| 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 |
| • To assess the safety and tolerability of GSK239512 in patients with mild to moderate Alzheimer’s disease on repeat dosing. |
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| E.2.2 | Secondary objectives of the trial |
• To assess the pharmacodynamic effects of GSK239512 on cognitive tests in patients with mild to moderate Alzheimer’s disease.
• To determine the single dose pharmacokinetics of GSK239512 in patients with mild to moderate Alzheimer’s disease.
• To investigate any PK/PD relationship between cognitive effects and GSK239512 exposure.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female subjects with a clinical diagnosis of probable Alzheimer’s disease in accordance with the NINCDS-ADRDA criteria and a Haschinski ischaemia score less than or equal to 4 and an MRI or CT scan in the last 12 months.
2. The subject has an MMSE score at screening of 12 to 26 for Part A and 16-26 for Part B.
3. Age ≥ 50 and above.
4. If female, the subject must be post-menopausal (i.e. 12 months without menstrual period) or surgically sterile.
5. Male subjects must be willing to abstain from sexual intercourse with pregnant or lactating women; or be willing to use a condom/spermicide in addition to having their female partner use another form of contraception such as an intra-uterine device (IUD), barrier methods (e.g. condom or occlusive cap (diaphragm or cervical vault/caps)), oral contraceptives, injectable progesterone, subdermal implants or a bilateral tubal ligation if the woman could become pregnant, from the time of the first dose of GSK239512 until 84 days following completion of the study.
6. The subject has the ability to comply with the study procedures.
7. The subject has a permanent caregiver and is willing to attend all study visits for Parts A and B.
8. The subject has provided full written informed consent prior to the performance of any protocol specific procedure, or if unable to provide informed consent due to cognitive status, full written informed consent on behalf of the subject has been provided by a legally acceptable representative.
9. The caregiver has provided his / her written consent prior to the performance of any protocol specific procedure.
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| E.4 | Principal exclusion criteria |
1. In the opinion of the investigator, following review of CT/MRI scans in the past 12 months and completion of neurological review there could be other probable causes of dementia which include, but are not limited to:
• History and/or evidence (CT or MRI scan performed since the onset of symptoms) of any other CNS disorder that could be interpreted as the primary cause of dementia: e.g. cerebrovascular disease, structural or developmental abnormality, epilepsy, infections, degenerative or inflammatory/demyelinating CNS conditions other than AD.
• Clinically significant focal findings on the neurological exam (excluding changes attributable to peripheral nervous system injury).
• Untreated abnormal result of any of the following tests: vitamin B12, syphilis serology, thyroid stimulating hormone (TSH), where this is thought to be the cause of, or to contribute to the severity of, the subject’s dementia.
• Diagnosis of possible, probable or definite vascular dementia in accordance with National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche l’Enseignement en Neurosciences (NINDS-AIREN) criteria.
2. 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, or current depression (a score of ≥8 on the Cornell Scale for Depression in Dementia), or subjects with other psychiatric features in their AD which would in the opinion of the investigator, would increase risk to safety.
3. History of significant sleep disturbance, for example, when it is associated with nocturnal wandering, nocturnal confusion / disorientation / agitation, which in the opinion of the investigator, may increase safety risk.
4. History or presence of known or suspected seizures, unexplained significant loss of consciousness within last 6 months. Subjects who had febrile seizures in childhood may be included if these ceased by age 10 and they have had no other type of seizure in their medical history and have not been on anti-epileptic medications.
5. History or presence of significant cardiovascular, gastro-intestinal, hepatic, or renal disease or other condition 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.
6. History of alcohol or other substance abuse, according to the Diagnostic and Statistical Manual of Mental Disorders – Substance related disorders (DSM-IV) criteria.
7. Clinically significant abnormalities in laboratory tests, including subjects with active liver disease (to include subjects with ALT or AST greater than 3 times the upper limit of normal and/or bilirubin greater than 1.5 times the upper limit of normal) or uncontrolled thyroid disease.
8. Uncontrolled hypertension with systolic BP ≥160 and/or diastolic ≥95 mmHg. Subjects with controlled hypertension with systolic BP < 160 mmHg and diastolic <95 mmHg for at least 4 weeks are acceptable.
9. Systolic BP <100 mmHg and/or diastolic <60 mmHg.
10. Subjects with a QTc of >450ms or >480ms if they have bundle branch block or other ECG abnormalities which, in the opinion of the investigator is clinically significant in that they may increase safety risk.
11. History of hypersensivity to GSK239512 or its excipients.
12. Treatment with cholinesterase inhibitors, (including Tacrine), memantine or selegiline within the previous month. No patients with AD who are already on these medications at the time of screening will be recruited, as it would be unethical to withdraw these medications for study participation. Only AD subjects who are not yet on these medications, or who have withdrawn from these medications for other reasons previously, may be enrolled into this study.
13. Subjects who are currently taking or who have taken in the last month anti-psychotic drugs (typical or atypical dopaminergic antagonists or modulators) or mood stabilization drugs (including SSRI, DNRI, SNRI, MAO inhibitors, tricyclic antidepressants, lithium, valproate, cabamazepine).
14. Subjects who are currently taking Pgp inhibitors or any CYP3A4 inhibitors.
15. Subjects on chronic sedative medications (≥ 4 days per week for the past 4 weeks).
16. Subject or caregiver is an immediate family member or employee of the participating Investigator, any of the participating site staff or GSK staff.
17. Has received any other investigational treatment in the previous 3 months.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part A
• Adverse events
• 12-lead ECG, vital signs (systolic and diastolic blood pressure, heart rate)
• Clinical laboratory evaluations (including haematology, clinical chemistry, urinalysis)
• Patient’s global impression of change (PGIC)
• Carer’s global impression of change (CrGIC)
• Clinician’s global impression of change (CGIC)
• Leeds Sleep Evaluation Questionnaire (LSEQ)
• Neuropsychiatric Inventory (NPI)
• Modified Nurses’ Observation Scale for geriatric Patients (NOSGER)
Part B
• Adverse events
• 12-lead ECG, vital signs (systolic and diastolic blood pressure, heart rate)
• Clinical laboratory evaluations (including haematology, clinical chemistry, urinalysis)
• Actigraphy Data
• Patient’s global impression of change (PGIC)
• Carer’s global impression of change (CrGIC)
• Clinician’s global impression of change (CGIC)
• Leeds Sleep Evaluation Questionnaire (LSEQ)
• Neuropsychiatric Inventory (NPI)
• Modified Nurses’ Observation Scale for geriatric Patients (NOSGER)
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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 | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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 | Yes |
| E.8.1.4 | Double blind | No |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| 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 | No |
| 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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| The end of the trial is the last visit by 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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