Chemotherapy-Induced Peripheral Neuropathy
Conditions
Brief summary
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.
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.
Interventions
DEVICEPlacebo Administration
Wear placebo TENS device
OTHERQuestionnaire Administration
Ancillary studies
DEVICETranscutaneous Electrical Nerve Stimulation
Wear active TENS device
Sponsors
National Cancer Institute (NCI)
University of Rochester NCORP Research Base
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Chemotherapy-induced Peripheral Neuropathy (CIPN) Symptoms | 6 weeks after the start of intervention | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of TENS on Hot/Burning Pain | 6 weeks after the start of intervention | 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). |
| Effect of TENS on Sharp/Shooting Pain | 6 weeks after the start of intervention | 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) |
| Effect of TENS on Numbness | 6 weeks after the start of intervention | 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) |
| Effect of TENS on Tingling | 6 weeks after the start of intervention | 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) |
| Effect of TENS on Cramping | 6 weeks after the start of intervention | 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) |
Countries
United States
Participant flow
Pre-assignment details
7 participants withdrew from the study before randomization to an arm for the following reasons: Became ineligible after registration, Lost to follow-up, Changed their mind.
Participants by arm
| Arm | Count |
|---|---|
| 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.
Questionnaire Administration: Ancillary studies
Transcutaneous Electrical Nerve Stimulation: Wear active TENS device | 72 |
| 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.
Placebo Administration: Wear placebo TENS device
Questionnaire Administration: Ancillary studies | 70 |
| Total | 142 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | App glitch during the study | 1 | 0 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Device Distribution Error | 0 | 2 |
| Overall Study | Ineligible after Randomization | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Other Medical Reasons | 0 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 3 |
Baseline characteristics
| Characteristic | Group II (Placebo TENS) | Total | Group I (Active TENS) |
|---|---|---|---|
| Age, Continuous | 63.3 years STANDARD_DEVIATION 10.7 | 62.9 years STANDARD_DEVIATION 9.7 | 62.6 years STANDARD_DEVIATION 8.6 |
| BMI | 32 kg/m^2 STANDARD_DEVIATION 7.9 | 31 kg/m^2 STANDARD_DEVIATION 7 | 30 kg/m^2 STANDARD_DEVIATION 5.8 |
| Cancer Type Breast | 31 Participants | 51 Participants | 20 Participants |
| Cancer Type GI | 20 Participants | 49 Participants | 29 Participants |
| Cancer Type Gynecologic | 6 Participants | 13 Participants | 7 Participants |
| Cancer Type Hematologic | 5 Participants | 14 Participants | 9 Participants |
| Cancer Type Other | 8 Participants | 15 Participants | 7 Participants |
| Education level Chose not to answer | 1 Participants | 1 Participants | 0 Participants |
| Education level College Degree | 27 Participants | 57 Participants | 30 Participants |
| Education level Graduate Degree | 14 Participants | 28 Participants | 14 Participants |
| Education level High School Graduate | 26 Participants | 53 Participants | 27 Participants |
| Education level Less than High School | 2 Participants | 3 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 67 Participants | 133 Participants | 66 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 7 Participants | 5 Participants |
| Neurotoxic Chemo Class Bortezomib | 4 Participants | 7 Participants | 3 Participants |
| Neurotoxic Chemo Class Platinum | 22 Participants | 53 Participants | 31 Participants |
| Neurotoxic Chemo Class Platinum and Taxane | 11 Participants | 23 Participants | 12 Participants |
| Neurotoxic Chemo Class Taxane | 32 Participants | 52 Participants | 20 Participants |
| Neurotoxic Chemo Class Vinca alkaloid | 1 Participants | 7 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 15 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 5 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 60 Participants | 120 Participants | 60 Participants |
| Sex: Female, Male Female | 51 Participants | 92 Participants | 41 Participants |
| Sex: Female, Male Male | 19 Participants | 50 Participants | 31 Participants |
| Time since Neurotoxic Chemo | 667 days | 454 days | 303 days |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 72 | 0 / 70 |
| other Total, other adverse events | 17 / 72 | 12 / 70 |
| serious Total, serious adverse events | 1 / 72 | 1 / 70 |
Outcome results
Primary
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
Time frame: 6 weeks after the start of intervention
Population: Participants who completed the baseline assessment were included in the analysis (N=141) except one extreme outlier that was removed from the Active TENS group due to data discordance among similar measures at baseline.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Group I (Active TENS) | Chemotherapy-induced Peripheral Neuropathy (CIPN) Symptoms | 32.32 score on a scale | Standard Error 0.57 |
| Group II (Placebo TENS) | Chemotherapy-induced Peripheral Neuropathy (CIPN) Symptoms | 33.37 score on a scale | Standard Error 0.59 |
Comparison: Missing data were accounted for using multiple imputation (MI) with the fully conditional specification (FCS) method. 100 replicates were imputed.~ANCOVA analysis was applied within each replicate. SAS PROC MI and MIANALYZE were used to calculate the reported estimates. (N: Active TENS=71, Placebo TENS=70)p-value: 0.19995% CI: [-0.56, 2.67]ANCOVA
Secondary
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)
Time frame: 6 weeks after the start of intervention
Population: All participants who completed the study were included in the analysis, except one who did not provide Cramping pain data at post-intervention.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Group I (Active TENS) | Effect of TENS on Cramping | Study Completers | 1.61 mean of a score on a scale | Standard Error 0.24 |
| Group I (Active TENS) | Effect of TENS on Cramping | Sample with Baseline >=4 | 2.92 mean of a score on a scale | Standard Error 0.58 |
| Group II (Placebo TENS) | Effect of TENS on Cramping | Study Completers | 2.25 mean of a score on a scale | Standard Error 0.25 |
| Group II (Placebo TENS) | Effect of TENS on Cramping | Sample with Baseline >=4 | 4.27 mean of a score on a scale | Standard Error 0.58 |
Comparison: Analysis on the Study Completers (N: Active TENS=67, Placebo TENS=62)p-value: 0.05895% CI: [-0.02, 1.31]ANCOVA
Comparison: Subgroup analysis was performed on participants who reported at least 4 out of 10 at baseline for Cramping. (N: Active TENS=18, Placebo TENS=18)p-value: 0.1195% CI: [-0.32, 3.02]ANCOVA
Secondary
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).
Time frame: 6 weeks after the start of intervention
Population: All participants who completed the study were included in the analysis, except one who did not provide Hot/Burning pain data at post-intervention.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Group I (Active TENS) | Effect of TENS on Hot/Burning Pain | Study Completers | 1.80 mean of a score on a scale | Standard Error 0.26 |
| Group I (Active TENS) | Effect of TENS on Hot/Burning Pain | Sample with Baseline >=4 | 3.32 mean of a score on a scale | Standard Error 0.6 |
| Group II (Placebo TENS) | Effect of TENS on Hot/Burning Pain | Study Completers | 2.17 mean of a score on a scale | Standard Error 0.27 |
| Group II (Placebo TENS) | Effect of TENS on Hot/Burning Pain | Sample with Baseline >=4 | 4.69 mean of a score on a scale | Standard Error 0.6 |
Comparison: Analysis on the Study Completers (N: Active TENS=67, Placebo TENS=62)p-value: 0.30295% CI: [-0.34, 1.08]ANCOVA
Comparison: Subgroup analysis on participants who reported at least 4 out of 10 at baseline for Hot/Burning Pain. (N: Active TENS=22, Placebo TENS=22)p-value: 0.11295% CI: [-0.33, 3.08]ANCOVA
Secondary
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)
Time frame: 6 weeks after the start of intervention
Population: All participants who completed the study were included in the analysis, except one who did not provide Numbness data at post-intervention.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Group I (Active TENS) | Effect of TENS on Numbness | Study Completers | 4.78 mean of a score on a scale | Standard Error 0.27 |
| Group I (Active TENS) | Effect of TENS on Numbness | Sample with Baseline >=4 | 5.30 mean of a score on a scale | Standard Error 0.26 |
| Group II (Placebo TENS) | Effect of TENS on Numbness | Study Completers | 5.30 mean of a score on a scale | Standard Error 0.28 |
| Group II (Placebo TENS) | Effect of TENS on Numbness | Sample with Baseline >=4 | 5.57 mean of a score on a scale | Standard Error 0.29 |
Comparison: Analysis on the Study Completers (N: Active TENS=67, Placebo TENS=62)p-value: 0.16695% CI: [-0.22, 1.27]ANCOVA
Comparison: Subgroup analysis was performed on participants who reported at least 4 out of 10 at baseline for Numbness. (N: Active TENS=60, Placebo TENS=50)p-value: 0.49295% CI: [-0.51, 1.05]ANCOVA
Secondary
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)
Time frame: 6 weeks after the start of intervention
Population: All participants who completed the study were included in the analysis, except one who did not provide Sharp/Shooting pain data at post-intervention.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Group I (Active TENS) | Effect of TENS on Sharp/Shooting Pain | Study Completers | 1.71 mean of a score on a scale | Standard Error 0.25 |
| Group I (Active TENS) | Effect of TENS on Sharp/Shooting Pain | Sample with Baseline >=4 | 2.87 mean of a score on a scale | Standard Error 0.55 |
| Group II (Placebo TENS) | Effect of TENS on Sharp/Shooting Pain | Study Completers | 2.04 mean of a score on a scale | Standard Error 0.26 |
| Group II (Placebo TENS) | Effect of TENS on Sharp/Shooting Pain | Sample with Baseline >=4 | 4.08 mean of a score on a scale | Standard Error 0.56 |
Comparison: Analysis on the Study Completers (N: Active TENS=67, Placebo TENS=62)p-value: 0.35195% CI: [-0.37, 1.02]ANCOVA
Comparison: Subgroup analysis was performed on participants who reported at least 4 out of 10 at baseline for Sharp/Shooting Pain. (N: Active TENS=24, Placebo TENS=23)p-value: 0.12895% CI: [-0.36, 2.79]ANCOVA
Secondary
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)
Time frame: 6 weeks after the start of intervention
Population: All participants who completed the study were included in the analysis, except one who did not provide Tingling pain data at post-intervention.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Group I (Active TENS) | Effect of TENS on Tingling | Study Completers | 4.32 mean of a score on a scale | Standard Error 0.27 |
| Group I (Active TENS) | Effect of TENS on Tingling | Sample with Baseline >=4 | 4.86 mean of a score on a scale | Standard Error 0.29 |
| Group II (Placebo TENS) | Effect of TENS on Tingling | Study Completers | 4.51 mean of a score on a scale | Standard Error 0.28 |
| Group II (Placebo TENS) | Effect of TENS on Tingling | Sample with Baseline >=4 | 5.10 mean of a score on a scale | Standard Error 0.31 |
Comparison: Analysis on the Study Completers (N: Active TENS=67, Placebo TENS=62)p-value: 0.62295% CI: [-0.56, 0.94]ANCOVA
Comparison: Subgroup analysis was performed on participants who reported at least 4 out of 10 at baseline for Tingling. (N: Active TENS=55, Placebo TENS=50)p-value: 0.58795% CI: [-0.61, 1.08]ANCOVA