PEA for the Relief of Chemotherapy-Induced Peripheral Neuropathy

Treatment of Established Chemotherapy-Induced Neuropathy With N-Palmitoylethanolamide, a Cannabimimetic Nutraceutical: A Randomized Double-Blind Phase II Pilot Trial

This phase II trial tests whether PEA works to relieve the symptoms of chemotherapy-induced peripheral neuropathy in patients with cancer. Chemotherapy-induced peripheral neuropathy refers to a nerve problem that causes pain, numbness, tingling, or muscle weakness in different parts of the body, and is caused by chemotherapy. PEA may be useful against bothersome nerve symptoms.

Study Overview

• Status: Active, not recruiting
• Conditions: Hematopoietic and Lymphoid Cell Neoplasm; Malignant Solid Neoplasm; Chemotherapy-Induced Peripheral Neuropathy
• Intervention / Treatment: Other: Quality-of-Life Assessment; Drug: Placebo Administration; Drug: Palmidrol

Detailed Description

PRIMARY OBJECTIVE:

I. To look for evidence of the efficacy of PEA (N-palmitoylethanolamide) at two different doses relative to placebo responses, as a treatment for chemotherapy-induced neuropathy (CIPN).

SECONDARY OBJECTIVES:

I. To assess the safety of PEA at the two study doses. II. To evaluate changes in patient-reported quality of life from baseline to the end of 8 weeks.

EXPLORATORY OBJECTIVES:

I. To explore whether PEA appears to affect cognition in the study patients. II. To explore the weekly trajectory of CIPN from baseline to 8 weeks. III. To explore the weekly trajectory of pain using the single-item numerical rating scale from baseline to 8 weeks.

IV. To explore the weekly patient global impression of change in each treatment arm from baseline to 8 weeks.

V. To explore the weekly chemotherapy induced peripheral neuropathy in each treatment arm from baseline to 8 weeks.

VI. To explore the PEA effects on CIPN20 between two PEA dosage arms. VII. To explore the number of recurrent cancer events by study arm. VIII. To explore the overall survival by study arm.

OUTLINE: Patients are randomized to 1 of 4 arms.

ARM I: Patients receive PEA orally (PO) once daily (QD) for 8 weeks as long as there is not any unacceptable toxicity.

ARM II: Patients receive PEA PO twice daily (BID) for 8 weeks as long as there is not any unacceptable toxicity.

ARM III: Patients receive placebo PO QD for 8 weeks.

ARM IV: Patients receive placebo PO BID for 8 weeks.

After completion of study intervention, patients are followed up at 6 and 12 months.

• Study Type: Interventional
• Enrollment (Actual): 88
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • Middletown, Connecticut, United States, 06457
      • Middlesex Hospital
  • Illinois
    • Urbana, Illinois, United States, 61801
      • Carle Cancer Center NCI Community Oncology Research Program
  • Iowa
    • Sioux City, Iowa, United States, 51101
      • Siouxland Regional Cancer Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • North Carolina
    • Greensboro, North Carolina, United States, 27403
      • Cone Health Cancer Center
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Medical Center
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Rapid City Regional Hospital
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University/Ingram Cancer Center
  • Wisconsin
    • Eau Claire, Wisconsin, United States, 54703
      • Mayo Clinic Health System Eau Claire Hospital-Luther Campus
    • La Crosse, Wisconsin, United States, 54601
      • Mayo Clinic Health System-Franciscan Healthcare

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age >= 18 years

• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, 2

  • NOTE: Patients with a history of metastatic cancer or an ECOG performance status of 2 must have laboratory (lab) work completed =< 28 days prior to registration
• Pain, numbness, tingling or other symptoms of CIPN of >= 3 months (90 days) duration for which the patient is seeking an intervention
• Neurotoxic chemotherapy must have been completed >= 3 months (90 days) prior to registration and there must be no further planned neurotoxic -chemotherapy for > 2 months after registration Note: The study is limited to those with taxane- and/or platinum-based neuropathy

• Patient must note tingling, numbness or pain symptoms of at least a four out of ten =< 7 days prior to registration.

  • Note: On a 0-10 scale where zero was 'no problem' and ten being 'as bad a problem that could be imagined': how much of a problem has numbness, tingling, and/or pain in your fingers and/or toes been in the past week?
• Patient must be able to speak, read and comprehend English

• For women of childbearing potential only, a negative urine or serum pregnancy test done =< 14 days prior to registration is required

  • A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)

    • NOTE: If the urine test cannot be confirmed as negative, a serum pregnancy test will be required
• Life expectancy >= 6 months

• Platelet count > 100,000/mm^3

  • NOTE: Patients with a history of metastatic breast cancer or an ECOG performance status of 2 must have this lab completed =< 28 days prior to registration

• Absolute neutrophil count (ANC) >= 1,000/mm^3

  • NOTE: Patients with a history of metastatic breast cancer or an ECOG performance status of 2 must have this lab completed =< 28 days prior to registration

• Hemoglobin > 11 g/dL

  • NOTE: Patients with a history of metastatic breast cancer or an ECOG performance status of 2 must have this lab completed =< 28 days prior to registration

• Serum transaminase (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) =< 1.2 x upper limit of normal (ULN)

  • NOTE: Patients with a history of metastatic breast cancer or an ECOG performance status of 2 must have these labs completed =< 28 days prior to registration

• Alkaline phosphatase =< 1.2 x ULN

  • NOTE: Patients with a history of metastatic breast cancer or an ECOG performance status of 2 must have this lab completed =< 28 days prior to registration

• Serum creatinine =< 1.2 x ULN

  • NOTE: Patients with a history of metastatic cancer or an ECOG performance status of 2 must have this lab completed =< 28 days prior to registration
• Able to swallow oral medication
• Provide written informed consent =< 28 days prior to registration

Exclusion Criteria:

• Currently receiving neurotoxic chemotherapy for a second cancer or recurrence of the primary cancer
• Impaired decision-making capacity (such as with a diagnosis of dementia or memory loss)
• Evidence of residual cancer, per routine clinical practice-based parameters

• Comorbid conditions:

  • Previous diagnosis of diabetic or another non chemotherapy induced peripheral neuropathy
  • Previous history of peripheral neuropathy prior to receiving neurotoxic chemotherapy
  • Neuropathy from human immunodeficiency virus (HIV) infection. Note: Patients with HIV infections are eligible as long as they do not have a neuropathy from their viral illness
• Concurrent use of a cannabis product (tetrahydrocannabinol [THC] and/or cannabidiol [CBD]). Patients should have discontinued these products >= 4 weeks prior to registration
• Current or previous use of PEA
• Currently receiving or planning to start any of the following agents: opioids, duloxetine, gabapentin or pregabalin. Patients are eligible if they discontinue these medications >= 1 week prior to registration

• Any of the following because the study involves an investigational agent whose genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn are unknown:

  • Pregnant persons
  • Nursing persons
  • Persons of childbearing potential who are unwilling to employ adequate contraception

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: BID placebo; Patients receive placebo PO BID for 8 weeks.	Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Drug: Placebo Administration; Given PO
Experimental: Higher-dose PEA; Patients receive PEA PO BID for 8 weeks as long as there is not any unacceptable toxicity.	Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Drug: Palmidrol; Given PEA PO; Other Names: PEA; N-Palmitoyl Ethanolamide; N-Palmitoylethanolamide; OptiPEA; Palmitoyl Ethanolamide; Palmitoylethanolamide
Experimental: Lower-dose PEA; Patients receive PEA PO QD for 8 weeks as long as there is not any unacceptable toxicity.	Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Drug: Palmidrol; Given PEA PO; Other Names: PEA; N-Palmitoyl Ethanolamide; N-Palmitoylethanolamide; OptiPEA; Palmitoyl Ethanolamide; Palmitoylethanolamide
Placebo Comparator: QD placebo; Patients receive placebo PO QD for 8 weeks.	Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Drug: Placebo Administration; Given PO

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in Quality of Life Questionnaire - Chemotherapy-Induced Peripheral Neuropathy 20 (CIPN20) Score	Will be scored and summarized at each time point for each patient. The change from baseline to 8 weeks will then be calculated for each patient. The mean, standard deviation, and median (range) of the change will be calculated for each PEA arm and the combined placebo arm. The difference in change scores between each PEA arm and the combined placebo will be estimated along with a 95% confidence interval. For the primary analysis, the CIPN20 analysis dataset will include all eligible patients who are randomized, initiated treatment, and completed the baseline questionnaire. For patients who go off protocol treatment before 8 weeks, the score at their final observation will be used to calculate the change. The CIPN20 includes 20 items, each asking a participant to rate their experience with certain symptoms from 1 to 4, with 1 being no difficulty with the symptom and 4 being the most difficulty with the symptom. Answers are then summed to give a total score from 20 to 80.	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing Grade 3+ Adverse Events	Adverse events by patient will be summarized by frequencies and severity using Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. The proportion of patients who experience at least one grade 3+ adverse event (regardless of attribution) will be reported. The overall adverse event rates for grade 3 or higher adverse events will be compared across the three arms (the two PEA arms and combined placebo).	8 weeks
Mean Change of Quality of Life	Will be assessed by Question 3, patient-reported outcomes-quality of life (PRO-QOL). The mean and standard deviation of the change will be reported for each PEA arm and the combined placebo arm. Additional analysis using data collected from the Symptom Experience Diary may be performed. For patients who go off protocol treatment before 8 weeks, the question 3 response at their final observation will be used to calculate the change. For patients who do not have any post baseline data, they will be considered to have no change from baseline. Question 3 of the PRO-QOL is a 10 point scale asking participants to rate their quality of life, with 0 being the worst and 10 being the best.	8 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Chemotherapy Induced Peripheral Neuropathy Assessment Tool	Will be summarized by mean (SD) and median (range) at each time point for each treatment arm and the combine placebo arm.	Baseline up to 8 weeks
Change in the Two Cognitive Items of the Cognitive Functioning Assessment	Will be summarized by mean (SD) and median (range) by treatment arm and the combined placebo arm. The difference in change score will be estimated along with the 95% confidence interval.	Baseline up to 8 weeks
Weekly CIPN20 Scores	Will be summarized at each time point by mean (SD) and median (range) and will be plotted longitudinally by treatment arm and the combine placebo arm.	Baseline up to 8 weeks
Weekly Pain Scores	Will be summarized at each time point by mean (SD) and median (range) and will be plotted longitudinally by treatment arm and the combine placebo arm.	Baseline up to 8 weeks
Items of the Global Impression of Change Tool	Will be summarized by frequency (percentage) of each level at each time point for each treatment arm and the combine placebo arm. Bar plots for each PEA arm and the combined placebo arm of frequency over time will be> constructed.	Baseline up to 8 weeks
CIPN20 Score	Will be calculated for each patient. The mean and standard deviation of the change will be calculated for each PEA arm. The difference in CIPN20 change scores between the two PEA dosage arms will be estimated along with a 95% confidence interval.	Baseline up to 8 weeks
Disease Recurrence	The number of events and percentage will be reported by each PEA arm and combined placebo arm. No hypothesis test will be performed between arms.	At 6 and 12 months
Overall Survival (OS)	For each PEA arm and combined placebo arm, the distributions of OS time will be estimated using the Kaplan-Meier method. Log-rank test will be used to compare the survival distributions between each PEA and the combined placebo arm.	From registration to death due to any cause, assessed up to 12 months

Collaborators and Investigators

• Sponsor: Academic and Community Cancer Research United
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Mellar P Davis, Academic and Community Cancer Research United

Study record dates

Study Major Dates

• Study Start (Actual): May 16, 2022
• Primary Completion (Actual): February 12, 2024
• Study Completion (Estimated): February 28, 2026

Study Registration Dates

• First Submitted: February 11, 2022
• First Submitted That Met QC Criteria: February 17, 2022
• First Posted (Actual): February 18, 2022

Study Record Updates

• Last Update Posted (Actual): September 22, 2025
• Last Update Submitted That Met QC Criteria: September 10, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Hematologic Neoplasms; Anti-Infective Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Peripheral Nervous System Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antirheumatic Agents; Sensory System Agents; Antiviral Agents; Analgesics, Non-Narcotic; Analgesics; Neurotransmitter Agents; Anti-Inflammatory Agents, Non-Steroidal; Cannabinoid Receptor Agonists; Cannabinoid Receptor Modulators; palmidrol
• Other Study ID Numbers: ACCRU-SC-2102 (Other Identifier: Academic and Community Cancer Research United); P30CA015083 (U.S. NIH Grant/Contract); NCI-2022-00002 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No