| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Cerebral autosomal dominant arteriopathy with subcortical infracts and leukoencephalopathy (CADASIL).
CADASIL is a genetic disorder representing a minority of the patients who develop vascular dementia. |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 7.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10057678 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to determine whether donepezil HCl confers cognitive benefit in patients with CADASIL who have cognitive impairment. |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of this study are to evaluate the safety and tolerability of donepezil HCl in patients with CADASIL who have cognitive impairment. |
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
5) Head MRI: Evidence of disease consistent with CADASIL, and no evidence of another disease, which might account for cognitive impairment or dementia (as judged by the Investigator/physician at the site). Must be obtained within 6 months of the Screening visit. If no such head MRI had been previously obtained, a head MRI will be obtained as part of Screening after all other inclusion and exclusion criteria (except clinical laboratory determinations) are satisfied. Patients in whom an MRI is contraindicated can have a CT instead, however, MRI is the preferred modality.
9) Patients with vitamin B12 deficiency who are on a stable dose of medication for at least 12 weeks prior to Baseline and who have normal or elevated serum B12 levels at Screening will be eligible. Patients who might otherwise have been eligible can be re-screened when they meet this criterion. This stable dose of vitamin B12 must be maintained throughout the study. Patients with high serum levels of vitamin B12 or folate are eligible.
10) Patients with hypothyroidism or hyperthyroidism who are on a stable dose of medication for at least 12 weeks prior to Baseline are eligible. If Screening laboratory testing of thyroid function (TSH and free T4) abnormalities are found, patients will not be considered ineligible if they are on a stable dose of medication for at least 12 weeks prior to Baseline or they are considered euthyroid by their primary care physician and are therefore not eligible for medicaiton therapy. Patients who might otherwise have been eligible can be re-screened when they meet this criterion. This stable dose must be maintained throughout the study.
11) Patients must have a reliable study partner who has regular contact with the patient (e.g, an average of 4 or more contacts per week), can observe for possible adverse events, and can accompany the patient to visits as described in Section 10.5.
12) Patients with a history of hypertension, cardiac disease, diabetes, or peripheral vascular disease, may be enrolled in the study provided that the following standards are met. Hypertension must be medication controlled (sitting SBP < 175, sitting DBP < 100 mm Hg) (per Administrative Change 01) and cardiac disease (e.g. angina pectoris, congestive heart failure, right bundle branch block, or arrhythmias) is stable on appropriate medication for 12 weeks prior to Screening. Peripheral vascular disease must have been stable for 12 weeks prior to Screening. No elective surgical procedures should be planned during the course of the study (e.g. hernia repair and bunion removal). Patient with diabetes must be stable as demonstrated by an HbA1c of ≤ 8.0% or a random serum glucose value of ≤ 170 mg/dL. Patients with abnormal glucose values at Screening, who are not considered diabetic by their personal physicians, will be considered eligible. Patients with HbA1c values in the diabetic range must be stable before study entry.
13) All patients with CADASIL are at risk for stroke / TIA and may be enrolled in the study provided that no new strokes have been diagnosed or identified to have occurred within the three months prior to Screening. Patients who might otherwise be eligible can be screened 12 weeks after the stroke. Patients with TIAs are eligible without a waiting period. Patients who are already enrolled will continue in the study as assessed by the Investigator/physician
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| E.4 | Principal exclusion criteria |
11) Use of any unapproved prior or concomitant medications as defined in Sections 8.4 and Appendix 2 (This list is not exhaustive. If there are questions, please ask the Medical Monitor.) (per Administrative Change 01) For allowed medications that act on cognition, anti-depressants for example, the dosage and the condition treated (e.g., depression) must be stable for 12 weeks prior to enrollment. If a medication is used to treat a condition that does not affect the patient's cognition, in the opinion of the investigator, then the wash-out period is 6 weeks. The wash-out for oxybutinin, an anti-cholinergic agent, is 4 weeks for 5mg/day and 8 weeks for higher dosages. Similar agents will likewise have dose-dependent wash-outs. Please ask the medical monitor.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint will be based on the V-ADAS-Cog score at 18 weeks or Early Termination. Secondary endpoints include evaluation of ADAS-Cog, Mini-Mental State Exam (MMSE), Trail Making Test (TMT), Stroop Test, EXIT25, CLOX, Disability Assessment for Dementia (DAD), and correlation of MRI findings with treatment effect in these patients. Further analyses will evaluate all of these endpoints in the subset of patients with NINDS-AIREN defined vascular dementia. Parameters will be measured at the Screening/Baseline visit, during, and at the end of the study. Safety and tolerability will be collected from adverse events, medical history, physical and neurological examination, EKGs and clinical laboratory tests. |
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| 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 | No |
| 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 | Information not present in EudraCT |
| 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) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| 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 |
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| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
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| The end of the trial is the last visit of the last subject undergoing the trial. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| 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 months | 19 |
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