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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00471445
Recruitment Status : Completed
First Posted : May 10, 2007
Results First Posted : June 10, 2015
Last Update Posted : November 9, 2015
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Gary Morrow, University of Rochester NCORP Research Base

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.

Condition or disease Intervention/treatment Phase
Neurotoxicity Pain Peripheral Neuropathy Unspecified Adult Solid Tumor, Protocol Specific Drug: ketamine/amitriptyline NP-H cream Other: placebo Phase 3

Detailed Description:


  • 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 462 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Supportive Care
Official Title: Assessment of Topical Treatment Response With Amitriptyline and Ketamine: Combination Trial in Chemotherapy Peripheral Neuropathy (ATTRACT-CPN)
Study Start Date : October 2007
Actual Primary Completion Date : September 2013
Actual Study Completion Date : November 2013

Arm Intervention/treatment
Experimental: ketamine/amitriptyline NP-H cream
Patients apply 4 grams amitriptyline (4%) and ketamine (2%) hydrochloride topical analgesic cream twice daily to areas of pain, numbness, or tingling in the hands and/or feet.
Drug: ketamine/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.
Other Name: EpiCept NP-1

Placebo Comparator: Placebo Cream
Patients apply a placebo cream twice daily to areas of pain, numbness, or tingling in the hands and/or feet.
Other: placebo
Applied topically

Primary Outcome Measures :
  1. Change in Average Daily Peripheral Neuropathy Intensity Score From Baseline to Week 6 in Patients Treated With Amitriptyline and Ketamine Hydrochloride vs Placebo [ Time Frame: Week 6 - Baseline ]
    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).

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 120 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • 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


  • 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


  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00471445

Show Show 17 study locations
Sponsors and Collaborators
Gary Morrow
National Cancer Institute (NCI)
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Study Chair: Supriya Mohile, MD James P. Wilmot Cancer Center
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Gary Morrow, Director, URCC NCORP Research Base, University of Rochester NCORP Research Base Identifier: NCT00471445    
Other Study ID Numbers: CDR0000543103
U10CA037420 ( U.S. NIH Grant/Contract )
URCC-0605 ( Other Identifier: NCI/DCP )
URCC07004 ( Other Identifier: University of Rochester )
First Posted: May 10, 2007    Key Record Dates
Results First Posted: June 10, 2015
Last Update Posted: November 9, 2015
Last Verified: October 2015
Keywords provided by Gary Morrow, University of Rochester NCORP Research Base:
unspecified adult solid tumor, protocol specific
peripheral neuropathy
Additional relevant MeSH terms:
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Peripheral Nervous System Diseases
Neurotoxicity Syndromes
Neuromuscular Diseases
Nervous System Diseases
Chemically-Induced Disorders
Amitriptyline, perphenazine drug combination
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anesthetics, Dissociative
Anesthetics, Intravenous
Anesthetics, General
Central Nervous System Depressants
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antidepressive Agents, Tricyclic
Antidepressive Agents
Psychotropic Drugs
Analgesics, Non-Narcotic
Adrenergic Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Adrenergic Agents