Lamotrigine in Treating Peripheral Neuropathy Caused by Chemotherapy in Patients With Cancer

The Efficacy of Lamotrigine in the Management of Chemotherapy-Induced Peripheral Neuropathy: A Phase III Randomized, Double Blind, Placebo-Controlled Trial

RATIONALE: Lamotrigine may be effective in reducing pain, numbness, tingling, and other symptoms of peripheral neuropathy. It is not yet known whether lamotrigine is effective in treating peripheral neuropathy caused by chemotherapy.

PURPOSE: This randomized phase III trial is studying how well lamotrigine works in reducing pain, numbness, tingling, and other symptoms of peripheral neuropathy caused by chemotherapy in patients with cancer.

Study Overview

• Status: Completed
• Conditions: Pain; Unspecified Adult Solid Tumor, Protocol Specific; Neurotoxicity
• Intervention / Treatment: Other: Placebo; Drug: lamotrigine

Detailed Description

OBJECTIVES:

• Compare the efficacy of lamotrigine vs placebo in reducing pain and symptoms of chemotherapy-induced peripheral neuropathy in patients with cancer.
• Compare symptom distress, mood states, functional abilities, and overall quality of life of patients treated with these agents.
• Determine the toxic effects of lamotrigine in these patients.

OUTLINE: This is a randomized, placebo-controlled, double-blind study. Patients are stratified according to neurotoxic chemotherapy received (taxanes vs platinum-based compounds vs vinca alkaloids vs combination vs other), status of neurotoxic chemotherapy (actively receiving therapy vs discontinued or completed), and duration of pain or neuropathy symptoms (1-3 months vs 3-6 months vs more than 6 months). Patients are randomized to 1 of 2 treatment arms.

• Study Type: Interventional
• Enrollment (Actual): 131
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic Scottsdale
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic - Jacksonville
  • Georgia
    • Atlanta, Georgia, United States, 30342-1701
      • CCOP - Atlanta Regional
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • MBCCOP - Hawaii
  • Illinois
    • Peoria, Illinois, United States, 61615-7828
      • CCOP - Illinois Oncology Research Association
    • Urbana, Illinois, United States, 61801
      • CCOP - Carle Cancer Center
  • Iowa
    • Cedar Rapids, Iowa, United States, 52403-1206
      • CCOP - Cedar Rapids Oncology Project
    • Des Moines, Iowa, United States, 50309-1854
      • CCOP - Iowa Oncology Research Association
    • Sioux City, Iowa, United States, 51101-1733
      • Siouxland Hematology-Oncology Associates at June E. Nylen Cancer Center
  • Kansas
    • Wichita, Kansas, United States, 67214-3882
      • CCOP - Wichita
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • CCOP - Michigan Cancer Research Consortium
  • Minnesota
    • Duluth, Minnesota, United States, 55805
      • CCOP - Duluth
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
    • Saint Cloud, Minnesota, United States, 56303
      • Coborn Cancer Center
    • Saint Louis Park, Minnesota, United States, 55416
      • CCOP - Metro-Minnesota
  • Nebraska
    • Omaha, Nebraska, United States, 68106
      • CCOP - Missouri Valley Cancer Consortium
  • North Dakota
    • Bismarck, North Dakota, United States, 58501-5505
      • Cancer Care Center at Medcenter One Hospital
  • Ohio
    • Dayton, Ohio, United States, 45429
      • CCOP - Dayton
    • Toledo, Ohio, United States, 43623-3456
      • CCOP - Toledo Community Hospital
  • South Carolina
    • Spartanburg, South Carolina, United States, 29303
      • CCOP - Upstate Carolina
  • South Dakota
    • Rapid City, South Dakota, United States, 57709
      • Rapid City Regional Hospital
    • Sioux Falls, South Dakota, United States, 57104
      • CCOP - Sioux Community Cancer Consortium
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54301
      • CCOP - St. Vincent Hospital Cancer Center, Green Bay

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Diagnosis of cancer

• Received, or are currently receiving, neurotoxic chemotherapy, including any of the following:

  • Taxanes (e.g., paclitaxel or docetaxel)
  • Platinum-based compounds (e.g., carboplatin, cisplatin, or oxaliplatin)
  • Vinca alkaloids (e.g., vincristine or vinblastine)

• Experiencing pain or symptoms of peripheral neuropathy for at least 1 month attributed to chemotherapy

  • Average daily pain rating of at least 4 out of 10 OR
  • Peripheral neuropathy at least grade 1 out of 3 using ECOG sensory neuropathy rating

PATIENT CHARACTERISTICS:

Age

• 18 and over

Life expectancy

• At least 6 months

Hepatic

• Bilirubin < 2 times upper limit of normal (ULN)

Renal

• Creatinine ≤ 1.5 times ULN

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No prior allergic reaction or intolerance to lamotrigine
• No extreme difficulty swallowing pills

• No other identified causes of painful paresthesia preceding chemotherapy, including any of the following:

  • Radiation or malignant plexopathy
  • Lumbar or cervical radiculopathy

  • Pre-existing peripheral neuropathy of another etiology, such as any of the following:

    • Cyanocobalamin deficiency
    • AIDS
    • Monoclonal gammopathy
    • Diabetes
    • Heavy metal poisoning amyloidosis
    • Syphilis
    • Hyperthyroidism or hypothyroidism
    • Inherited neuropathy
• No significant psychiatric illness (e.g., mania, psychosis, or schizophrenia) that would preclude study participation
• Able to complete questionnaires

PRIOR CONCURRENT THERAPY:

Chemotherapy

• See Disease Characteristics
• More than 7 days since prior methotrexate or other dihydrofolate inhibitors

Other

• More than 7 days since prior, and no concurrent use of any of the following:

  • Tricyclic antidepressants (e.g., amitriptyline, nortriptyline, or desipramine)

    • Concurrent selective serotonin reuptake inhibitors allowed
  • Monoamine oxidase inhibitors
  • Opioid analgesics
  • Anticonvulsants (e.g., gabapentin, topiramate, valproic acid, or clonazepam)

  • Adjuvant analgesics (e.g., mexiletine)

    • Prior nonsteroidal anti-inflammatory drugs allowed
  • Topical analgesics (e.g., lidocaine gel or patch) to the affected area
  • Amifostine
• More than 30 days since prior investigational agents for pain control
• No other concurrent investigational agents for pain control

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I - lamotrigine; Patients receive oral lamotrigine once daily for 2 weeks and then twice daily for 8 weeks. Treatment continues for 10 weeks in the absence of unacceptable toxicity. Quality of life, pain, mood states, and symptom distress are assessed at baseline and at 4, 6, 8, and 10 weeks. Patients are followed at 3-7 days.	Drug: lamotrigine
Other: Arm II - placebo; Patients receive oral placebo once daily for 2 weeks and then twice daily for 8 weeks. Treatment continues for 10 weeks in the absence of unacceptable toxicity. Quality of life, pain, mood states, and symptom distress are assessed at baseline and at 4, 6, 8, and 10 weeks. Patients are followed at 3-7 days.	Other: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Average Daily Pain Score as Measured Using a Pain Intensity Rating (NRS)	The change in mean score for average daily pain from baseline to week 10 using the Pain Intensity Rating (NRS) are reported below. The NRS scale ranges from 0 to 10 with higher scores corresponding to having more pain.	From baseline to week 10
Change in Average Pain Score as Measured Using the European Cooperative Oncology Group (ECOG) Neuropathy Scale (ENS)	The change in mean score for average daily pain from baseline to week 10 using the European Cooperative Oncology Group (ECOG) neuropathy scale (ENS) are reported below. The ENS scale goes from 0 to 3 with 0=none, 1=mild paresthesias, 2=mild or moderate sensory loss and/or moderate paresthesias, and 3=severe sensory loss or paresthesias that interfere with function.	From baseline to week 10

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Change in Overall Quality of Life as Measured by the Uniscale QOL From Baseline to Week 10	The change in overall quality of life as measured by the Uniscale QOL (Week 10 minus Baseline) using the Wilcoxon test is reported for each arm below. The Uniscale is a score that ranges from 0 to 100, with 0 being QOL as bad as it can be and 100 being as good as it can be.	From baseline to week 10
Change in Brief Pain Inventory (BPI) Worst Pain Score [Week 10 Minus Baseline]	The average change in Brief Pain Inventory (BPI) Worst Pain scores between baseline and week 10 using Wilcoxon test are reported for each arm below. The BPI scales range from 0 to 10 with 0 meaning no pain and 10 meaning pain as bad as you can imagine.	From baseline to week 10
Change in Brief Pain Inventory (BPI) Least Pain Score [Week 10 Minus Baseline]	The average change in Brief Pain Inventory (BPI) Least Pain scores between baseline and week 10 using Wilcoxon test are reported for each arm below. The BPI scales range from 0 to 10 with 0 meaning no pain and 10 meaning pain as bad as you can imagine. Time Frame: Up to 1 week post-treatment	From baseline to week 10
Change in Brief Pain Inventory (BPI) Average Pain Score [Week 10 Minus Baseline]	The average change in Brief Pain Inventory (BPI) Average Pain scores between baseline and week 10 using Wilcoxon test are reported for each arm below. The BPI scales range from 0 to 10 with 0 meaning no pain and 10 meaning pain as bad as you can imagine.	From baseline to week 10
Change in Brief Pain Inventory (BPI) Pain Now Score [Week 10 Minus Baseline]	The average change in Brief Pain Inventory (BPI) Pain Now scores between baseline and week 10 using Wilcoxon test are reported for each arm below. The BPI scales range from 0 to 10 with 0 meaning no pain and 10 meaning pain as bad as you can imagine.	From baseline to week 10
Change in Brief Pain Inventory (BPI) Pain Relief Score [Week 10 Minus Baseline]	The average change in Brief Pain Inventory (BPI) Pain Relief scores between baseline and week 10 using Wilcoxon test are reported for each arm below. The BPI scales range from 0 to 10 with 0 meaning no pain and 10 meaning pain as bad as you can imagine.	From baseline to week 10
Change in Brief Pain Inventory (BPI) Pain Interference Score [Week 10 Minus Baseline]	The average change in Brief Pain Inventory (BPI) Pain Interference scores between baseline and week 10 using Wilcoxon test are reported for each arm below. The BPI scales range from 0 to 10 with 0 meaning no pain and 10 meaning pain as bad as you can imagine.	From baseline to week 10
Change in POMS Total Score [Week 10 Minus Baseline]	The average change in POMS Total scores between baseline and week 10 using Wilcoxon test are reported for each arm below. The POMS scales are calculated from patient responses on 30 questions asking how they have been feeling during the past week. The scores are all transformed so that 0 is the worst possible value and 100 is the best possible value.	From baseline to week 10

Collaborators and Investigators

• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborators: National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Renno SI, Rao RD, Sloan J, et al.: The efficacy of lamotrigine in the management of chemotherapy-induced peripheral neuropathy: a phase III randomized, double blind, placebo-controlled NCCTG trial, N01C3. [Abstract] J Clin Oncol 24 (Suppl 18): A-8530, 475s, 2006.

Study record dates

Study Major Dates

• Study Start: February 1, 2004
• Primary Completion (Actual): May 1, 2006
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: September 10, 2003
• First Submitted That Met QC Criteria: September 10, 2003
• First Posted (Estimate): September 11, 2003

Study Record Updates

• Last Update Posted (Actual): May 4, 2018
• Last Update Submitted That Met QC Criteria: April 3, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: unspecified adult solid tumor, protocol specific; pain; neurotoxicity
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Nervous System Diseases; Neuromuscular Diseases; Poisoning; Peripheral Nervous System Diseases; Neurotoxicity Syndromes; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Membrane Transport Modulators; Anticonvulsants; Sodium Channel Blockers; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Lamotrigine
• Other Study ID Numbers: NCCTG-N01C3; CDR0000322830 (Registry Identifier: PDQ (Physician Data Query))