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Topical Amitriptyline and Ketamine Cream in Treating Peripheral Neuropathy Caused by Chemotherapy in Cancer Patients

Assessment of Topical Treatment Response With Amitriptyline and Ketamine: Combination Trial in Chemotherapy Peripheral Neuropathy (ATTRACT-CPN)

Status
Completed
Phases
Phase 3
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT00471445
Enrollment
462
Registered
2007-05-10
Start date
2007-10-31
Completion date
2013-11-30
Last updated
2015-11-09

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Neurotoxicity, Pain, Peripheral Neuropathy, Unspecified Adult Solid Tumor, Protocol Specific

Keywords

unspecified adult solid tumor, protocol specific, pain, neurotoxicity, peripheral neuropathy

Brief summary

RATIONALE: Topical cream containing amitriptyline and ketamine may help relieve pain, numbness, tingling, and other symptoms of peripheral neuropathy. It is not yet known whether topical amitriptyline and ketamine cream is more effective than a placebo in treating peripheral neuropathy caused by chemotherapy. PURPOSE: This randomized phase III trial is studying the side effects and how well topical amitriptyline and ketamine cream work compared with a placebo in treating peripheral neuropathy caused by chemotherapy in patients with cancer.

Detailed description

OBJECTIVES: * Compare the analgesic properties and safety of topical amitriptyline and ketamine hydrochloride cream vs placebo in cancer patients with chemotherapy peripheral neuropathy (CPN) who have received taxanes or other cancer chemotherapy agents. OUTLINE: This is a multicenter, double-blind, randomized, placebo-controlled study. Patients are stratified according to Community Clinical Oncology Program (CCOP) site. Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients apply amitriptyline and ketamine hydrochloride topical analgesic cream twice daily to areas of pain, numbness, or tingling in the hands and/or feet. * Arm II: Patients apply a placebo cream twice daily to areas of pain, numbness, or tingling in the hands and/or feet. In both arms, treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients may continue treatment for up to a total of 12 weeks. Patients complete a peripheral neuropathy intensity and quality of sleep diary daily. Patients also complete the European Organization for Research and Treatment of Cancer Quality of Life-Chemotherapy-Induced Peripheral Neuropathy (EORTC-CIPN20) to assess change in sensory score and the Brief Pain Inventory and Hospital Anxiety and Depression Scale to assess health-related quality of life in week 3 and 6. The Vulnerable Elders Survey (VES-13) is administered at baseline to assess level of physical activity and the University of Rochester Cancer Center (URCC) symptom inventory is administered to track other potentially important symptoms. The Patient Global Impression of Change Questionnaire is administered in week 6 to assess the patient's overall assessment of change since beginning treatment, including changes in pain, side effects, functional status, and overall satisfaction with treatment. PROJECTED ACCRUAL: A total of 462 patients will be accrued for this study.

Interventions

DRUGketamine/amitriptyline NP-H cream

Subjects were instructed to apply up to, but not exceeding, 4 g of ketamine/amitriptyline NP-H cream two times per day to each area with pain, numbness, and/or tingling. A measuring device was provided to assist in dispensing the proper amount of the cream.

OTHERplacebo

Applied topically

Sponsors

National Cancer Institute (NCI)
CollaboratorNIH
Gary Morrow
Lead SponsorOTHER

Study design

Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No

Inclusion criteria

DISEASE CHARACTERISTICS: * History of cancer * Pain, numbness, or tingling in the hands or feet beginning in association with a cancer chemotherapy agent (taxane or other chemotherapeutic agent) and persisting for at least 28 days following the conclusion of chemotherapy * Pain, numbness, or tingling can be assessed 28 days or more after the conclusion of chemotherapy * An average score of ≥ 4 for the 7 daily ratings of the baseline week on the 11-point rating scale of peripheral neuropathy associated with chemotherapy, with a minimum of 5 daily diary ratings completed during the baseline week * No preexisting or history of peripheral neuropathy due to any cause other than chemotherapy (e.g., hereditary, alcohol, or diabetes) * Patients with stable systemic metastases and/or bone involvement AND has not received chemotherapy within 3 months of screening assessment are eligible * Patients receiving ongoing treatment with non-chemotherapy agents (e.g., monoclonal antibodies or hormonal treatment) allowed * No concurrent active chemotherapy in the adjuvant setting or for progressive systemic disease PATIENT CHARACTERISTICS: * Karnofsky performance status 60-100% * Creatinine ≤ 2 mg/dL * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * Able to adequately understand English * No allergy or hypersensitivity to ketamine hydrochloride or amitriptyline or any of the components of study drug * No clinically significant illness (e.g., endocrine, cardiac, hepatic, renal, neurologic, hematologic, or skeletal illness) that, in the investigator's clinical judgment, could interfere with the efficacy or safety assessments in this study * No glaucoma or recurrent urinary retention * No clinically significant depression or dementia that, in the opinion of the investigator, may interfere with a patient's adherence to the study protocol and/or the accurate and consistent reporting of CPN * No open skin lesions in the area where the cream is to be applied * No HIV positivity PRIOR CONCURRENT THERAPY: * See Disease Characteristics * At least 30 days since prior unapproved experimental drugs or biological agents * No prior topical treatment, nerve blocks, implantable therapy, peripheral nerve or spinal cord stimulation, or neurosurgical procedure for chemotherapy-related peripheral neuropathy (CPN) * No prior exposure to a peripheral neurotoxin other than chemotherapy * No concurrent medications (e.g., phenytoin) known to be associated with sensory neuropathy * No concurrent selective serotonin reuptake inhibitors (e.g., fluoxetine, paroxetine, or sertraline), which inhibit CP450 2D6, unless the patient is being treated for depression or another psychiatric disorder and, in the investigator's judgment, the patient's participation in the study can be permitted given the minimal systemic levels of amitriptyline found within the cream * No concurrent monoamine oxidase inhibitors, barbiturates, anticholinergic agents, or sympathomimetic drugs, including epinephrine combined with local anesthetics * Oral inhalers that include any of the drugs listed above are allowed * Concurrent opioid analgesics, tricyclic or dual reuptake inhibitor antidepressants, or gabapentin or pregabalin for CPN, or benzodiazepines for sleep allowed, provided dose has been stable for ≥ 2 weeks and the following are true: * Gabapentin dose ≤ 1,800 mg per day * Pregabalin dose ≤ 300 mg per day * Opioid analgesic dose ≤ 60 mg oxycodone hydrochloride equivalent per day * Tricyclic antidepressant dose ≤ 75 mg amitriptyline equivalent per day * Duloxetine dose ≤ 60 mg per day * Venlafaxine dose ≤ 150 mg per day * Tramadol dose ≤ 200 mg per day * Concurrent adjunctive analgesic therapy, such as acupuncture, biofeedback, or herbal preparations, allowed provided dose has been stable for ≥ 2 weeks

Design outcomes

Primary

MeasureTime frameDescription
Change in Average Daily Peripheral Neuropathy Intensity Score From Baseline to Week 6 in Patients Treated With Amitriptyline and Ketamine Hydrochloride vs PlaceboWeek 6 - BaselineCancer survivors who completed chemotherapy at least 1 month prior and had Chemotherapy Induced Peripheral Neuropathy (CIPN) (greater than or equal to 4 out of 10) were enrolled. CIPN was assessed using average scores from a 7-day daily diary that asks patients to rate the average pain, numbness, or tingling in their hands and feet over the past 24 hours on an 11-point numeric rating scale at baseline and 6 weeks post intervention. CIPN ranges from 0 (no pain) to 10 (worst possible pain).

Countries

United States

Participant flow

Participants by arm

ArmCount
Amitriptyline and Ketamine Hydrochloride Topical Analgesic cr
Patients apply amitriptyline and ketamine hydrochloride topical analgesic cream twice daily to areas of pain, numbness, or tingling in the hands and/or feet. ketamine/amitriptyline NP-H cream: Applied topically
227
Placebo Cream
Patients apply a placebo cream twice daily to areas of pain, numbness, or tingling in the hands and/or feet. placebo: Applied topically
231
Total458

Withdrawals & dropouts

PeriodReasonFG000FG001
Overall StudyIneligible10
Overall StudyProtocol Violation01
Overall StudyWithdrawal by Subject11

Baseline characteristics

CharacteristicAmitriptyline and Ketamine Hydrochloride Topical Analgesic crPlacebo CreamTotal
Age, Continuous60.7 years
STANDARD_DEVIATION 10.5
60.6 years
STANDARD_DEVIATION 10
60.7 years
STANDARD_DEVIATION 10.2
Education
Completed graduate training
28 participants19 participants47 participants
Education
High school graduate
63 participants65 participants128 participants
Education
Not high school educated
7 participants12 participants19 participants
Education
Partial college training (<4 years)
76 participants80 participants156 participants
Education
Standard college or university (4 years)
53 participants55 participants108 participants
Ethnicity (NIH/OMB)
Hispanic or Latino
6 Participants6 Participants12 Participants
Ethnicity (NIH/OMB)
Not Hispanic or Latino
220 Participants224 Participants444 Participants
Ethnicity (NIH/OMB)
Unknown or Not Reported
1 Participants1 Participants2 Participants
Marital status
Divorced
20 participants25 participants45 participants
Marital status
Married
165 participants160 participants325 participants
Marital status
Separated
2 participants3 participants5 participants
Marital status
Single
23 participants21 participants44 participants
Marital status
Widowed
17 participants22 participants39 participants
Previous treatment
Previous chemotherapy
227 participants231 participants458 participants
Previous treatment
Previous radiation therapy
114 participants109 participants223 participants
Previous treatment
Previous surgery
198 participants195 participants393 participants
Race (NIH/OMB)
American Indian or Alaska Native
0 Participants0 Participants0 Participants
Race (NIH/OMB)
Asian
0 Participants0 Participants0 Participants
Race (NIH/OMB)
Black or African American
20 Participants18 Participants38 Participants
Race (NIH/OMB)
More than one race
8 Participants7 Participants15 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
0 Participants0 Participants0 Participants
Race (NIH/OMB)
Unknown or Not Reported
0 Participants0 Participants0 Participants
Race (NIH/OMB)
White
199 Participants206 Participants405 Participants
Regimen
Non-Taxane
101 participants111 participants212 participants
Regimen
Taxanes
126 participants120 participants246 participants
Region of Enrollment
United States
227 participants231 participants458 participants
Sex: Female, Male
Female
156 Participants171 Participants327 Participants
Sex: Female, Male
Male
71 Participants60 Participants131 Participants
Site
Bone and cartilaginous
2 participants0 participants2 participants
Site
Breast
96 participants88 participants184 participants
Site
Cardiac
0 participants1 participants1 participants
Site
Genitourinary tract
15 participants9 participants24 participants
Site
GI
55 participants69 participants124 participants
Site
Gynecologic
15 participants16 participants31 participants
Site
Head and neck
7 participants5 participants12 participants
Site
Hematologic
24 participants18 participants42 participants
Site
Lung
12 participants23 participants35 participants
Site
Melanoma
0 participants1 participants1 participants
Site
Other
5 participants4 participants9 participants
Site
Skin
1 participants1 participants2 participants
Site
Soft tissue sarcoma
2 participants1 participants3 participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
deaths
Total, all-cause mortality
— / —— / —
other
Total, other adverse events
147 / 227158 / 231
serious
Total, serious adverse events
4 / 2274 / 231

Outcome results

Primary

Change in Average Daily Peripheral Neuropathy Intensity Score From Baseline to Week 6 in Patients Treated With Amitriptyline and Ketamine Hydrochloride vs Placebo

Cancer survivors who completed chemotherapy at least 1 month prior and had Chemotherapy Induced Peripheral Neuropathy (CIPN) (greater than or equal to 4 out of 10) were enrolled. CIPN was assessed using average scores from a 7-day daily diary that asks patients to rate the average pain, numbness, or tingling in their hands and feet over the past 24 hours on an 11-point numeric rating scale at baseline and 6 weeks post intervention. CIPN ranges from 0 (no pain) to 10 (worst possible pain).

Time frame: Week 6 - Baseline

ArmMeasureGroupValue (MEAN)
Ketamine/Amitriptyline NP-H CreamChange in Average Daily Peripheral Neuropathy Intensity Score From Baseline to Week 6 in Patients Treated With Amitriptyline and Ketamine Hydrochloride vs PlaceboBaseline6.55 units on a scale
Ketamine/Amitriptyline NP-H CreamChange in Average Daily Peripheral Neuropathy Intensity Score From Baseline to Week 6 in Patients Treated With Amitriptyline and Ketamine Hydrochloride vs PlaceboWeek 64.93 units on a scale
Placebo CreamChange in Average Daily Peripheral Neuropathy Intensity Score From Baseline to Week 6 in Patients Treated With Amitriptyline and Ketamine Hydrochloride vs PlaceboBaseline6.47 units on a scale
Placebo CreamChange in Average Daily Peripheral Neuropathy Intensity Score From Baseline to Week 6 in Patients Treated With Amitriptyline and Ketamine Hydrochloride vs PlaceboWeek 65.19 units on a scale
Comparison: Tested at the two-sided 0.05 significance level.p-value: 0.36395% CI: [-0.548, 0.201]ANCOVA

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026