Brain Tumors, Metastatic Disease
Conditions
Keywords
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
Brief summary
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
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.
Interventions
DRUGdonepezil hydrochloride
Weeks 1-6: One tablet Donepezil 5 mg given daily Weeks 7-24: Two Donepezil 5 mg tablets given daily
DRUGPlacebo
Weeks 1-6: One tablet per day Weeks 7-24: Two tablets per day
Sponsors
National Cancer Institute (NCI)
Wake Forest University Health Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Memory as Quantified by HVLT-immediate Recall | 24 weeks | 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. |
| Memory as Quantified by the HVLT-discrimination | 24 weeks | 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. |
Countries
United States
Participant flow
Recruitment details
Patients were accrued between 2/2008 and 12/2011 at NCI CCOP sites across the nation.
Participants by arm
| Arm | Count |
|---|---|
| Arm I - Donepezil Weeks 1-6: One 5 mg tablet orally donepezil hydrochloride Weeks 7-24: Two 5mg tablets per day
donepezil hydrochloride: Weeks 1-6: One tablet Donepezil 5 mg given daily Weeks 7-24: Two Donepezil 5 mg tablets given daily | 99 |
| Arm II - Control Weeks 1-6: One placebo tablet per day Weeks 7-24: Two placebo tablets per day
Placebo: Weeks 1-6: One tablet per day Weeks 7-24: Two tablets per day | 99 |
| Total | 198 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 2 |
| Overall Study | Multiple reasons | 6 | 5 |
| Overall Study | Never started | 0 | 2 |
| Overall Study | Physician Decision | 3 | 2 |
| Overall Study | Progression | 4 | 4 |
| Overall Study | Toxicity | 6 | 4 |
| Overall Study | Withdrawal by Subject | 7 | 6 |
Baseline characteristics
| Characteristic | Arm I - Donepezil | Arm II - Control | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 27 Participants | 16 Participants | 43 Participants |
| Age, Categorical Between 18 and 65 years | 72 Participants | 83 Participants | 155 Participants |
| Age, Continuous | 56.1 years | 54.9 years | 55.1 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 96 Participants | 97 Participants | 193 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 9 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 91 Participants | 90 Participants | 181 Participants |
| Region of Enrollment United States | 99 participants | 99 participants | 198 participants |
| Sex: Female, Male Female | 56 Participants | 50 Participants | 106 Participants |
| Sex: Female, Male Male | 43 Participants | 49 Participants | 92 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 88 / 96 | 80 / 92 |
| serious Total, serious adverse events | 12 / 96 | 10 / 92 |
Outcome results
Primary
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.
Time frame: 24 weeks
Population: Participants with 24 week HVLT data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Arm I - Donepezil | Memory as Quantified by HVLT-immediate Recall | 22.5 units on a scale | Standard Error 0.45 |
| Arm II - Control | Memory as Quantified by HVLT-immediate Recall | 22.2 units on a scale | Standard Error 0.45 |
Comparison: Null Hypothesis: No difference in immediate recall memory at 24 weeksp-value: 0.62Mixed Models Analysis
Primary
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.
Time frame: 24 weeks
Population: Number of participants with 24 week memory data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Arm I - Donepezil | Memory as Quantified by the HVLT-discrimination | 10.1 units on a scale | Standard Error 0.24 |
| Arm II - Control | Memory as Quantified by the HVLT-discrimination | 9.2 units on a scale | Standard Error 0.24 |
Comparison: Null Hypothesis: No difference in discrimination memory between the two groupsp-value: 0.007Mixed Models Analysis