E2020-G000-334

Eisai

100 Tice Boulevard, Woodcliff Lake, United States, 07677

EISAI Medical Information, Eisai Ltd., +1 888-274-2378, esi_medinfo@eisai.com

EISAI Medical Information, Eisai Ltd., +1 888-274-2378, esi_medinfo@eisai.com

No

No

No

Final

20 May 2009

Yes

20 May 2009

Yes

20 May 2009

No

The purpose of this study was 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 study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: - Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2008) - International Conference on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, International Conference on Harmonisation of Pharmaceuticals for Human Use - Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312 - European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies conducted within any European Union (EU) country. All suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states. - Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP Subject Information and Informed Consent.

06 Aug 2008

No

No

France: 11

Germany: 1

Spain: 4

Argentina: 1

Australia: 2

United Kingdom: 2

Belgium: 3

South Africa: 9

Chile: 4

Canada: 1

United States: 33

71

21

0

0

0

0

22

49

0

0

0

Double-blind Phase (overall period)

Randomised - controlled

During the Blinded Extension Phase, study personnel, subjects, and parents/legal guardians continued to be blinded to the treatment that each subject received during the preceding Double-blind Phase.

Yes

Donepezil

Aricept, E2020

Tablet

Oral use

During the double-blind phase, all subjects randomized to receive donepezil started on 3 mg/day. Subjects who weighed 35 to 49.9 kilogram (kg) were titrated up to 5 mg/day final dose three weeks later. Subjects weighing 50.0 kg or more were titrated up after three weeks to 5 mg/day, then to a final dose of 10 mg/day three week later. No down-titrations were allowed. At Week 12, the double-blind phase ended, and the blinded extension phase began. Subjects who were randomized to receive active treatment during the double-blind phase remained at the same dose level during the entire blinded extension phase.

Placebo

Tablet

Oral use

During the double-blind phase, matching 3 mg, 5 mg, and 10 mg placebo tablets were administered orally, once daily, to subjects receiving placebo. At Week 12, the double-blind phase ended, and the blinded extension phase began. Subjects who had been on placebo during the double-blind phase began receiving active treatment during the blinded extension phase. Dose titration was applied for those subjects on final doses of 5 mg and 10 mg donepezil, according to the dose increment (titration) schedule that was applied to active treatment subjects during the double-blind phase.

Donepezil

Placebo

Donepezil

Placebo

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” 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, the reaction time variability standard score, and the 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.ITT population LOCF.

Primary

Baseline and Week 12

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.

Donepezil v Placebo

69

Pre-specified

0.8

2-sided

The 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 number of "Hits" (correct responses), omission errors (failure to respond), commission errors/"False Alarms" (incorrect responses), response time, and sensitivity ("d-prime")."D-prime" 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. ITT population LOCF.

Secondary

Baseline and Week 6

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

Donepezil v Placebo

69

Pre-specified

-0.1

2-sided

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 subject. 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. Intent-to-Treat (ITT) Last Observed Carried Forward (LOCF) population included all safety subjects 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.

Secondary

Baseline, Weeks 6 and 12

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.

Donepezil v Placebo

69

Pre-specified

-1.4

2-sided

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.

Donepezil v Placebo

69

Pre-specified

0.2

2-sided

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.

Donepezil v Placebo

69

Pre-specified

2.5

2-sided

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.

Donepezil v Placebo

69

Pre-specified

-0.4

2-sided

Behavioral Rating Inventory of Executive Functioning test evaluates impairment of executive function,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 were 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 Index (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. ITT population LOCF.

Secondary

Baseline and Week 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.

Donepezil v Placebo

69

Pre-specified

1.7

2-sided

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.

Donepezil v Placebo

69

Pre-specified

2.1

2-sided

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.

Donepezil v Placebo

69

Pre-specified

1.7

2-sided

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.

Donepezil v Placebo

69

Pre-specified

-0.2

2-sided

For each subject, adverse events were collected from the time the subject signed the informed consent form up to 30 days after discontinuation, or approximately 203 days

Safety population included randomized subjects 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.

11.0

Donepezil Double-blind Phase

Placebo Double-blind Phase

Donepezil Blinded Extension Phase

Placebo Blinded Extension Phase