Donepezil in Treating Patients Who Have Undergone Radiation Therapy for Brain Tumors

Study Overview
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Brief Summary
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RATIONALE: Donepezil may help lessen confusion and fatigue and improve mood and quality of life in patients who have undergone radiation therapy for brain tumors. It is not yet known whether donepezil is more effective than a placebo in lessening side effects of radiation therapy in patients with brain tumors. PURPOSE: This randomized phase III trial is studying donepezil to see how well it works in lessening side effects of radiation therapy compared with a placebo in patients who have undergone radiation therapy for brain tumors.

Detailed Description
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OBJECTIVES: Primary Compare the effect of donepezil hydrochloride vs placebo, in terms of improving neurocognitive symptom cluster (i.e., cognitive impairment, subjective confusion, and fatigue), in patients who have undergone partial- or whole-brain irradiation for brain tumors. Secondary Compare the effect of these regimens on mood and quality of life in these patients. OUTLINE: This is a prospective, double-blind, placebo-controlled, randomized, multicenter study. Patients are stratified according to prior brain irradiation type (whole-brain vs partial-brain) and study site. Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive oral donepezil hydrochloride once or twice daily for up to 24 weeks in the absence of unacceptable toxicity. Arm II: Patients receive oral placebo once or twice daily for up to 24 weeks in the absence of unacceptable toxicity. Patients complete self-reported questionnaires (quality of life, fatigue, subjective confusion, neurocognitive battery, and mood) at baseline and 12 and 24 weeks. PROJECTED ACCRUAL: A total of 200 patients will be accrued for this study.

Official Title
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Phase III Double Blind, Placebo Controlled Study of Donepezil in the Irradiated Brain

Conditions
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Brain Tumors, Metastatic Disease

Intervention / Treatment
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* Drug: donepezil hydrochloride
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Adults >18 years old. Life expectancy of at least > 30 weeks. Must have received a prior course of at least 30 Gy fractionated whole or partial brain irradiation for treatment of a primary brain tumor or metastatic disease to the brain. Must have completed radiation > 6 months prior to enrollment and have no radiographic evidence of brain disease, or stable brain disease defined as no evidence of tumor progression in the 3 months prior to enrollment. Patients who have undergone one or more treatments with single fraction stereotactic radiosurgery (SRS) in addition to whole or partial brain irradiation are eligible, as long as the SRS was completed > 6 months prior to registration if NED or stable disease. Radiation treatment records must be available for all prior radiation treatments (external beam and/or SRS). Patients who have received PCI (prophylactic cranial irradiation) are eligible. Karnofsky Performance Status must be > 60 or ECOG 0-2. Treatment with steroids, anti-cholinergics, anti-epileptics, anti-depressants, and /or sedatives/benzodiazepines is acceptable, but the patient must be on a stable or decreasing dose at the time of study entry. Patients using narcotic analgesics on a stable dose and/or prn basis are eligible. Patients currently on a stable dose of Methylphenidate or Dextramphetamine are eligible. For patients with brain metastases, if extracranial primary or metastatic disease is present, it must have responded to local and/or systemic treatment. Must be stable in the 3 months prior to enrollment. Must not be receiving chemotherapy at the time of enrollment. Patient must not have any planned therapy, including surgery, brain radiation of any type, chemotherapy, or immunotherapy during the next 30 weeks for brain or extracranial primary metastatic disease. Hormonal therapy for patients with breast or prostate cancer is acceptable. Breast patients receiving therapy with Herceptin are allowed. Patients must be able to give informed consent to participate in the study, including signing the consent form. Patients must have a telephone. EXCLUSION CRITERIA: Patients cannot be currently taking dementia drugs, cognitive enhancers, neuroleptics, and/or anti-parkinsonian agents. For patients who have used these drugs in the past, they must not have used them in the 2 weeks prior to enrolling on the study. Hypersensitivity to donepezil. Patients may not currently be taking Ketoconazole or Quindine Arrythmias including bradycardia or heartblock Patients who have received, GliaSite or other type of brain brachytherapy, (Gliadel Wafers permitted) convection enhanced delivery of immunotoxins, and/or any other investigational modalities for treatment of their brain tumor. The effects of donepezil on the developing human fetus at the recommended therapeutic dose are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. It is unknown whether donepezil is excreted in breast milk, for this reason women who are currently breast-feeding are not eligible for this study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I - Donepezil<br>Weeks 1-6: One 5 mg tablet orally donepezil hydrochloride Weeks 7-24: Two 5mg tablets per day | Drug: donepezil hydrochloride<br>* Weeks 1-6: One tablet Donepezil 5 mg given daily Weeks 7-24: Two Donepezil 5 mg tablets given daily<br>* Other names: Donepezil;|
| Placebo Comparator: Arm II - Control<br>Weeks 1-6: One placebo tablet per day Weeks 7-24: Two placebo tablets per day | Drug: Placebo<br>* Weeks 1-6: One tablet per day Weeks 7-24: Two tablets per day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Memory as Quantified by HVLT-immediate Recall | Memory is quantified using the Hopkins Verbal Learning Test (HVLT) - immediate recall. Participants are asked to recall 12 words. Each recalled word is given one point. They are given three trials. The total score is the sum of the recalled words. The range for HVLT-Immediate recall is 0 to 36. Higher scores represent better memory. | 24 weeks | 
| Memory as Quantified by the HVLT-discrimination | In the Hopkins Verbal Learning Test - discrimination, participants are given lists of 12 correct words and 12 incorrect words. HVLT-discrimination is the number of correctly recognized words minus the number incorrectly recognized. The range for this outcome measure is -12 to 12. Higher scores represent better memory. | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cognitive/functional effects, fatigue, psychosocial effects of cancer and its treatment, radiation toxicity, tumors metastatic to brain, adult brain stem glioma, adult central nervous system germ cell tumor, adult choroid plexus tumor, adult craniopharyngioma, adult mixed glioma, adult anaplastic meningioma, meningeal melanocytoma, adult meningeal hemangiopericytoma, adult grade I meningioma, adult grade II meningioma, adult grade III meningioma, adult papillary meningioma, adult anaplastic oligodendroglioma, adult oligodendroglioma, adult pineoblastoma, adult pineocytoma, adult anaplastic astrocytoma, adult diffuse astrocytoma, adult glioblastoma, adult giant cell glioblastoma, adult gliosarcoma, adult pilocytic astrocytoma, adult ependymoblastoma, adult medulloblastoma, adult supratentorial primitive neuroectodermal tumor (PNET), adult anaplastic ependymoma, adult ependymoma, adult myxopapillary ependymoma, adult subependymoma