| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Probable Alzheimer's Disease of moderate severity. |
|
| 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 effects of memantine on the rate of brain atrophy in patients with probable AD over the course of one year’s treatment, using MRI technology. |
|
| E.2.2 | Secondary objectives of the trial |
| In addition, the study will evaluate the clinical efficacy of memantine treatment, through the use of cognitive and behavioural measures and explore associations between changes in clinical and MRI outcomes. The study will also evaluate the safety and tolerability of memantine over 1 year. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
Any patient who meets all the following criteria at both the Screening and the Baseline visits is eligible for inclusion in this study:
1. Written informed consent must be obtained from the patient (or a legally acceptable representative if applicable and if different from the responsible caregiver) and the responsible caregiver, prior to the initiation of any study specific procedures (see protocol for further details on the informed consent procedure).
2. Male or female ambulatory, or ambulatory aided (i.e., walker or cane) outpatients at least 50 years of age.
3. The patient has a current diagnosis of probable Alzheimer's disease consistent with NINCDS-ADRDA Criteria (see protocol Appendix 1).
4. The patient has a knowledgeable and reliable caregiver who will accompany the patient to all clinic visits during the course of the study.
5. The patient’s MRI scan conducted at Screening is consistent with a diagnosis of probable Alzheimer’s disease (approval will be centrally coordinated).
6. The patient’s Mini Mental State Examination (MMSE) total score is at least 12 and no greater than 20 at the Screening and Baseline visits.
7. Patients may enter the study if they are on existing ChEI treatment (e.g., donepezil, rivastigmine, galantamine) initiated at least 6 months prior to the Screening visit and stabilised with respect to dose for at least the last 3 months. This treatment and dose must remain fixed throughout the duration of the study. Furthermore, patients may enter the study if they are not on existing ChEI therapy. If ChEI treatment was previously taken by these patients, then this must have been discontinued for at least 3 months prior to the Baseline visit. Treatment with a ChEI cannot be initiated or modified during the trial.
8. On the basis of a physical examination, medical history, electrocardiogram and the results of blood biochemistry and haematological tests carried out at the Screening visit, the patient is, in the Investigator’s opinion, otherwise healthy. That is, the results are either normal or abnormal, but judged not clinically significant for this patient by the Investigator and documented as such in the patient records. The Investigator should contact the Sponsor to discuss individual cases as needed.
9. If female, the patient is at least 2 years post menopausal or surgically sterile.
10. The patient’s sight and hearing (a hearing aid is permitted if necessary) is sufficiently good to allow them to undertake the study-related procedures and cognitive tests without difficulty. (Note, colour blind patients unable to complete the Stroop must not be included).
11. Patients must speak the native language of their country fluently.
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|
| E.4 | Principal exclusion criteria |
Any patient who meets one or more of the following criteria at either the Screening or the Baseline visits cannot be included in the study:
1. Patients with evidence of clinically significant and active pulmonary, gastrointestinal, renal, hepatic, endocrine or cardiovascular system disease (including patients with recent myocardial infarction (< 3 months) and uncompensated congestive heart failure (NYHA II-IV). Note, patients with controlled diabetes, or patients with controlled hypertension, or right bundle branch block (complete or partial) may be included in the study).
2. Patients with severe renal impairment as measured by an estimated creatinine clearance of < 30 mL/min/1.73m2 at Screening.
3. Patients with a systolic blood pressure (while sitting) greater than 180 mm/Hg, or less than 90 mm/Hg, or a diastolic blood pressure (while sitting) greater than 100 mm/Hg, or less than 50 mm/Hg at the Screening or Baseline visits.
4. Patients with a recent history (within 3 months of screening), or currently untreated, B12, thyroid stimulating hormone (TSH) or folate deficiency, which is considered clinically significant. (Note, patients with thyroid disease may be included in the study, provided they are stable and euthyroid).
5. Patients with a history of severe drug allergy, or hypersensitivity, or patients with known hypersensitivity to memantine, amantadine, rimantidine or lactose.
6. Patients with evidence of any clinically significant neurodegenerative disease or other serious neurological disorders other than Alzheimer’s disease including but not limited to Lewy body dementia, fronto-temporal dementia, Parkinson’s disease, Huntington’s disease, major cortical stroke, major head trauma and primary or secondary cerebral neoplasia. The Investigator should contact the Sponsor to discuss individual cases as needed.
7. Patients with a Modified Hachinski Ischaemia score greater than 4 at Screening.
8. Patients with dementia complicated by other organic disease.
9. Patients with a DSM-IV-TR Axis I disorder other than Alzheimer’s disease including amnestic disorders, schizophrenia or schizoaffective disorder, bipolar disorder, current major depressive episode, psychosis, panic, or post traumatic stress disorder. (Note, patients may be included if symptoms of major depression are treated and stable).
10. Patients with an oncological diagnosis (haematological or solid tumour) which is currently being treated, or for which there has been treatment within the 1 year preceding screening, or for which there is still evidence of active disease. (Note, patients with local dermatological tumours such as basal or squamous cell carcinoma may be included.)
11. Patients with an object in their head or neck, which would invalidate or obstruct the successful completion of an MRI scan, or patients who are otherwise contraindicated for MRI including those with implanted ferromagnetic material or devices such as cardiac pacemakers, intraocular metallic shards, and cochlear implants.
12. Patients who are unable to tolerate an MRI scan at screening according to the defined imaging manual, or whom the Investigator believes will not be able to tolerate further scans scheduled during the course of the trial.
13. Patients who are considered inappropriate following centralised reading of their screening MRI scan, according to the requirements set out in the imaging manual.
14. Patients with a known or suspected history (within the past 10 years) of alcoholism or drug abuse.
15. Patients who are currently receiving memantine, have taken memantine in the past, or who have ever participated in an investigational study of memantine. Memantine (other than study medication) cannot be initiated during the course of the trial.
16. Patients who are taking, or have taken, any unapproved concomitant medications as defined in the protocol that cannot be discontinued or switched to a permissible alternative, according to the timelines provided.
17. Patients who have been in an investigational drug study, or who have received treatment with an investigational drug within 30 days (or 5 half-lives, whichever is longer) of the Screening visit.
18. Patients with any disease, or treated by any medication, which according to the Investigator’s judgement, could interfere with the assessments of neuroimaging, safety, tolerability or clinical efficacy.
19. Patients who, in the clinician’s judgement, are likely to be placed in a nursing or residential home within the next 12 months.
20. Patients, or patients with their caregivers, who are unwilling, or unable to abide by the visit schedule and other study requirements. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Rate of total brain volume loss (or rate of brain atrophy) on MRI. |
|
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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 |
|
| 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
|
| Last patient, last visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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