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

Pain Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00471445
• Other study ID #: CDR0000543103
• Secondary ID: U10CA037420URCC-
• Status: Completed
• Phase: Phase 3
• First received: May 8, 2007
• Last updated: October 13, 2015
• Start date: October 2007
• Est. completion date: November 2013

Study information

• Verified date: October 2015
• Source: University of Rochester
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 462
• Est. completion date: November 2013
• Est. primary completion date: September 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 120 Years

Eligibility

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

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Supportive Care

Related Conditions & MeSH terms

• Neurotoxicity
• Neurotoxicity Syndromes
• Pain
• Peripheral Nervous System Diseases
• Peripheral Neuropathy
• Unspecified Adult Solid Tumor, Protocol Specific

Intervention

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:
• placebo
Applied topically

Locations

Country	Name	City	State
United States	MBCCOP - University of Illinois at Chicago	Chicago	Illinois
United States	CCOP - Central Illinois	Decatur	Illinois
United States	CCOP - Hematology-Oncology Associates of Central New York	East Syracuse	New York
United States	CCOP - Evanston	Evanston	Illinois
United States	CCOP - Grand Rapids	Grand Rapids	Michigan
United States	CCOP - Greenville	Greenville	South Carolina
United States	MBCCOP - Hawaii	Honolulu	Hawaii
United States	CCOP - Nevada Cancer Research Foundation	Las Vegas	Nevada
United States	CCOP - North Shore University Hospital	Manhasset	New York
United States	CCOP - Marshfield Clinic Research Foundation	Marshfield	Wisconsin
United States	CCOP - Columbia River Oncology Program	Portland	Oregon
United States	CCOP - Virginia Mason Research Center	Seattle	Washington
United States	CCOP - Upstate Carolina	Spartanburg	South Carolina
United States	CCOP - Metro-Minnesota	St. Louis Park	Minnesota
United States	CCOP - Northwest	Tacoma	Washington
United States	CCOP - Wichita	Wichita	Kansas
United States	CCOP - Southeast Cancer Control Consortium	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Gary Morrow	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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).	Week 6 - Baseline	No