Attention Impairment
Conditions
Keywords
Attention, cancer, chemotherapy, donepezil, acetylcholinesterase, inhibitor
Brief summary
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.
Detailed description
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.
Interventions
DRUGDonepezil hydrochloride
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).
DRUGPlacebo
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).
Sponsors
Eisai Limited
Eisai Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
1. The subject must have received at least one cycle of chemotherapy and/or cranial radiation, and must have completed this treatment at least one year before screening takes place for entry into this study. 2. Subjects may be male or female; age range: 6 - 17.5 years; weight ≥ 20 kg. They must be physically healthy and able to move about, with or without aids, must be living in the community, and must have adequate motor skills as shown by tests that will be given at the time of screening. The subject's eyesight and hearing must be good enough to allow cooperation with tests and physical examinations. Additionally, they must be able to swallow tablets. 3. There must be subjective complaints by subject and/or parent of difficulties in school or other daily activities, possibly related to impairments in attention. These difficulties must have emerged after treatment for cancer and must still be present 12 months after cessation of treatment. There must also be objective evidence for this impairment, as shown by a test that will be given to the subject at the time of screening. 4. The IQ must be \>70 according to tests that will be given at the time of screening. 5. The first language in which the subject learned to read and write must be one that uses Roman lettering (a, b, c, etc.) and Arabic numerals (1, 2, 3, etc.). 6. The subject must not have previously taken any drugs in the class known as cholinesterase inhibitors. 7. A parent or legal guardian must be available who is willing and able to complete all of the outcome measures, to administer medications, and to accompany the subject to the required clinic visits. 8. Subjects with diabetes or thyroid disease may still be eligible if certain medical requirements are satisfied. 9. Female subjects who could become pregnant must undergo pregnancy testing and must agree to use contraception.
Exclusion criteria
Subjects who meet any of the following criteria will be excluded from the study: 1. Inability to perform the required tests (for example, because of aphasia, motor deficits affecting the dominant hand, or mental retardation). 2. Motor coordination not sufficient, according to tests to be conducted at the time of screening. 3. Recurrence of cancer. If this happens, the subject will have to withdraw from the study. 4. Mental retardation/developmental disability. 5. Certain medications, such as methylphenidate, are not allowed during the study. 6. Major depression. 7. Problems with the digestive tract that could affect the subject's ability to absorb the study drug. 8. Hypersensitivity to a chemical class known as piperidine derivatives. 9. Certain other medical conditions as determined by clinical staff. 10. Alcoholism, drug abuse, or organic brain disease other than that caused by the cancer or its treatment. 11. Pregnancy, nursing, or unwillingness to undergo pregnancy testing if requested by clinical staff. 12. Pregnancy, lactation or plans to become pregnant, or unwilling to take a screening Beta-human chorionic gonadotropin (ßhCG) test if a female \>10 years of age. 13. If sexually active, unwillingness to use birth control (males and females). 14. Plans for certain types of elective surgery that would occur while the study is in progress. 15. Plans for travel or other events that would interfere with the study schedule. 16. Active treatment with another investigational drug within 3 months of the screening visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Test of Variables in Attention-Continuous Performance Test (TOVA-CPT) D-prime Standard Score (SS) at Week 12 | Baseline and Week 12 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the TOVA-CPT D-prime Standard Score (SS) at Week 6 | Baseline and Week 6 | 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. |
| Change From Baseline in the Reaction Time Variability Standard Score (RTVSS) and Response Time Standard Score (RTSS) at Weeks 6 and 12 | Baseline, Weeks 6 and 12 | 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. |
| Change From Baseline in the Global Executive Composite Score, Behavioral Regulation Index, Metacognition Index, and Working Memory Subscale | Baseline and Week 12 | 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. |
Countries
Argentina, Australia, Canada, Chile, France, Germany, Netherlands, Spain, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 22 centers in the United States, France, Germany, the Netherlands, Spain, the UK, Argentina, Chile, and Australia during the period of 02 July 2008 to 26 May 2009.
Pre-assignment details
This trial had 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 participants received active drug. Eligible participants were randomized to receive placebo or donepezil.
Participants by arm
| Arm | Count |
|---|---|
| Donepezil Donepezil 3 mg, 5 mg, or 10 mg donepezil Immediate Release (IR) orally, once daily | 40 |
| Placebo Placebo, matching 3 mg, 5 mg, and 10 mg placebo tablets administered orally, once daily | 31 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Blinded Extension Phase | Adverse Event | 3 | 4 |
| Blinded Extension Phase | Other | 1 | 0 |
| Blinded Extension Phase | Physician Decision | 1 | 0 |
| Blinded Extension Phase | Withdrawal by Subject | 0 | 1 |
| Double-Blind Phase | Adverse Event | 4 | 4 |
| Double-Blind Phase | Not treated | 0 | 1 |
| Double-Blind Phase | Protocol Violation | 1 | 2 |
| Double-Blind Phase | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Donepezil | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 12.1 Years STANDARD_DEVIATION 3.06 | 11.6 Years STANDARD_DEVIATION 2.83 | 11.9 Years STANDARD_DEVIATION 2.95 |
| Sex: Female, Male Female | 15 Participants | 21 Participants | 36 Participants |
| Sex: Female, Male Male | 25 Participants | 10 Participants | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 40 | 0 / 31 | 0 / 34 | 0 / 25 |
| other Total, other adverse events | 30 / 40 | 20 / 31 | 21 / 34 | 15 / 25 |
| serious Total, serious adverse events | 1 / 40 | 1 / 31 | 0 / 34 | 0 / 25 |
Outcome results
Primary
Change From Baseline in the Test of Variables in Attention-Continuous Performance Test (TOVA-CPT) D-prime Standard Score (SS) at Week 12
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.
Time frame: Baseline and Week 12
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donepezil | Change From Baseline in the Test of Variables in Attention-Continuous Performance Test (TOVA-CPT) D-prime Standard Score (SS) at Week 12 | 5.2 d-prime | Standard Deviation 8.77 |
| Placebo | Change From Baseline in the Test of Variables in Attention-Continuous Performance Test (TOVA-CPT) D-prime Standard Score (SS) at Week 12 | 4.5 d-prime | Standard Deviation 7.39 |
Comparison: 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.p-value: 0.69495% CI: [-3.22, 4.8]ANCOVA
Secondary
Change From Baseline in the Global Executive Composite Score, Behavioral Regulation Index, Metacognition Index, and Working Memory Subscale
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.
Time frame: Baseline and Week 12
Population: ITT population LOCF
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Donepezil | Change From Baseline in the Global Executive Composite Score, Behavioral Regulation Index, Metacognition Index, and Working Memory Subscale | Global Executive Composite Score | -1.3 t-scores | Standard Deviation 6.73 |
| Donepezil | Change From Baseline in the Global Executive Composite Score, Behavioral Regulation Index, Metacognition Index, and Working Memory Subscale | Behavioral Regulation Index | 0.8 t-scores | Standard Deviation 7.54 |
| Donepezil | Change From Baseline in the Global Executive Composite Score, Behavioral Regulation Index, Metacognition Index, and Working Memory Subscale | Metacognition Index | -2.3 t-scores | Standard Deviation 7.29 |
| Donepezil | Change From Baseline in the Global Executive Composite Score, Behavioral Regulation Index, Metacognition Index, and Working Memory Subscale | Working Memory Scale | -3.6 t-scores | Standard Deviation 7.45 |
| Placebo | Change From Baseline in the Global Executive Composite Score, Behavioral Regulation Index, Metacognition Index, and Working Memory Subscale | Working Memory Scale | -3.3 t-scores | Standard Deviation 6.59 |
| Placebo | Change From Baseline in the Global Executive Composite Score, Behavioral Regulation Index, Metacognition Index, and Working Memory Subscale | Global Executive Composite Score | -3.8 t-scores | Standard Deviation 6.78 |
| Placebo | Change From Baseline in the Global Executive Composite Score, Behavioral Regulation Index, Metacognition Index, and Working Memory Subscale | Metacognition Index | -4.9 t-scores | Standard Deviation 6.99 |
| Placebo | Change From Baseline in the Global Executive Composite Score, Behavioral Regulation Index, Metacognition Index, and Working Memory Subscale | Behavioral Regulation Index | -1.9 t-scores | Standard Deviation 6.91 |
Comparison: 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.p-value: 0.288695% CI: [-1.5, 4.96]ANCOVA
Comparison: 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.p-value: 0.255595% CI: [-1.54, 5.69]ANCOVA
Comparison: 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.p-value: 0.315595% CI: [-1.63, 4.99]ANCOVA
Comparison: 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.p-value: 0.907595% CI: [-3.55, 3.16]ANCOVA
Secondary
Change From Baseline in the Reaction Time Variability Standard Score (RTVSS) and Response Time Standard Score (RTSS) at Weeks 6 and 12
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.
Time frame: Baseline, Weeks 6 and 12
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Donepezil | Change From Baseline in the Reaction Time Variability Standard Score (RTVSS) and Response Time Standard Score (RTSS) at Weeks 6 and 12 | RTVSS (Week 6) | -3.4 milliseconds | Standard Deviation 18.44 |
| Donepezil | Change From Baseline in the Reaction Time Variability Standard Score (RTVSS) and Response Time Standard Score (RTSS) at Weeks 6 and 12 | RTVSS (Week 12) | -3.9 milliseconds | Standard Deviation 15.21 |
| Donepezil | Change From Baseline in the Reaction Time Variability Standard Score (RTVSS) and Response Time Standard Score (RTSS) at Weeks 6 and 12 | RTSS (Week 6) | -6.9 milliseconds | Standard Deviation 13.17 |
| Donepezil | Change From Baseline in the Reaction Time Variability Standard Score (RTVSS) and Response Time Standard Score (RTSS) at Weeks 6 and 12 | RTSS (Week 12) | -9.0 milliseconds | Standard Deviation 13.15 |
| Placebo | Change From Baseline in the Reaction Time Variability Standard Score (RTVSS) and Response Time Standard Score (RTSS) at Weeks 6 and 12 | RTVSS (Week 12) | -5.0 milliseconds | Standard Deviation 17 |
| Placebo | Change From Baseline in the Reaction Time Variability Standard Score (RTVSS) and Response Time Standard Score (RTSS) at Weeks 6 and 12 | RTSS (Week 12) | -9.1 milliseconds | Standard Deviation 12.79 |
| Placebo | Change From Baseline in the Reaction Time Variability Standard Score (RTVSS) and Response Time Standard Score (RTSS) at Weeks 6 and 12 | RTVSS (Week 6) | -3.2 milliseconds | Standard Deviation 15.75 |
| Placebo | Change From Baseline in the Reaction Time Variability Standard Score (RTVSS) and Response Time Standard Score (RTSS) at Weeks 6 and 12 | RTSS (Week 6) | -9.6 milliseconds | Standard Deviation 13.25 |
Comparison: 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.p-value: 0.74395% CI: [-9.56, 6.85]ANCOVA
Comparison: 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.p-value: 0.956195% CI: [-7.42, 7.84]ANCOVA
Comparison: 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.p-value: 0.438595% CI: [-3.97, 9.04]ANCOVA
Comparison: 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.p-value: 0.908895% CI: [-6.74, 6]ANCOVA
Secondary
Change From Baseline in the TOVA-CPT D-prime Standard Score (SS) at Week 6
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.
Time frame: Baseline and Week 6
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donepezil | Change From Baseline in the TOVA-CPT D-prime Standard Score (SS) at Week 6 | 5.7 d-prime | Standard Deviation 8.41 |
| Placebo | Change From Baseline in the TOVA-CPT D-prime Standard Score (SS) at Week 6 | 6.2 d-prime | Standard Deviation 9.49 |
Comparison: P-values, LS mean, and 95% confidence intervals were obtained from ANCOVA model with treatment group as a factor and baseline value as covariate.p-value: 0.945895% CI: [-4.38, 4.09]ANCOVA