Effects of Transcutaneous Electrical Nerve Stimulation on Chemotherapy-Induced Peripheral Neuropathy

Wireless Transcutaneous Electrical Nerve Stimulation (TENS) for Chemotherapy-Induced Peripheral Neuropathy: A Phase II Clinical Trial

This phase II trial studies the effects of transcutaneous electrical nerve stimulation (TENS) for the treatment of peripheral neuropathy caused by chemotherapy, often called chemotherapy-induced peripheral neuropathy (CIPN). Peripheral neuropathy refers to the conditions that result when nerves that carry messages to and from the brain and spinal cord from and to the rest of the body are damaged or diseased. The TENS device emits high frequency electrical stimulation through the skin and may provide relief from chronic pain.

Study Overview

• Status: Completed
• Conditions: Chemotherapy-Induced Peripheral Neuropathy
• Intervention / Treatment: Other: Questionnaire Administration; Device: Transcutaneous Electrical Nerve Stimulation; Device: Placebo Administration

Detailed Description

PRIMARY OBJECTIVE:

I. Obtain efficacy estimates of daily TENS on CIPN (European Organization for Research and Treatment of Cancer-CIPN20 [EORTC-CIPN20]) to inform the design of a phase III confirmatory trial.

SECONDARY OBJECTIVES:

I. Obtain efficacy estimates of TENS on individual CIPN symptoms (i.e., hot/burning pain, sharp/shooting pain, tingling, numbness, cramping (measured daily via 0 - 10 numeric rating scale [NRS]).

II. Evaluate the feasibility of conducting, within the University of Rochester Cancer Center (URCC) National Cancer Institute Community Oncology Research Program (NCORP) network, a multisite, modified double-blind randomized control trial (RCT) of TENS for CIPN with physiologic assessments of descending inhibition (i.e., conditioned pain modulation [CPM] test) by assessing the proportions of (a) screened patients who enroll, (b) randomized participants who adhere to the treatment and complete the primary assessment, and (c) randomized participants who complete the CPM test.

EXPLORATORY OBJECTIVES:

I. Investigate the potential effects of TENS on balance, physical function, descending inhibition, lower limb sensation, and anxiety and depression.

II. Establish data to support the construct validity of the Treatment-Induced Neuropathy Assessment Scale (TNAS) and CIPN symptom inventory daily diary by comparison to the EORTC-CIPN20, which is the most commonly used measure of CIPN.

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP I: Patients wear an active wireless TENS device 5 hours daily for up to 6 weeks in the absence of unacceptable toxicity.

GROUP II: Patients wear a placebo wireless TENS device 5 hours daily for up to 6 weeks in the absence of unacceptable toxicity.

• Study Type: Interventional
• Enrollment (Actual): 151
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Delaware
    • Newark, Delaware, United States, 19713
      • Christiana Health Care System
  • Florida
    • Fort Myers, Florida, United States, 33905
      • Lee Memorial Health System
  • Illinois
    • Decatur, Illinois, United States, 62526
      • Decatur Memorial Hospital
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health at Butterworth Campus
    • Wyoming, Michigan, United States, 49519
      • Metro Health Hospital
  • South Carolina
    • Gaffney, South Carolina, United States, 29341
      • Gibbs Cancer Center-Gaffney
    • Greenville, South Carolina, United States, 29605
      • Prisma Health Cancer Institute - Faris
    • Greenville, South Carolina, United States, 29615
      • Prisma Health Cancer Institute - Eastside
    • Greenville, South Carolina, United States, 29605
      • Prisma Health Cancer Institute - Butternut
    • Greer, South Carolina, United States, 29651
      • Gibbs Cancer Center-Pelham
    • Spartanburg, South Carolina, United States, 29303
      • Spartanburg Medical Center
    • Union, South Carolina, United States, 29379
      • MGC Hematology Oncology-Union
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54301
      • Saint Vincent Hospital Cancer Center Green Bay
    • Green Bay, Wisconsin, United States, 54303
      • St. Vincent Hospital Cancer Center at St. Mary's
    • Wausau, Wisconsin, United States, 54401
      • Aspirus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Have completed treatment with a platinum agent, taxane, vinca alkaloid, or bortezomib at least 3 months prior to registration
• Have a clinical diagnosis of CIPN from their physician or physician designee based on the following criteria: bilateral (i.e., present on both sides of the body), abnormal sensory symptoms in their feet or legs (e.g., hot/burning pain, sharp/shooting pain, numbness, tingling, cramping)
• Report at least 1 non-painful symptom associated with CIPN in their lower limbs (e.g., tingling, burning that isn't reported as painful, numbness)
• Report at least 2 of the following symptoms in their lower limbs (at their worst) as at least 4 out of 10 on a 0 - 10 NRS: hot/burning pain, sharp/shooting pain, numbness, tingling, cramping at visit 1 (i.e., week -1). Use the CIPN Symptom Inventory - week recall form (questions 1-5 ONLY) to assess these symptoms at screening
• Be willing and able not to start any new analgesic medications or change the dosages of any current analgesic medications (except acetaminophen [Tylenol] or non-steroidal anti-inflammatory drugs [NSAIDs] [i.e., ibuprofen (Advil, Motrin), naproxen (Aleve)]) for the duration of the study
• Be able to read English (i.e., is not illiterate, can speak English, and is not blind)
• Have access to a smart phone or device with an Apple or Android operating system that can be used to access the TENS device's application (App) and ability to connect to the internet on a daily basis during the trial

Exclusion Criteria:

• Have pre-existing neuropathy of any cause documented in their medical record prior to the start of chemotherapy or respond "yes" to the question "Did you have frequent numbness, tingling, sharp/shooting pain, hot/burning pain, or cramping in your feet before you started your chemotherapy?"
• Have unilateral CIPN symptoms (i.e., symptoms occur on predominantly only one side of the body)
• Be currently using a TENS device for any other reason
• Be currently taking, or have taken in the past 3 months, medications known to cause neuropathy in a significant portion of patients
• Have an acute and symptomatic lower extremity deep vein thrombosis (DVT) (treated DVT with resolution of symptoms is acceptable for enrollment)
• Lower extremity edema that is 2+ or greater (i.e., slight indentation that takes less than 15 seconds to rebound)
• Have started a new prescription pain medication or altered dosages of a prescription pain medication within the last 2 weeks
• Have lower extremity wounds or ulcers
• Have a cardiac pace maker or defibrillator
• Have epilepsy
• Have a leg that is too small or too large for the TENS device to fit securely
• Have missing lower limbs or amputations
• Have impaired decision making capacity (i.e., requires a legally authorized representative or health care proxy)
• Be pregnant or planning to get pregnant before expected completion of the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group I (Active TENS); Patients wear an active wireless TENS device 5 hours daily for up to 6 weeks in the absence of unacceptable toxicity.	Other: Questionnaire Administration; Ancillary studies; Device: Transcutaneous Electrical Nerve Stimulation; Wear active TENS device; Other Names: TENS; transcutaneous electric nerve stimulation
Placebo Comparator: Group II (Placebo TENS); Patients wear a placebo wireless TENS device 5 hours daily for up to 6 weeks in the absence of unacceptable toxicity.	Other: Questionnaire Administration; Ancillary studies; Device: Placebo Administration; Wear placebo TENS device

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Chemotherapy-induced Peripheral Neuropathy (CIPN) Symptoms	Measured by the mean European Organization for Research and Treatment of Cancer-CIPN20 (EORTC-CIPN20). The effects of transcutaneous electrical nerve stimulation (TENS) on CIPN will be estimated using analysis of covariance (ANCOVA). A 20 -item patient self -report tool to assess symptoms and function in the sensory, motor and autonomic domains. Two items, Q49 and Q50, were excluded from the total score calculation. Q49 was relevant only for individuals who could drive, and Q50 was relevant only for men. 0 - 72, a higher score indicates worse neuropathy	6 weeks after the start of intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of TENS on Hot/Burning Pain	Measured by the CIPN Symptom Inventory; numeric rating scale of 0-10. Higher score is worse. The effects of transcutaneous electrical nerve stimulation (TENS) on hot/burning pain will be estimated using analysis of covariance (ANCOVA) for 2 study populations: (1) Study Completers (N: Active TENS=67, Placebo TENS=62) and (2) participants who reported at least 4 out of 10 at baseline for Hot/Burning Pain. (N: Active TENS=22, Placebo TENS=22).	6 weeks after the start of intervention
Effect of TENS on Sharp/Shooting Pain	Measured by the CIPN Symptom Inventory; numeric rating scale of 0-10. Higher score is worse. The effects of transcutaneous electrical nerve stimulation (TENS) on sharp/shooting pain will be estimated using analysis of covariance (ANCOVA) for 2 study populations: (1) Study Completers (N: Active TENS=67, Placebo TENS=62) and (2) participants who reported at least 4 out of 10 at baseline for Sharp/Shooting Pain. (N: Active TENS=24, Placebo TENS=23)	6 weeks after the start of intervention
Effect of TENS on Numbness	Measured by the CIPN Symptom Inventory; numeric rating scale of 0-10. Higher score is worse. The effects of transcutaneous electrical nerve stimulation (TENS) on numbness will be estimated using analysis of covariance (ANCOVA) for 2 study populations: (1) Study Completers (N: Active TENS=67, Placebo TENS=62) and (2) participants who reported at least 4 out of 10 at baseline for Numbness. (N: Active TENS=60, Placebo TENS=50)	6 weeks after the start of intervention
Effect of TENS on Tingling	Measured by the CIPN Symptom Inventory; numeric rating scale of 0-10. Higher score is worse. The effects of transcutaneous electrical nerve stimulation (TENS) on tingling will be estimated using analysis of covariance (ANCOVA) for 2 study populations: (1) Study Completers (N: Active TENS=67, Placebo TENS=62) and (2) participants who reported at least 4 out of 10 at baseline for Tingling. (N: Active TENS=55, Placebo TENS=50)	6 weeks after the start of intervention
Effect of TENS on Cramping	Measured by the CIPN Symptom Inventory; numeric rating scale of 0-10. Higher score is worse. The effects of transcutaneous electrical nerve stimulation (TENS) on cramping will be estimated using analysis of covariance (ANCOVA) for 2 study populations: (1) Study Completers (N: Active TENS=67, Placebo TENS=62) and (2) participants who reported at least 4 out of 10 at baseline for Cramping. (N: Active TENS=18, Placebo TENS=18)	6 weeks after the start of intervention

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of TENS on balance (on Short Physical Performance Battery [SPPB])	Estimated using ANCOVA.	At baseline and 6 weeks
Descending inhibition (on Conditioned Pain Modulation [CPM] test)	Estimated using ANCOVA. Descriptive statistics will be used to characterize the distribution of descending inhibition as measured by CPM at baseline. ANCOVA analysis will be used to investigate whether baseline descending inhibition predicts the effect of TENS on CIPN.	At baseline and 6 weeks
Effect of TENS on physical function	Measured by Patient Reported Outcomes Measurement Information System (PROMIS) short form. 4 physical activity items are rated from 1-5 corresponding to "Cannot Do" to "Without any difficulty" and 4 items regarding how health limits activity are rated from 1-5 "Cannot Do" to "Not at all". Estimated using ANCOVA.	At baseline and 6 weeks
CIPN-interference in daily life	Measured by the CIPN-interference in daily life questionnaire which uses 0-10 numeric rating scale [0 = does not interfere, 10 = completely interferes]. Estimated using ANCOVA.	At baseline and 6 weeks
CIPN	Will be measured by Treatment-Induced Neuropathy Assessment Scale (TNAS) and CIPN symptom inventory composite measure. The correlation of descending inhibition with CIPN severity (via CIPN20, TNAS, and symptom numeric rating scale [NRS] scores) will be evaluated using a Spearman's correlations. Estimated using ANCOVA.	At baseline and 6 weeks
Depression and anxiety	Estimated using ANCOVA.	At baseline and 6 weeks
Analgesic use	The proportion of participants who decreased "as-needed" usage of acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) (defined as taking acetaminophen or NSAIDs, on average, at least 30% fewer days per week in the last week of the trial compared to the baseline week) will be compared by groups using a chi-square test.	At baseline and 6 weeks
Patient reported change in CIPN symptoms	The proportion of participants who report, for the impression of change in CIPN symptoms question "very much improved", "much improved", "minimally improved", "no change", "minimally worse", "much worse", and "very much worse") will be compared between treatment groups using a Cochran Armitage Trend Test.	At baseline and 6 weeks
Patient sensation threshold from monofilament test	The proportion of participants whose sensation threshold from the monofilament test improved will be reported together with the 95% confidence interval (CI) and tested against the null hypothesis of no improvement.	At baseline and 6 weeks
Percentage of participants and outcome assessors that correctly identify the group to which the participant was assigned	Descriptive statistics and 95% CIs will be used to assess the percentage of participants and outcome assessors that correctly identify the group to which the participant was assigned as well as the basis for the guesses.	After 6 weeks of device use
Test, re-test reliability for CPM test	Will be evaluated using intraclass correlation coefficients (ICCs). Test, re-test reliability for the lower limb sensation threshold test will be measured using Kappa statistics.	After 6 weeks of device use

Collaborators and Investigators

• Sponsor: University of Rochester NCORP Research Base
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Jennifer Gewandter, University of Rochester NCORP Research Base

Study record dates

Study Major Dates

• Study Start (Actual): September 10, 2020
• Primary Completion (Actual): October 3, 2022
• Study Completion (Actual): October 3, 2022

Study Registration Dates

• First Submitted: April 21, 2020
• First Submitted That Met QC Criteria: April 24, 2020
• First Posted (Actual): April 29, 2020

Study Record Updates

• Last Update Posted (Actual): September 8, 2023
• Last Update Submitted That Met QC Criteria: August 16, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neuromuscular Diseases; Peripheral Nervous System Diseases
• Other Study ID Numbers: URCC19085 (Other Identifier: University of Rochester NCORP Research Base); UG1CA189961 (U.S. NIH Grant/Contract); NCI-2019-07566 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); URCC-19085 (Other Identifier: CTEP); R21CA235389 (U.S. NIH Grant/Contract)

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