervention / Treatment: Device: transcranial direct current stimulation Soterix REMOTE 1x1 miniCT

Detailed Description

More than half of patients treated with commonly used platinum- and taxane-based anti-cancer agents suffer painful chemotherapy-induced peripheral neuropathy (CIPN). Non-Hispanic Black (NHB) patients have a greater risk (risk ratio=1.6-2.4) of experiencing clinically relevant CIPN and consequent chemotherapy dose reductions compared to non-Hispanic Whites (NHWs). Despite the greater risk of painful CIPN in NHB cancer patients, clinical trials in patients suffering with CIPN have historically included homogeneous patient populations of NHWs. Only duloxetine is approved to treat painful CIPN and is not effective for or tolerated by all patients. Transcranial direct current stimulation (tDCS) of the motor cortex is emerging as a promising, safe, and effective intervention for the pain of neuropathy. An additional benefit of tDCS is that it can be administered at home and supervised remotely, minimizing stressful visits to a hospital venue for treatment. A recent randomized experimental study in healthy individuals completed by the PI showed that one 20-minute session of motor cortex tDCS reduced capsaicin-induced hyperalgesia. To understand the mechanism of pain ameliorating effects of motor cortex tDCS, the PI found enhanced neurophysiological responses of the descending pain modulatory network (DPMN), a group of brain structures activated in response to painful stimuli, after active compared to sham stimulation. Previous investigations have observed differences in opioid receptor binding and pain responses in the DPMN (notably the cingulate cortex and ventral striatum) between healthy NHBs and NHWs as well as differences in pain sensitivity. Likely relevant to the mechanism of CIPN, PET scanning of chemotherapy patients reveals neuroinflammation throughout the brain. The facts that 1) NHB individuals experience a greater rate of CIPN, but have not been represented in relevant clinical studies, 2) non-invasive tDCS is emerging as a safe and effective treatment for neuropathic pain and can be implemented in the home 3) the DPMN is implicated in central pain responses and is activity is enhanced after tDCS and 4) neuroinflammation likely plays a role in CIPN have led us to the present research plan. The overarching goal of this proposal to conduct an exploratory double-blind randomized controlled trial (RCT) addressing 3 specific aims: 1) determine the feasibility and efficacy of active tDCS targeting motor cortex as an analgesic and antihyperalgesic intervention in patients with painful CIPN, 2) determine structural and functional brain correlates of painful CIPN in the DPMN in NHBs and NHWs, and 3) determine inflammatory mediators in patients with painful CIPN and their relationship to the severity of painful CIPN and DPMN structure and function. The investigators expect NHB subjects will experience greater therapeutic effects of tDCS compared to NHW subjects, since NHBs have a dysregulated DPMN potentially affected by neuroinflammation. The goals of this project align with the mission of RCMI@Morgan to understand and combat urban health disparity issues in the City of Baltimore and elsewhere.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Timothy J Meeker, PhD; Phone Number: 443-885-4468; Email: timothy.meeker@morgan.edu
• Study Contact Backup: Name: Cynthia Renn, PhD; Phone Number: 410-706-5736; Email: renn@umaryland.edu

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Cynthia Renn
      • Contact: Cynthia Renn, PhD; Phone Number: 410-706-5736; Email: renn@umaryland.edu
    • Baltimore, Maryland, United States, 21251
      • Morgan State University
      • Contact: Timothy J Meeker, PhD; Phone Number: 443-885-4468; Email: timothy.meeker@morgan.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Able to read, write, and comprehend English
• Non-Hispanic White or Non-Hispanic Black
• Stable medication dosage over previous 4 weeks
• Completed primary surgery or chemotherapy for cancer at least 3 months prior to signing consent form
• Diagnosed with painful chemotherapy-induced neuropathy

Exclusion Criteria:

• Chronic pain due to another painful condition (e.g., fibromyalgia, chronic low back pain, etc.)
• Any neurological deficits (e.g., lower extremity weakness or bowel/bladder dysfunction, etc.)
• Deficient folate levels (<7 nmol/ml serum)
• Deficient vitamin B12 levels (<200 pg/mL serum)
• Deficient Vitamin D levels (<50 nmol/L or <20 ng/ml)
• Comorbidities affecting sensorimotor function (e.g., multiple sclerosis, diabetes, etc.)
• Unstable mental health condition (acute medical management/hospitalization in the past 6 mo.)
• Elevated hemoglobin A1c levels indicative of uncontrolled diabetes (>6.5%)
• Self-reported Substance abuse (current)
• Drug test positive for illicit drugs except THC
• Excessive alcohol consumption defined as: 1) More than 3 glasses of wine a day; 2) More than 3 beers a day; 3) More than 60 mL of hard liquor a day
• Presence of cardiac pacemaker or automatic implantable cardioverter-defibrillator (AICD).
• Pregnancy, lactation (will be screened with urine pregnancy test)
• Non-removable metal or tattoos around head, excepting dental appliances and fillings
• Use of implantable copper birth control device
• History of frequent severe headaches
• Unstable coronary artery disease
• Uncontrolled Seizure disorder
• Uncontrolled hypertension
• Stage IV cancer

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Device Feasibility
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Left motor cortex targeted anodal transcranial direct current stimulation; Active left motor cortex targeted anodal transcranial direct current stimulation at 2 milliamperes applied for 20 minutes once daily on Monday through Friday for two consecutive weeks.	Device: transcranial direct current stimulation Soterix REMOTE 1x1 miniCT; Soterix Medical REMOTE Neuromodulation is the only system with device, accessories, and software designed for deployed use. Safe transcranial Electrical Stimulation requires advanced systems designed for consistency and control. REMOTE Neuromodulation is the only system designed from the ground up to allow translation of clinical tES, including tDCS protocols, to diverse deployed environments, while maintaining medical standards.; Other Names: tDCS; Soterix REMOTE 1x1 miniCT
Sham Comparator: Left motor cortex targeted sham transcranial direct current stimulation; Active left motor cortex targeted anodal transcranial direct current stimulation at 0 milliamperes applied for 20 minutes once daily on Monday through Friday for two consecutive weeks. The sham consists of a ramp up to 2 mA and immediate ramp down to 0 mA at the beginning of the 20 minute period and a ramp up to 2 mA and immediate ramp down to 0 mA at the end of the 20 minute period.	Device: transcranial direct current stimulation Soterix REMOTE 1x1 miniCT; Soterix Medical REMOTE Neuromodulation is the only system with device, accessories, and software designed for deployed use. Safe transcranial Electrical Stimulation requires advanced systems designed for consistency and control. REMOTE Neuromodulation is the only system designed from the ground up to allow translation of clinical tES, including tDCS protocols, to diverse deployed environments, while maintaining medical standards.; Other Names: tDCS; Soterix REMOTE 1x1 miniCT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants able to adhere to the at home remote stimulation protocol	Number of participants able to adhere to the at home study protocol comparing non-Hispanic blacks to non-Hispanic whites for both active and sham stimulation groups	2 weeks
Number of side effects reported on the transcranial direct current stimulation side effect questionnaire	Number of side effects reported on the transcranial direct current stimulation side effect questionnaire comparing non-Hispanic blacks to non-Hispanic whites for both active and sham stimulation groups (n=20 per group; 4 groups)	2 weeks
Cortical thickness	Cortical thickness comparison between non-Hispanic blacks and non-Hispanic whites	10 minutes
Blood oxygen level dependent (BOLD) response to sharp mechanical stimuli	Comparison between non-Hispanic black and non-Hispanic white participants with and without painful chemotherapy induced peripheral neuropathy	10 minutes
Blood oxygen level dependent (BOLD) response to painful heat stimuli	Comparison between non-Hispanic black and non-Hispanic white participants with and without painful chemotherapy induced peripheral neuropathy	10 minutes
Blood oxygen level dependent (BOLD) response to cold heat stimuli	Comparison between non-Hispanic black and non-Hispanic white participants with and without painful chemotherapy induced peripheral neuropathy	10 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brief pain inventory short form score	Comparing active to sham transcranial direct current stimulation in non-Hispanic black participants and non-Hispanic white participants	2 weeks
Brief pain inventory short form score	Comparing active to sham transcranial direct current stimulation in non-Hispanic black participants and non-Hispanic white participants	At 6 week follow-up

Collaborators and Investigators

• Sponsor: Morgan State University
• Collaborators: University of Maryland, Baltimore

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2025
• Primary Completion (Estimated): January 31, 2029
• Study Completion (Estimated): June 30, 2029

Study Registration Dates

• First Submitted: July 17, 2024
• First Submitted That Met QC Criteria: July 22, 2024
• First Posted (Actual): July 26, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 4, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: transcranial direct current stimulation; Chronic Pain; Neuropathy; Neuropathic Pain; Non-invasive brain stimulation
• Additional Relevant MeSH Terms: Nervous System Diseases; Neuromuscular Diseases; Peripheral Nervous System Diseases
• Other Study ID Numbers: HP-00111489

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual Participant Data will be shared through supplementary materials in primary journals and by 01/2030 are planned to be shared in data repositories or journals.

IPD Sharing Time Frame

Study protocol and statistical analysis plan are planned to be submitted to a per-registration service or journal about December 2024.

Clinical study reports and structural and functional MRI will be submitted to data repositories or peer-reviewed data journals and the Enhancing Neuro Imaging Genetics through Meta Analysis (ENIGMA) Chronic Pain Working group by about December 2030.

• IPD Sharing Access Criteria: Any de-identified data not published will be available from the study authors upon reasonable request.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• 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.: No