| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 6.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10012271 |
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| 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 |
| The primary objective of this study is to compare 23 mg donepezil SR with 10 mg donepezil IR in the treatment of patients with moderate to severe Alzheimer’s disease. |
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| E.2.2 | Secondary objectives of the trial |
| Assess secondary efficacy parameters in support of the co-primary efficacy parameters Perform exploratory quality-of-life assessments in patients administered 23 mg donepezil SR and in their caregivers for comparison with 10 mg donepezil IR Assess the safety and tolerability of 23 mg donepezil SR during long-term administration to Alzheimer’s disease patients |
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
| 1) Written informed consent will be obtained from the patient (if possible) or from the patient’s legal guardian or other representative prior to beginning screening activities. Even if unable to provide written informed consent, the patient must assent verbally to participating in the study and the record should note this assent. The caregiver must separately give informed consent for his or her own participation in the study. 2) Age range: Adult patients, 45 to 90 years of age inclusive 3) The caregiver must separately meet the specified inclusion/exclusion criteria for caregivers (Section 9.2.2 and Section 9.3.2). 4) Gender distribution: men and women. Women must be of non-child-bearing potential (> 1 year post-menopausal or surgically sterile). 5) Diagnosis: diagnostic evidence of probable AD consistent with DSM-IV 290.00 or 290.10 and NINCDS-ADRDA criteria (Appendix 5 and Appendix 6, respectively) 6) Stable Aricept dose of 10 mg IR (or 10 mg dose of generic donepezil bioequivalent to Aricept), taken as a single, daily dose for more than 3 months prior to the Screening visit. Tablets must not be broken or crushed. Any patient who splits daily doses (for example, Aricept taken as two daily 5 mg doses instead of a single 10 mg dose) will not be enrolled in the study. (Revised as per Amendment 02) 7) Cranial image: no evidence of focal disease to account for dementia on any cranial image (MRI or CT) obtained within 12 months prior to Baseline (Revised as per Amendment 02) 8) Degree of dementia: MMSE score minor/equal to 20 at Screening and Baseline 9) CSDD < 12 at Screening (Revised as per Amendment 02) 10) SIB minor/equal to 90 at both Screening and Baseline (Renumbered as per Amendment 2) 11) Health: physically healthy and ambulatory or ambulatory-aided (ie, walker or cane); Corrected vision and hearing sufficient for compliance with testing procedures, and able to read pre-morbidly (Revised as per Amendment 02) 12) Clinical laboratory values must be within normal limits or, if abnormal, must be judged not clinically significant by the investigator (Renumbered as per Amendment 02). 13) Patients undergoing treatment with selective serotonin reuptake inhibitors (SSRI)(< 20 mg daily of citalopram, < 10 mg daily of escitalopram,fluoxetine, fluvoxamine,< 30 mg daily of paroxetine or <100 mg daily of sertraline) may enter the study provided that the SSRI dose has been stable for at least three months prior to Screening (added as per Amendment 02). 14) Patients with risk factors of hypertension and cardiac disease may be enrolled in the study, provided that hypertension is medication controlled (supine diastolic BP < 95 mm Hg) and cardiac disease (e.g. angina pectoris, congestive heart failure,right bundle branch block, or arrhythmias) is stable on appropriate medication for 3 months prior to Screening. Peripheral vascular disease must have been stable for 3 months prior to Screening. 15) Patients with diabetes mellitus or risk factors for diabetes mellitus may be enrolled in the study provided that the patient’s disease is stable and that there have been no recent (within 3 months of Screening) hospitalizations for diabetic ketoacidosis,hyperosmolar coma, or hypoglycemia (revised as per Amendment 02). Patients with non-insulin-dependent diabetes may enroll in the study if controlled on diet or oral medications. 16) All diabetic patients must have an HbA1c concentration of < 10% and a fasting (8 hours) serum glucose concentration of < 170 mg/dL, or a random serum glucose concentration of < 250 mg/dL at Screening (revised as per Amendment 01). 17) Patients with a history of Vitamin B12 deficiency who are on a stable dose of medication for at least 3 months prior to Screening (revised as per Amendment 02), and who have normal serum vitamin B12 levels at Screening, will be eligible. This stable dose of vitamin B12 must be maintained throughout the study. [see also protocol] |
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| E.4 | Principal exclusion criteria |
| 1) Patients taking (a) no medication for Alzheimer’s disease, (b) Aricept or bioequivalent generic donepezil at doses other than 10 mg daily, or 10 mg for < 3 months before Screening; (c) other medications for Alzheimer’s disease, with the following exceptions (revised as per Amendment 02): a. Memantine is allowed if taken at prescribed doses of 20 mg daily for at least 3 months prior to the Screening visit b. Vitamin E and/or fish oil are allowed if dose has been stable for at least 3 months prior to the Screening visit, provided that doses are not changed during the study 2) No caregiver available to meet the inclusion criteria for caregivers 3) Patients who have no measurable concentrations of donepezil in blood samples collected at Screening (corrected as per Amendment 02) 4) Patients with neurological disorders that affect cognition or the ability to assess cognition but are distinguishable from Alzheimer’s disease, such as Parkinson’s disease, multi-infarct dementia, dementia due to cerebrovascular disease, Huntington’s disease, Pick’s disease, Creutzfeld-Jacob disease, Lewy Body disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, or multiple sclerosis, as well as patients with known human immunodeficiency virus (HIV) disease, neurosyphilis, or a history of significant head trauma followed by persistent neurological deficits or known structural brain abnormalities 5) Patients with psychiatric disorders affecting the ability to assess cognition such as schizophrenia, bipolar or unipolar depression. Patients with clinically significant sleep disorders will also be excluded unless these are controlled by treatment and clinically stable for > 3 months prior to screening (revised as per Amendment 01). 6) Patients with dementia complicated by other organic disease or Alzheimer’s disease with delirium (DSM IV 290.30 or 290.11; Appendix 5) 7) Patients with drug or alcohol abuse or dependence within the past 5 years according to DSM IV criteria (Appendix 5) 8) Patients with any active or clinically significant conditions affecting absorption,distribution, or metabolism of the study medication (eg, inflammatory bowel disease,gastric or duodenal ulcers, hepatic disease, or severe lactose intolerance) 9) Patients with evidence of clinically significant, active gastrointestinal, renal, hepatic,respiratory, endocrine, or cardiovascular system disease (Revised as per Amendment 02) 10) Patients with a history of malignant neoplasms (does not include basal or squamous cell carcinoma of the skin) treated within 5 years prior to study entry, current evidence of malignant neoplasm, recurrent, metastatic disease. Males with localized prostate cancer requiring no treatment would not be excluded. 11) Known plan for elective surgery during the treatment period that would require general anesthesia and administration of neuromuscular blocking agents, such as succinylcholine, to induce paralysis/muscle relaxation. Minor surgery, such as colonoscopy or cataract surgery, will be permitted as long as it does not require the use of these paralytic agents. (Revised as per Amendment 02) 12) Donation of blood or blood products during 30 days prior to Screening or plans to donate blood while participating in the study or within 30 days after completion of the study 13) Patients who are unwilling or unable to fulfill the requirements of the study 14) Known hypersensitivity to acetylcholinesterase inhibitors or memantine (revised as per Amendment 01) 15) Use of any prohibited prior or concomitant medications as described in Section 10.7 and listed in Appendix 4 16) Any condition that would make the patient, in the opinion of the investigator,unsuitable for the study 17) Involvement in any other investigational drug clinical trial during the preceding 3 months, or likely involvement in any other such trial [see also protocol] |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The co-primary parameters for this study are the Severe Impairment Battery (SIB) change from Baseline and the CIBIC+ change from Baseline in the Intent to Treat population using Last Observation Carried Forward (ITT-LOCF) imputation for missing data. For registration applications in Europe, the ADCS-ADL will replace the CIBIC+ as the second co-primary parameter. Severe Impairment Battery (SIB) The SIB will be administered to patients during the Screening and Baseline Visits and at the 6-, 12-, 18- and 24-week visits. It is essential that the SIB be completed in its entirety at Baseline. If for any reason this assessment is not completed at this visit, the patient will be discontinued. Modified Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL). The ADCS-ADL (severe scale) consists of a comprehensive battery of ADL questions used to measure a patient’s functional capabilities. The modified ADCS-ADL-severe scale is a 19-item scale that has been validated for the assessment of patients with moderate to severe dementia. It measures the most appropriate basic and instrumental abilities (such as walking, grooming, bathing, and eating) in this patient population. Each ADL item is rated from the highest level of independent performance to complete dependence. The scale has a scoring range of 0 to 54, with the lower scores indicating greater functional impairment. This inventory will be administered at Baseline and at the 6-, 12-, 18-, and 24-week (or early termination) visits as a rater-administered interview with the caregiver, and will cover the patient’s most typical and consistent performance of each ADL during the previous 4 weeks. It is essential that the ADCS-ADL be completed in its entirety at Baseline. If for any reason this assessment is not completed at this visit, the patient will be discontinued. |
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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 | Information not present in EudraCT |
| 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) | Yes |
| 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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| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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