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Donepezil

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Ginkgo

EGb761

donepezil hydrochloride

cognitive assessment

Edward G. Shaw, MD

RATIONALE: Donepezil and EGb761 may be effective in improving neurocognitive function (such as thinking, attention, concentration, and memory) and may improve quality of life in patients who have undergone radiation therapy to the brain.

PURPOSE: This phase II trial is studying how well donepezil or EGb761 works in improving neurocognitive function in patients who have undergone radiation therapy for primary brain tumor or brain metastases.

OBJECTIVES:

Primary

* Determine the effect of donepezil or EGb761 on neurocognitive function in patients who underwent radiotherapy for a primary brain tumor or brain metastases at least 6 months before study registration.

Secondary

* Determine the toxicity of these drugs in these patients.
* Determine the quality of life of patients treated with these drugs.
* Quantify the extent of radiation-induced white matter disease and temporal lobe atrophy in patients treated with these drugs.

OUTLINE: This is an open-label, multicenter study.

* Group 1 (closed to accrual 10/09/03): Patients receive oral donepezil once daily for 24 weeks.
* Group 2: Patients receive oral EGb761 three times daily for 24 weeks. In both groups (group 1 closed to accrual 10/09/03), treatment continues in the absence of unacceptable toxicity.

In both groups (group 1 closed to accrual 10/09/03), quality of life and neurocognitive assessment is performed at baseline and at weeks 6 (group 1 only), 12, 24, and 30.

Patients are followed at 6 weeks.

PROJECTED ACCRUAL: A total of 70 patients (35 per treatment group) will be accrued for this study within 9.5 months. (Group 1 closed to accrual 10/09/03)

Phase II Studies Of Donepezil And Ginkgo Biloba In Irradiated Brain Tumor

Donepezil and EGb761 in Improving Neurocognitive Function in Patients Who Have Previously Undergone Radiation Therapy for Primary Brain Tumor or Brain Metastases

National Cancer Institute (NCI)

Wake Forest University Health Sciences

During the 12-week Double-Blind Phase, subjects will receive oral donepezil hydrochloride tablets starting at a dose of 3 mg once daily. Doses will be increased incrementally at successive 3-week intervals on the basis of weight and tolerability. The final daily dose will be 3, 5, or 10 mg depending on body weight.

During the Blinded Extension Phase, all subjects will receive active treatment (donepezil).

Donepezil hydrochloride

During the 12-week Double-Blind Phase, subjects will receive matching placebo tablets (3, 5, of 10 mg) once daily.

During the 12-week Blinded Extension Phase, all subjects will receive active treatment (donepezil).

Placebo

The purpose of this study is to evaluate the efficacy, safety and tolerability of donepezil in children with persistent attention impairment that is present at least 12 months after the completion of cancer treatment.

This is a double-blind, placebo-controlled, parallel group study in pediatric subjects who have persistent attention impairment following treatment for cancer. This trial has three phases: (1) pre-randomization to establish eligibility, (2) a 12-week, double-blind, placebo-controlled, parallel-group phase with dose escalation based on body weight, (3) a 12-week, blinded extension phase during which all subjects will receive active drug.

Efficacy and Safety of Donepezil Hydrochloride in Preadolescent and Adolescent Children With Attention Impairment Following Cancer Treatment

Randomized, Double-Blind, Placebo-Controlled Study of Efficacy and Safety of Donepezil Hydrochloride in Preadolescent and Adolescent Children With Attention Impairment Following Cancer Treatment

TOVA-CPT test has a standardized computer game-like format that tests attention and simple impulse control. It precisely measures a person's reaction time to clicking on correct targets versus incorrect targets. Scores are based on the number of "Hits" (correct responses), omission errors (failure to respond), commission errors/"False Alarms" (incorrect responses), response time, and sensitivity ("d-prime"). "D-prime" a dimensionless statistics is a measure of distractibility and reflects how well a person reacts correctly versus incorrectly. A higher value of "d-prime" is reached by having more "Hits" (correct response) and fewer "False Alarms" (incorrect response). Analysis was based on three factors: the "d-prime" standard score, reaction time variability standard score, and response time standard score. Standard scores less than or equal to 80 were significant for an attention deficit disorder. Standard scores greater than 80 were not significant for an attention deficit disorder.

The Reaction Time Variability is defined as the time measurement of how consistently the switch is pressed. The Response Time is the measurement of how fast or slow information is processed and responded to by the participant. The testing process was as described in a previous outcome measure. Standard scores less than or equal to 80 were significant for an attention deficit disorder. Standard scores greater than 80 were not significant for an attention deficit disorder.

Behavioral Rating Inventory of Executive Functioning test evaluates impairment of executive function(planning and organization),memory,and sustained attention in children aged 5-18 years with wide range of developmental and acquired neurological conditions.Survey assess parent/guardian's perception of their child's executive functioning in home and school environments,which relate to daily function(as judged by parent).Each survey contains 86 items scored as;1(behavior is never a problem),2(behavior is sometimes a problem),or 3(behavior is often a problem).Data was presented as t-scores(raw scale scores are used to generate t-scores)for Global Executive Composite Score(t-score range 72-216),Behavioral Regulation Index(t-score range 28-84;inhibit,shift,and emotional control),Metacognition Inde (t-score range 44-132;initiate,working memory,plan/organize,organization of materials, and monitor),and Working Memory Subscale(t-score range 35-90).Higher scores indicate decline in performance.

Eisai Limited

Eisai Inc.

Safety population included randomized participants who received at least one dose of study medication and who had at least one post-Baseline safety assessment. Treatment-emergent adverse events (TEAEs), defined as an adverse event that started/increased in severity on/after the first dose of study medication are presented in this section.

Donepezil 3 mg, 5 mg, or 10 mg donepezil Immediate Release (IR) orally, once daily

Donepezil Double-Blind Phase

Placebo, matching 3 mg, 5 mg, and 10 mg placebo tablets administered orally, once daily

Placebo Double-Blind Phase

Donepezil Blinded Extension Phase

Placebo Blinded Extension Phase

Total

Age, Continuous

Sex: Female, Male

Safety population (SP) included randomized participants who took at least one dose of study medication and who had at least one post-Baseline safety assessment. One participant from the placebo group was not evaluable for safety resulting in one less total participants (71) in the SP as compared to the randomized population (72).

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data.

Eisai Medical Information

P-values, least squares (LS) mean, and 95% confidence interval (CI) were obtained from Analysis of Covariance (ANCOVA) model with treatment group as a factor and Baseline value as covariate.

Intent-to-Treat (ITT) Last Observed Carried Forward (LOCF) population included all safety participants for whom the TOVA-CPT "d-prime" standard score was available at both Screening and at least one "d-prime" score from the treatment period, in addition to having a post-Baseline safety assessment.

Change From Baseline in the Test of Variables in Attention-Continuous Performance Test (TOVA-CPT) "D-prime" Standard Score (SS) at Week 12

P-values, LS mean, and 95% confidence intervals were obtained from ANCOVA model with treatment group as a factor and baseline value as covariate.

Intent-to-Treat (ITT) Last Observed Carried Forward (LOCF) population included all safety participants for whom the TOVA-CPT d-prime standard score was available at both Screening and at least one visit after the first dose of study drug during the Double-Blind Phase.

Change From Baseline in the TOVA-CPT "D-prime" Standard Score (SS) at Week 6

RTVSS Change from Baseline to Week 6 (LOCF). P-values, LS mean, and 95% confidence intervals were obtained from ANCOVA model with treatment group as a factor and baseline value as covariate.

RTVSS Change from Baseline to Week 12 (LOCF). P-values, LS mean, and 95% confidence intervals were obtained from ANCOVA model with treatment group as a factor and baseline value as covariate.

RTSS Change from Baseline to Week 6 (LOCF). P-values, LS mean, and 95% confidence intervals were obtained from ANCOVA model with treatment group as a factor and baseline value as covariate.

RTSS Change from Baseline to Week 12 (LOCF). P-values, LS mean, and 95% confidence intervals were obtained from ANCOVA model with treatment group as a factor and baseline value as covariate.

RTVSS (Week 6)

RTVSS (Week 12)

RTSS (Week 6)

RTSS (Week 12)

Change From Baseline in the Reaction Time Variability Standard Score (RTVSS) and Response Time Standard Score (RTSS) at Weeks 6 and 12

Global Executive Composite Score Analysis. P-values, LS mean, and 95% confidence intervals were obtained from ANCOVA model with treatment group as a factor and baseline value as covariate.

Behavioral Regulation Index Analysis. P-values, LS mean, and 95% confidence intervals were obtained from ANCOVA model with treatment group as a factor and baseline value as covariate.

Metacognition Index Analysis. P-values, LS mean, and 95% confidence intervals were obtained from ANCOVA model with treatment group as a factor and baseline value as covariate.

Working Memory Scale Analysis. P-values, LS mean, and 95% confidence intervals were obtained from ANCOVA model with treatment group as a factor and baseline value as covariate.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Phase II Studies Of Donepezil And Ginkgo Biloba In Irradiated Brain Tumor	NCT00070161	Brain and Centr... Radiation Toxic...	EGb761 donepezil hydro... cognitive asses...	18 Years - 120 Years	Wake Forest University Health Sciences
Efficacy and Safety of Donepezil Hydrochloride in Preadolescent and Adolescent Children With Attention Impairment Following Cancer Treatment	NCT00688376	Attention Impai...	Donepezil hydro... Placebo	6 Years - 17 Years	Eisai Inc.

Spots Global Cancer Trial Database for donepezil hydrochloride