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

• Sponsor: Wake Forest University Health Sciences (Other)
• Overall Status: Completed
• CT.gov ID: NCT00369785
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 198
• Locations: 16
• Arms: 2
• Actual Duration (Months): 53
• Patients Per Site: 12.4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Brain Tumors; Metastatic Disease	Drug: donepezil hydrochloride; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 198 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: Phase III Double Blind, Placebo Controlled Study of Donepezil in the Irradiated Brain
• Actual Study Start Date: Feb 1, 2008
• Actual Primary Completion Date: Jul 1, 2012
• Actual Study Completion Date: Jul 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I - Donepezil Weeks 1-6: One 5 mg tablet orally donepezil hydrochloride Weeks 7-24: Two 5mg tablets per day	Drug: donepezil hydrochloride; Weeks 1-6: One tablet Donepezil 5 mg given daily Weeks 7-24: Two Donepezil 5 mg tablets given daily; Other Names: Donepezil
Placebo Comparator: Arm II - Control Weeks 1-6: One placebo tablet per day Weeks 7-24: Two placebo tablets per day	Drug: Placebo; Weeks 1-6: One tablet per day Weeks 7-24: Two tablets per day

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Associates in Womens Health, PA - North Review	Wichita	Kansas	United States	67208
2	Cancer Center of Kansas, PA - Medical Arts Tower	Wichita	Kansas	United States	67208
3	Cancer Center of Kansas, PA - Wichita	Wichita	Kansas	United States	67214
4	CCOP - Wichita	Wichita	Kansas	United States	67214
5	Via Christi Cancer Center at Via Christi Regional Medical Center	Wichita	Kansas	United States	67214
6	Central Maine Comprehensive Cancer Center at Central Maine Medical Center	Lewiston	Maine	United States	04240
7	New Hampshire Oncology - Hematology, PA - Hooksett	Hooksett	New Hampshire	United States	03106
8	Lakes Region General Hospital	Laconia	New Hampshire	United States	03246
9	Don Monti Comprehensive Cancer Center at North Shore University Hospital	Manhasset	New York	United States	11030
10	CCOP - MeritCare Hospital	Fargo	North Dakota	United States	58122
11	Trinity CancerCare Center	Minot	North Dakota	United States	58701
12	Summa Center for Cancer Care at Akron City Hospital	Akron	Ohio	United States	44309-2090
13	MetroHealth Cancer Care Center at MetroHealth Medical Center	Cleveland	Ohio	United States	44109
14	United States Air Force Medical Center - Wright-Patterson	Wright-Patterson Air Force Base	Ohio	United States	45433-5529
15	Thompson Cancer Survival Center	Knoxville	Tennessee	United States	37916
16	Gundersen Lutheran Center for Cancer and Blood	La Crosse	Wisconsin	United States	54601

Sponsors and Collaborators

• Wake Forest University Health Sciences
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Stephen Rapp, PhD, Wake Forest University Health Sciences

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Data Available: Select individual patient-level data form this trial can be requested from the NCTN/NCORP Data Archive

Publications

None provided.

• Responsible Party: Wake Forest University Health Sciences
• ClinicalTrials.gov Identifier: NCT00369785
• Other Study ID Numbers: IRB00000551; U10CA081851; REBACCCWFU 91105
• First Posted: Aug 29, 2006
• Last Update Posted: Oct 20, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Wake Forest University Health Sciences: 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
• Additional relevant MeSH terms: Brain Neoplasms; Neoplasm Metastasis; Donepezil

Study Results

Participant Flow

Recruitment Details	Patients were accrued between 2/2008 and 12/2011 at NCI CCOP sites across the nation.

Arm/Group Title	Arm I - Donepezil	Arm II - Control
Arm/Group Description	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	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
Period Title: Overall Study
STARTED	99	99
COMPLETED	72	74
NOT COMPLETED	27	25

Baseline Characteristics

Arm/Group Title	Arm I - Donepezil	Arm II - Control	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	99	99	198
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	72 72.7%	83 83.8%	155 78.3%
>=65 years	27 27.3%	16 16.2%	43 21.7%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	56.1	54.9	55.1
Sex: Female, Male (Count of Participants)
Female	56 56.6%	50 50.5%	106 53.5%
Male	43 43.4%	49 49.5%	92 46.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 1%	0 0%	1 0.5%
Not Hispanic or Latino	96 97%	97 98%	193 97.5%
Unknown or Not Reported	2 2%	2 2%	4 2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 1%	0 0%	1 0.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	7 7.1%	9 9.1%	16 8.1%
White	91 91.9%	90 90.9%	181 91.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	99 100%	99 100%	198 100%

Outcome Measures

1. Primary Outcome

Title	Memory as Quantified by HVLT-immediate Recall
Description	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

Outcome Measure Data

Analysis Population Description

Participants with 24 week HVLT data.

Arm/Group Title	Arm I - Donepezil	Arm II - Control
Arm/Group Description	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	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
Measure Participants	72	73
Least Squares Mean (Standard Error) [units on a scale]	22.5 (0.45)	22.2 (0.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I - Donepezil, Arm II - Control
	Comments	Null Hypothesis: No difference in immediate recall memory at 24 weeks
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	.62
	Comments	Not adjusted for multiple comparisons.
	Method	Mixed Models Analysis
	Comments

2. Primary Outcome

Title	Memory as Quantified by the HVLT-discrimination
Description	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

Outcome Measure Data

Analysis Population Description

Number of participants with 24 week memory data

Arm/Group Title	Arm I - Donepezil	Arm II - Control
Arm/Group Description	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	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
Measure Participants	72	73
Least Squares Mean (Standard Error) [units on a scale]	10.1 (0.24)	9.2 (0.24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I - Donepezil, Arm II - Control
	Comments	Null Hypothesis: No difference in discrimination memory between the two groups
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	.007
	Comments	Not adjusted for multiple comparisons.
	Method	Mixed Models Analysis
	Comments

Adverse Events

Time Frame	24 weeks
Adverse Event Reporting Description	Analysis includes everyone with post-treatment AE/toxicity data.
Arm/Group Title	Arm I - Donepezil		Arm II - Control
Arm/Group Description	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		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
All Cause Mortality
	Arm I - Donepezil		Arm II - Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm I - Donepezil		Arm II - Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/96 (12.5%)		10/92 (10.9%)
Ear and labyrinth disorders
Auditory/Ear - Other	0/96 (0%)	0	1/92 (1.1%)	3
Hearing	1/96 (1%)	2	1/92 (1.1%)	3
Gastrointestinal disorders
Dental: teeth	0/96 (0%)	0	1/92 (1.1%)	2
Diarrhea	0/96 (0%)	0	1/92 (1.1%)	1
Nausea	0/96 (0%)	0	2/92 (2.2%)	2
Vomiting	0/96 (0%)	0	2/92 (2.2%)	2
General disorders
Death NOS	1/96 (1%)	1	2/92 (2.2%)	2
Dental: peridontal disease	0/96 (0%)	0	1/92 (1.1%)	1
Fatigue	3/96 (3.1%)	5	0/92 (0%)	0
Syncope (fainting)	1/96 (1%)	1	1/92 (1.1%)	1
Infections and infestations
Infection	1/96 (1%)	1	1/92 (1.1%)	1
Musculoskeletal and connective tissue disorders
Muscle weakness	2/96 (2.1%)	2	0/92 (0%)	0
Muscle Cramps	1/96 (1%)	1	1/92 (1.1%)	2
Nervous system disorders
Confusion	0/96 (0%)	0	1/92 (1.1%)	2
Headache	0/96 (0%)	0	1/92 (1.1%)	1
Neuropathy: cranial: CN II Vision	0/96 (0%)	0	1/92 (1.1%)	3
Neuropathy: cranial: CN VII Motor-face; Sensory-taste	0/96 (0%)	0	1/92 (1.1%)	3
Neuropathy: sensory	0/96 (0%)	0	1/92 (1.1%)	1
Pain - Other	1/96 (1%)	1	0/92 (0%)	0
Pain: Back	1/96 (1%)	1	0/92 (0%)	0
Seizure	1/96 (1%)	1	0/92 (0%)	0
Somnolence/depressed level of consciousness	0/96 (0%)	0	1/92 (1.1%)	1
Psychiatric disorders
Cognitive Disturbance	0/96 (0%)	0	1/92 (1.1%)	2
Insomnia	1/96 (1%)	1	1/92 (1.1%)	1
Mood Alteration: Depression	1/96 (1%)	1	0/92 (0%)	0
Respiratory, thoracic and mediastinal disorders
Aspiration	0/96 (0%)	0	1/92 (1.1%)	1
Other (Not Including Serious) Adverse Events
	Arm I - Donepezil		Arm II - Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	88/96 (91.7%)		80/92 (87%)
Ear and labyrinth disorders
Dizziness	5/96 (5.2%)	5	7/92 (7.6%)	13
Gastrointestinal disorders
Constipation	3/96 (3.1%)	6	5/92 (5.4%)	11
Diarrhea	24/96 (25%)	29	7/92 (7.6%)	13
Nausea	13/96 (13.5%)	19	17/92 (18.5%)	21
Vomiting	8/96 (8.3%)	10	4/92 (4.3%)	4
General disorders
Insomnia	43/96 (44.8%)	81	36/92 (39.1%)	70
Metabolism and nutrition disorders
Fatigue	55/96 (57.3%)	105	61/92 (66.3%)	122
Musculoskeletal and connective tissue disorders
Muscle Weakness	2/96 (2.1%)	5	5/92 (5.4%)	11
Muscle Cramps	32/96 (33.3%)	58	26/92 (28.3%)	48
Nervous system disorders
Headache	42/96 (43.8%)	70	40/92 (43.5%)	73
Memory Impairment	34/96 (35.4%)	83	34/92 (37%)	91
Psychiatric disorders
Anorexia	21/96 (21.9%)	33	13/92 (14.1%)	17
Cognitive Disturbance	26/96 (27.1%)	64	28/92 (30.4%)	73

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.