E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects with mild-to-moderate probable Alzheimer's disease |
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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 | 10012271 |
E.1.2 | Term | Dementia Alzheimer's type |
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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 |
-To assess the effects of once daily os SB-742457 versus placebo as adjunct therapy to stable donepezil treatment after 24 weeks of treatment on cognitive function -To assess the effects of once daily dosing of SB-742457 versus placebo as an adjunct therapy to stable donepezil treatment after 24 weeks of treatment on global function |
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E.2.2 | Secondary objectives of the trial |
To investigate how baseline severity affects efficacy outcome measures (cognitive and global function) after 24 weeks of treatment To investigate effects on cognitive and global function of SB-742457 versus placebo as an adjunct therapy to stable donepezil treatment after 12 weeks of treatment To investigate how baseline severity affects efficacy outcome measures (cognitive and global function) after 12 weeks of treatment To investigate effects on activities of daily living of SB-742457 versus placebo as an adjunct therapy to stable donepezil treatment after 12 and 24 weeks of treatment To verify the SB-742457 plasma concentrations and donepezil plasma concentrations in the subjects To estimate the individual exposures of SB-742457 so they can be related to efficacy or safety endpoints as appropriate To confirm the lack of pharmacokinetic interaction between SB-742457 and donepezil To assess the safety and tolerability of SB-742457 as an adjunct therapy to stable donepezil trea |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
FARMACOGENETICA: Versione: Data: Titolo:Pharmacogenetics endpoints Obiettivi:The effects of genetic markers located within the following APOE gene, 5-HT6 recptor gene, 5-HT2a recepor gene and possibly others on ADAS-Cog, CDR-SB and possibly other measures of efficacy and/or safety.
FARMACOCINETICA/FARMACODINAMICA: Versione: Data: Titolo:Pharmacokinetics and Pharmacodynamics endpoints Obiettivi:-Exposure estimates for SB-742457 and donepezil -Change from baseline in red blood cell acetylcholinesterase activity
ALTRI SOTTOSTUDI: Exploratotory Health Outcomes Endpoints: change from baseline in the caregiver time spent caring for the subject(caregiver burden) at week 24
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E.3 | Principal inclusion criteria |
1. Male or female subject with a clinical diagnosis of probable Alzheimer's disease in accordance with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria and National Institute of Neurological and Communicative Diseases and Stroke/Alzheimers Disease and Related Disorders Association (NINCDS-ADRDA)2. Subject has a documented history of at least 6 months of ongoing donepezil therapy for Alzheimers disease, with stable dosing of 5-10mg/day for at least the last 2 months (and with no intent to change for the duration of the study). 3. Subject has MMSE score 12-24 inclusive at Screening and a baseline MMSE score 10-26 inclusive. The MMSE score at baseline must be within ± 3 points of the Screening value. 4. Hachinski Ischaemia score ≤ 4 at Screening. 5. Age ≥ 50 to ≤ 85 years. 6. A female subject must be: a. Of non-childbearing potential i.e., any female who is post-menopausal [ > 1 year without menstrual period in the absence of hormone replacement therapy]1 or surgically sterile; or, b. If pre-menopausal or menopausal for 1 year or less, must have a negative pregnancy test and must not be lactating at the Screening and Baseline Visits and agrees to satisfy one of the requirements listed in Section 11.4 Appendix 4. 7. Subject has the ability to comply with procedures for cognitive and other testing in the opinion of the investigator 8. Subject lives with (or has substantial periods of contact with) a regular caregiver who is willing to attend all visits, oversee the subject's compliance with protocol specified procedures and study medication, and report on subject's status. Note: A non-cohabiting caregiver must spend sufficient time with the subject so that in the opinion of the Investigator, the caregiver can reliably assess cognitive function, activities and behaviour, and report on the subjects compliance and health. GSK should be consulted if adequacy of a caregiver situation is in doubt. However, as guidance, the ability for a caregiver to meet his/her expected responsibilities for this study would normally be possible when the caregiver spends no less than 10 hours per week with the subject, divided over multiple days. 9. Subject has provided full written informed consent prior to the performance of any protocol-specified procedure; or if unable to provide informed consent due to cognitive status, subject has provided assent and full written informed consent on behalf of the subject has been provided by a legally acceptable representative. 10. Caregiver has provided full written informed consent on his/her own behalf prior to the performance of any protocol-specified procedure. |
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E.4 | Principal exclusion criteria |
-Diagnosis of possible, probable or definite vascular dementia in accordance with National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche lEnseignement en Neurosciences (NINDS-AIREN) criteria -History and/or evidence (CT or MRI scan performed within the past 12 months or at Screening) of any other central nervous system (CNS) disorder that could be interpreted as a cause of dementia: (in the opinion of the investigator) e.g. cerebrovascular disease (stroke, haemorrhage), structural or developmental abnormality, epilepsy, infectious, degenerative or inflammatory/demyelinating CNS conditions, Parkinsons disease1. -Focal findings on the neurological exam (excluding changes attributable to peripheral injury). -Evidence of the following disorders: current vitamin B12 deficiency, positive syphilis serology (unless neurosyphilis was ruled out) or active thyroid dysfunction (particularly suggestive of hypothyroidism), including abnormally high or low serum levels of thyroid stimulating hormone (TSH), where this is thought to be the cause of,or to contribute to the severity of,the subject's dementia -History of significant psychiatric illness such as schizophrenia or bipolar affective disorder that in the opinion of the investigator would interfere with participation in the study, major depressive disorder (according to DSM-IV;in the past year, or current active depression requiring initiation of treatment -History of known or suspected seizures, including febrile seizures, unexplained recent loss of consciousness or history of significant head trauma with loss of consciousness. -Known history of photosensitivity or presence of skin conditions (such as porphyria, (photo-dermatitis) or treatments (such as medications, UV light) that may predispose the subject to photosensitivity reactions. -History or presence of significant cardiovascular, gastro-intestinal, endocrine, hepatic or renal disease or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs, or any other clinically relevant abnormality, medical or psychiatric condition, which, in the opinion of the investigator, makes the subject unsuitable for inclusion in the study. -History of alcohol or other substance abuse, according to the DSM-IV criteria,or recent or remote history of the same if that could be a contributing factor to the dementia -Participation in another investigational drug or device study in AD during the 6 months prior to the Screening visit -Treatment with any concomitant medications detailed in Table 1 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in ADAS-Cog total score at Week 24 Change from baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) score at Week 24 |
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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 | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
- same IMP used at different dosage |
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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 | 18 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 47 |
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 | 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
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 1 |
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 | 1 |