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

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ClinicalTrials.gov Identifier: NCT00471445
Recruitment Status : Completed
First Posted : May 10, 2007
Results First Posted : June 10, 2015
Last Update Posted : November 9, 2015
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Gary Morrow, University of Rochester NCORP Research Base

Tracking Information
First Submitted Date  ICMJE May 8, 2007
First Posted Date  ICMJE May 10, 2007
Results First Submitted Date  ICMJE August 20, 2014
Results First Posted Date  ICMJE June 10, 2015
Last Update Posted Date November 9, 2015
Study Start Date  ICMJE October 2007
Actual Primary Completion Date September 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 8, 2015)
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).
Original Primary Outcome Measures  ICMJE
 (submitted: May 8, 2007)
Change in average daily pain intensity score in amitriptyline and ketamine hydrochloride group and placebo group from baseline to day 84
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: May 8, 2007)
  • Percentages of patients in the amitriptyline and ketamine hydrochloride group and placebo groups whose pain intensity deceases by ≥ 30%
  • Percentage of patents with ≥ 50% pain intensity reduction
  • Percentage of patients with continuous proportion of responder distribution function
  • Change in average daily pain intensity score from baseline to each of the 12 treatment weeks
  • Quality of sleep scores
  • Short-Form McGill Pain Questionnaire-II
  • Brief Pain Inventory interference scale
  • Hamilton Anxiety and Depression Scale
  • Patient Global Impression of Change
  • Evaluation of the double-blind
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Topical Amitriptyline and Ketamine Cream in Treating Peripheral Neuropathy Caused by Chemotherapy in Cancer Patients
Official Title  ICMJE Assessment of Topical Treatment Response With Amitriptyline and Ketamine: Combination Trial in Chemotherapy Peripheral Neuropathy (ATTRACT-CPN)
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Supportive Care
Condition  ICMJE
  • Neurotoxicity
  • Pain
  • Peripheral Neuropathy
  • Unspecified Adult Solid Tumor, Protocol Specific
Intervention  ICMJE
  • 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
  • Other: placebo
    Applied topically
Study Arms  ICMJE
  • 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.
    Intervention: Drug: ketamine/amitriptyline NP-H cream
  • Placebo Comparator: Placebo Cream
    Patients apply a placebo cream twice daily to areas of pain, numbness, or tingling in the hands and/or feet.
    Intervention: Other: placebo
Publications * Gewandter JS, Mohile SG, Heckler CE, Ryan JL, Kirshner JJ, Flynn PJ, Hopkins JO, Morrow GR. A phase III randomized, placebo-controlled study of topical amitriptyline and ketamine for chemotherapy-induced peripheral neuropathy (CIPN): a University of Rochester CCOP study of 462 cancer survivors. Support Care Cancer. 2014 Jul;22(7):1807-14. doi: 10.1007/s00520-014-2158-7. Epub 2014 Feb 16.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 8, 2015)
462
Original Enrollment  ICMJE
 (submitted: May 8, 2007)
400
Actual Study Completion Date  ICMJE November 2013
Actual Primary Completion Date September 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 120 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00471445
Other Study ID Numbers  ICMJE CDR0000543103
U10CA037420 ( U.S. NIH Grant/Contract )
URCC-0605 ( Other Identifier: NCI/DCP )
URCC07004 ( Other Identifier: University of Rochester )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Gary Morrow, University of Rochester NCORP Research Base
Study Sponsor  ICMJE Gary Morrow
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Study Chair: Supriya Mohile, MD James P. Wilmot Cancer Center
PRS Account University of Rochester
Verification Date October 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP