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

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.

Study Type: Interventional

Study Design: Supportive Care, Randomized, Double-Blind, Placebo Control

OBJECTIVES: - Compare the analgesic properties and safety of topical amitriptyline and ketamine hydrochloride cream vs placebo in cancer patients 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 type of prior chemotherapy (taxanes vs other). Patients are randomized to 1 of 2 treatment arms. - Arm I: Patients apply amitriptyline and ketamine hydrochloride topical analgesic cream twice daily to the areas of their worst pain. - Arm II: Patients apply a placebo cream twice daily to the areas of their worst pain.

In both arms, treatment continues for 84 days in the absence of disease progression or unacceptable toxicity.

Patients complete a pain intensity and quality of sleep diary daily. Patients also complete the Short-Form McGill Pain Questionnaire to assess pain quality and the Brief Pain Inventory and Hospital Anxiety and Depression Scale to assess health-related quality of life on days 1 and 84. The Patient Global Impression of Change Questionnaire is administered on day 84 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 400 patients will be accrued for this study.

Intervention(s) in this Clinical Trial

• Drug: ketamine/amitriptyline NP-H cream
  • Applied topically
• Drug: placebo
  • Applied topically

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Arm I
  • Patients apply amitriptyline and ketamine hydrochloride topical analgesic cream twice daily to the areas of their worst pain.
• Placebo Comparator: Arm II
  • Patients apply a placebo cream twice daily to the areas of their worst pain.

Primary Measures

• Change in average daily pain intensity score from baseline to day 84 in patients treated with amitriptyline and ketamine hydrochloride vs placebo

Secondary Measures

• Percentage of patients treated with amitriptyline and ketamine hydrochloride vs placebo 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 the end of treatment
• Quality of sleep scores
• Quality of pain as measured by the Short-Form McGill Pain Questionnaire-II
• Health-related quality of life as measured by the Brief Pain Inventory Interference Scale and Hamilton Anxiety and Depression Scale
• Overall assessment of change since beginning of treatment, including changes in pain, side effects, functional status, and overall satisfaction with treatment as measured by the Patient Global Impression of Change Questionnaire

DISEASE CHARACTERISTICS:

• History of cancer
• Pain in the lower extremities 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 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 lower-extremity pain associated with chemotherapy, with a minimum of 5 daily diary ratings completed during the baseline week
• Evidence of a clinically defined painful peripheral neuropathy following chemotherapy administration defined by the presence of both of the following:
• Bilateral lower extremity pain with or without other symptoms of neuropathy, including dysesthesias or paresthesias (asleep numbness, pins and needles, prickling in a stocking, or stocking and glove distribution) or sensory ataxia
• Neurological examination consistent with a distal predominantly sensory polyneuropathy with bilateral abnormalities of one or more of ankle reflexes (decreased, present with Jendrassik maneuver only, or absent), vibration sense at the toes (decreased or absent), pin (pain) sensation (decreased stocking > glove distribution), or position sense (decreased or absent at the toes)
• No systemic metastases or bone involvement
• No signs of another neurological disorder (e.g., myelopathy) known to be associated with neuropathic pain on screening neurological examination

PATIENT CHARACTERISTICS:

• Fasting glucose < 100 mg/dL
• BUN < 30 mg/dL
• Creatinine < 2 mg/dL
• Vitamin B12 level normal
• Thyroid stimulating hormone level normal
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Able to adequately understand English
• Able to complete assessment forms
• 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 pain
• No suicide attempt within the past 5 years or current suicide intent or plan
• No excessive alcohol use or any illicit drug use within the past 2 years
• No other pain more severe than lower extremity pain
• No open skin lesions in the area where the cream is to be applied
• No history or clinical evidence of any of the following:
• Lower limb amputation
• Neuromuscular syndrome or systemic disorder (e.g., diabetes mellitus, peripheral vascular disease, or systemic lupus erythematosus) known to be associated with sensory neuropathy
• Family history of hereditary peripheral neuropathy
• Personal history of foot deformity (e.g., pes cavus) or any other known cause of neuropathy
• No HIV positivity

PRIOR CONCURRENT THERAPY:

• 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 painful chemotherapy-related peripheral neuropathy
• 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 CP450 2D6 inhibitors, including quinidine, cimetidine, phenothiazine antidepressants, type C antiarrhythmics, or propafenone
• 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
• Concurrent opioid analgesics, tricyclic or dual reuptake inhibitor antidepressants, or gabapentin or pregabalin for chemotherapy-related peripheral neuropathy pain, or benzodiazepines for sleep allowed provided dose has been stable for at least 2 weeks and the following are true:
• Gabapentin dose must be ≤ 1,800 mg per day
• Pregabalin dose must be ≤ 300 mg per day
• Opioid analgesic dose must be ≤ 60 mg of oxycodone hydrochloride equivalent per day
• Tricyclic antidepressant dose must be ≤ 75 mg amitriptyline equivalent per day
• Duloxetine dose must be ≤ 60 mg per day
• Venlafaxine dose must be ≤ 150 mg per day
• Tramadol dose must be ≤ 200 mg per day
• Only two of the following three medication classes may be used concurrently for chemotherapy-related peripheral neuropathy pain:
• Gabapentin or pregabalin
• Opioids or tramadol
• Tricyclic antidepressants, duloxetine, or venlafaxine
• Concurrent adjunctive analgesic therapy, such as acupuncture, biofeedback, or herbal preparations, allowed provided dose has been stable for at least 2 weeks

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: University of Rochester

Overall Clinical Trial Officials and Contacts

Robert H. Dworkin, PhD Study Chair University of Rochester  

Information obtained from ClinicalTrials.gov on August 29, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00471445

Study ID Number: CDR0000543103

ClinicalTrials.gov Identifier: NCT00471445

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database