E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Alzheimers disease is caused by a loss of nerve cells in the brain, particularly in the areas associated with memory and learning. The onset of Alzheimers's also affects the levels of a certain neurotransmitter in the brain. |
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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 |
·Cognitive performance [Alzheimer’s Disease Assessment Scale – Cognitive Items (ADAS-COG)];
·Activities of daily living [Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL)]. |
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E.2.2 | Secondary objectives of the trial |
ADAS-COG+ [Modified Alzheimer’s Disease Assessment Scale – Cognitive Items (ADCS-COG+)];
Global clinical impression of therapeutic effect [Clinician’s Interview Based Impression of Change (CIBIC+)];
Behavioural / psychiatric symptoms [Neuropsychiatric Inventory (NPI)]. |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
To be eligible for inclusion in this study, each patient must fulfil the following criteria:· Males of at least 50 years of age; Females of at least 50 years of age, who are either at least 2 years post-menopausal or surgically sterile; Probable Alzheimer’s disease consistent with National Institute of Neurological and Communicative Diseases and Stroke / Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria; Have had a computed tomography (CT) or magnetic resonance imaging (MRI) brain scan within the 12 months prior to inclusion in the study that is indicative of probable Alzheimer’s disease; A Mini-Mental State Examination (MMSE) score of between 12 and 24 (inclusive) at Visit 1 (screening); A modified Hachinsky Ischemic Scale (mHIS) score equal to or below 4 at Visit 1 (screening); Reliable caregiver available, and if not living in the same household, caregiver sees patient at least 4 times a week or a total of 15 to 20 hours per week; Patients who do not need continuous nursing care and who are either living at home or in an institutional setting; General health status acceptable for participation in a 6 month clinical study; Is capable of understanding and has given written informed consent [or this has been provided by their acceptable representative (according to local requirements)] and a separate caregiver responsibilities and consent form has also been signed by the patient’s caregiver; Agrees to comply with protocol requirements. |
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E.4 | Principal exclusion criteria |
Patients are not eligible for inclusion in this study if they fulfil one or more of the following criteria: General· Failure to perform or comply with screening or baseline examinations; Hospitalisation (except for study purposes or due to social reasons, e.g. hospitalisation to unburden the caregiver); Change of concomitant medication 4 weeks prior to screening or during screening period; Participation in another therapeutic clinical study within the 3 months before Visit 2 (baseline); Inability to swallow tablets.
Medical Vitamin B12 or folate deficiency unless treated in which case treatment needs to have been stable for 3 months before study entry; Hypothyroidism, defined as any thyroid-stimulating hormone elevation. Corrected hypothyroidism is allowed provided treatment has been stable for 3 months before study entry; Juvenile onset diabetes mellitus; Adult onset diabetes mellitus insufficiently controlled [Haemoglobin A1c (HbA1c) > 8%]; A malignancy within the last 5 years; HIV infection; Any history of hepatic insufficiency or abnormal liver enzymes; Renal insufficiency with abnormal serum creatinine outside the age appropriate normal range; Serum electrolytes (sodium, potassium, magnesium) outside the age appropriate normal range; Clinically significant abnormal laboratory values outside the age appropriate normal range; Hypersensitivity to cholinergic drugs; Uncontrolled asthma. Cardiovascular Myocardial infarction or unstable angina within the 6 months prior to Visit 1 (screening); History of more than one myocardial infarction during the last 5 years;Cardiomyopathy;Myocarditis;Severe hypotension; Severe hypertension requiring treatment with more than 2 drugs;Bradycardia (frequency of heart beat < 50/minute);Tachycardia (frequency of heart beat > 90/minute);Presence of AV block (type II / Mobitz II and type III);Congenital long QT syndrome;Sinus node dysfunction; Prolonged QTcB-interval (males > 450 msec; females > 470 msec);Presence of U wave. Psychiatric Axis I diagnosis within 1 year prior to study entry; Previous diagnosis of bipolar affective disorder or schizophrenia;Current alcohol or substance abuse or dependence;Metabolic or toxic encephalopathy or dementia due to a general medical condition;Geriatric Depression Score (GDS) > 5 at Visit 1 (screening). Neurological Stroke within the 6 months prior to Visit 1 (screening) or concomitant with onset of dementia; Tumours, subdural haematoma or other space-occupying processes on CT/MRI; Head trauma with loss of consciousness within 1 year of the onset of dementia;Head trauma with loss of consciousness concurrent with the onset of dementia;Onset of dementia within 1 year following cardiac arrest, surgery with general anaesthetic or resuscitation;Degenerative central nervous system conditions e.g. Huntington’s disease (Huntington’s chorea), Creutzfeld-Jakob disease, Parkinson’s disease, etc.;Genetic cognitive impairment e.g. Trisomy 21 (Down’s syndrome);Wernicke’s encephalopathy;Acute or chronic central nervous system infection including tertiary syphilis;Epilepsy.
Previous MedicationHas previously received: Any acetylcholinesterase inhibitor in the 3 months before study entry; Any experimental drug 3 months before Visit 2 (baseline); Nootropics 1 month before Visit 1 (screening); Benzodiazepines administered on a chronic basis; Antipsychotics (unless prescribed for sleep disturbances) in the 3 months preceding study entry. If prescribed for sleep disturbance, then these should be discontinued 2 weeks prior to screening; Antidepressants, except stable treatment with selective serotonin reuptake inhibitors (SSRIs) for at least 3 months prior to screening. Concomitant MedicationNeeds concomitant use of, or treatment with the following: Peripherally acting drugs with effects on cholinergic transmission; Immunosuppressants; Antiparkinsonian therapy; Antiepileptics; Centrally active anti-hypertensive drugs like clonidine, alpha methyl-dopa, guanidine, guanfacine or moxonidine; Chronic intake of opioid containing analgesics or use within 3 days of a study visit; Chronic intake of sedating antihistamines or acute use within 3 days of a study visit; Chronic intake of systemic corticosteroids; Any other medication not covered by the above that impacts upon cognition within 3 days of a study visit. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The following efficacy assessments will be conducted in this study: · ADAS-COG / ADAS-COG+; · ADCS-ADL; · Clinician’s Interview Based Impression (CIBI+) comprising the Clinician’s Interview Based Impression of Disease Severity (CIBIS+) or the Clinician’s Interview based Impression of Change (CIBIC+); · NPI. |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | 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 | No |
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 | No |
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 | |
E.8.9.1 | In the Member State concerned months | 15 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 15 |