| 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 | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001896 |
| E.1.2 | Term | Alzheimer's disease |
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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 |
The secondary objectives are:
• To assess secondary efficacy parameters in support of the co-primary efficacy parameters
• To perform exploratory quality-of-life assessments in patients administered 23 mg donepezil SR and in their caregivers for comparison with 10 mg donepezil IR
• To assess the safety and tolerability of 23 mg donepezil SR during administration to Alzheimer’s disease patients
• To determine whether treatment response is related to rate of drug metabolism as modified by CYP2D6 alleles and whether treatment response is related to the presence of AD risk factor APOE4; exploratory analyses only (Revised per Amendment
03). |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
9.2 INCLUSION CRITERIA
9.2.1 Inclusion Criteria for Patients
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 ≥ 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 beenrolled in the study.
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. If no cranial image (MRI or CT) obtained within 12 months prior to Baseline is available, an attempt should be made to obtain the cranial image with contrast (CT and MRI), unless the use of contrast is clinically contra-indicated.
8) Degree of dementia: MMSE score 1 to 20 at Screening and Baseline
10) SIB ≤ 90 at both Screening and Baseline. Patients will be allowed to re-screen at a later time if their SIB scores are borderline (after 3 months if these scores are 91 or 92, or after 6 months if these scores are 93 or 94) (revised per amendment 04). At re-screening a new patient ID number will be assigned to these patients, and all screening assessments will be repeated.
13) Specified doses of SSRIs are allowed in the study. Patients undergoing treatment with selective serotonin reuptake inhibitors (SSRIs) at doses that are less than or equal to the approved dose range of therapeutic efficacy as specified in the Physician’s Desk Reference or regional equivalent may enter the study provided that the SSRI dose has been stable for at least 3 months prior to Screening. (Added per Amendment 03).
14) Co-morbid medical conditions must be well-controlled and the patient maintained on stable doses of medications for 3 months. Patients with risk factors of hypertension and cardiac disease may be enrolled in the study, provided that hypertension is controlled by medication in the clinical judgement of the investigator(supine diastolic BP < 95 mm Hg) and cardiac disease (e.g. angina pectoris, congestive heart failure or right bundle branch block is stable on appropriate medication for 3 months prior to Screening. Peripheral vascular disease must have been stable for 3 months prior to Screening.
16) Patients whose serum B12 levels at Screening are below the normal range may nonetheless be admitted to the study if they subsequently show normal levels prior to Baseline. Patients who are receiving Vitamin B12 supplements should maintain a stable dose/regimen throughout the study.
18) Concomitant Medications: Patients undergoing treatment with the following medications may be enrolled in the study provided these conditions are met:
a) Chronic daily benzodiazepine use may be allowed if doses are stable within
approved dose range consistent with currently accepted standards of practice for at
least 1 year prior to screening, to be confirmed by Medical Monitor. Chronic
intermittent use of benzodiazepines may be allowed pending consultation and
approval by the Medical Monitor but not within 48 hours of scheduled assessment.
b). Bronchodilator medications for treatment of COPD may be allowed as long as
drug is administered via metered dose inhaler within approved dose range.
c). Memantine is allowed if taken at prescribed doses that are less than or equal to
20mg/day, provided that the dose has been stable for at least 3months prior to Screening.
d) Additional prescription treatments for AD, such as other cholinesterase
inhibitors, must have been discontinued for at least 3 months prior to screening.
Concomitant use of memantine is allowed as noted above.
19) The patient must have a relative/caregiver who supervises the regular taking of the drug at the correct dose and is alert for possible side effects, unless the patient’s legal guardian takes on this task (Added per Amendment A - Germany).
20) No history of life-threatening arrhythmias. These include (but are not limited to): unstable atrial flutter, unstable atrial fibrillation, ventricular tachycardia, ventricular fibrillation or tosades de pointes. In any case of doubt, a specialist should be consulted. (Added per Amendment 03).
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| E.4 | Principal exclusion criteria |
9.3 EXCLUSION CRITERIA
9.3.1 Exclusion Criteria for Patients
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 per Amendment 02):
a. Memantine is allowed if taken at prescribed doses up to 20 mg/day provided the dose has been stable for at least 3 months prior to Screening.
b. Vitamin E and/or fish oil and/or gingko bilboa are allowed if the doses have been stable for at least 3 months prior to the Screening visit, provided that doses are not changed during the study. Patients undergoing any alternative medical techniques such as acupuncture or acupressure, specifically for the treatment of AD are not eligible to participate in this study.
3) Patients who have no measurable concentrations of donepezil in blood samples collected at Screening (Corrected per Amendment 02).
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.
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 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.
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 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 during the course of this study
18) Patients taking concomitant antidepressant medication known to have significant
anticholinergic effects, such as tricyclic antidepressants prescribed at doses recommended.for the treatment of major depression. Prohibited antidepressants are listed in Appendix 4 (Added per Amendment 02).
19) Patients who cannot swallow or who have difficult swallowing whole tablets. (Added per Amendment 02).
20) Patients with fecal and/or urinary incontinence who are unable to cooperate with
routine specimen collection (Added per Amendment 03).
9.3.2 Exclusion Criteria for Caregivers
1) Caregivers who are unwilling or unable to give informed consent or otherwise to
fulfill the requirements of the study.
2) Caregivers who score above 15 on the CES-D or below 27 on the MMSE (below 25 if the caregiver is illiterate) (Revised per Amendment 02).
3) Any condition that would make the caregiver, in the opinion of the Investigator,
unsuitable for the study.
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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.40, 48 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 | 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 | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 97 |
| 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
|
| The end of the study are defined as the last visit of the last subject undergoing the trial. |
|
| 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 | 0 |
| 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 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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