| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Attention impairment after cancer treatment |
|
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of donepezil in children with attention impairment that is present at least 12 months after the completion of cancer treatment |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the safety and tolerability of donepezil in children for whom at least 12 months have elapsed since the completion of cancer treatment |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female subjects must have received treatment for underlying cancer consisting of at least one cycle of chemotherapy and/or cranial radiation (the latter for an underlying brain tumor or for cranial prophylaxis). Treatment, including maintenance chemotherapy, must have ceased at least one year before Screening. Treatment cessation is defined as the final dose or the end of the last cycle of chemotherapy during the subject’s most recent course of therapy, or the last dose (fraction) of radiation.
2. Age range: 6 – 17.5 years
3. Weight ≥ 20 kg
4. Subjective complaint by subject and/or parent of difficulties in school or other daily activities, possibly related to impairments in attention. These difficulties must have emerged or worsened after treatment for cancer and must still be present 12 months after cessation of treatment.
5. Objective evidence for attention impairment as indicated by a TOVA-CPT test result, using the d’ statistic score, that is more than 1.0 standard deviation (SD) below age/gender adjusted norms at Screening and at Baseline
6. Physically healthy ambulatory or ambulatory aided subjects who reside in the community and who have fine motor skills sufficient to complete assessments such that score (time) reflects cognitive function, not an interaction with slow fine motor movements
7. IQ > 70, as estimated by the block design and vocabulary subscales of the WISC III or WISC-IV (or as demonstrated in a previously administered test)
8. The first language in which the subject learned to read and write must be one that uses Roman lettering and Arabic numerals.
9. Naïve to cholinesterase inhibitors
10. Availability of a reliable parent or legal guardian who is willing and able to complete all of the outcome measures and fulfill the requirements of this study including administration of medications and accompanying subject to all study visits
11. Vision and hearing (eyeglasses and/or hearing aid permissible) sufficient for cooperating with examinations
12. Able to swallow tablets
13. Subjects with Type I or Type II diabetes are eligible provided that the subject’s disease is stable, that there have been no recent (within 3 months of Screening) hospitalizations for diabetic ketoacidosis, hyperosmolar coma, or hypoglycemia, that the HbA1c concentration is < 10%, and that laboratory tests show a fasting (8 hours) serum glucose concentration of < 170 mg/dL or a random serum glucose concentration of < 250 mg/dL at Screening.
14. Subjects with thyroid disease may be included provided they are euthyroid and stable on treatment for at least 3 months prior to Baseline.
15. Females of childbearing potential must have a negative serum ßhCG test result at Screening. They must agree to use a medically acceptable method of contraception (eg, abstinence, a double-barrier method such as condom + spermicide or condom + diaphragm with spermicide, an intrauterine device, a contraceptive implant, or an oral contraceptive) throughout the entire study period and for 30 days after the last dose of study drug. |
|
| E.4 | Principal exclusion criteria |
1. Inability to perform the testing procedure (for example, because of aphasia, motor deficits affecting the dominant hand, or mental retardation)
2. Premorbid cognitive function in the mentally retarded/developmentally disabled range
3. Subjects scoring below the standard score of 70 in the WRAVMA Fine Motor Assessment pegboard test
4. Subjects scoring higher than the t-score of 75 on the oppositional subscale of the CPRS-R
5. Recurrent cancer requiring intervention. Subject will need to withdraw if cancer recurs during the study.
6. Current use of prohibited medications (Appendix 3), including medications known to affect attention or cognition processes (such as methylphenidate or atomoxetine), or to interfere with absorption of donepezil.
7. Subjects scoring higher than the t-score of 75 on the CDI. A subject who scores above this criterion may undergo clinical evaluation (by an independent child psychiatrist who is not a member of the study team) for depression. If the subject is determined not to be clinically depressed, he/she may enter the study, the CDI score notwithstanding.
8. Subjects with active or clinically significant conditions affecting absorption, distribution or metabolism of the study drug (eg, inflammatory bowel disease, gastric or duodenal ulcers).
9. Subjects with a known hypersensitivity to piperidine derivatives.
10. Evidence of active, clinically significant, and unstable gastrointestinal, pulmonary, renal, hepatic, endocrine, sleep, psychiatric, or cardiovascular system disease (such as sick sinus syndrome as detected by ECG), as well as any medical conditions requiring changes in medications within one month of Screening.
11. Alcoholism, drug abuse, organic brain disease other than that caused by the cancer or its treatment.
12. Any condition which would make the subject, the parent or (if applicable) the legal guardian, in the opinion of the investigator, unsuitable for the study.
13. Pregnancy, lactation or plans to become pregnant, or unwilling to take a screening ßhCG test if a female is of childbearing potential.
14. Plans for elective surgery requiring cholinergic anesthesia within study period.
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 Screening.
17. A diagnosis of Attention Deficit Hyperactivity Disorder (DSM IV criteria) before or after cancer therapy.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| To evaluate the efficacy of donepezil in children with attention impairment that is present at least 12 months after the completion of cancer treatment. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Subjects will be considered to have completed the study when the Final Visit (Week 24) procedures have been completed, and will be discharged at this time. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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