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 | 8.1 |
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 compare changes in cerebral glucose metabolism in subjects receiving a 12- month course of Rosiglitazone XR to those receiving placebo, including the time course of any changes. |
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E.2.2 | Secondary objectives of the trial |
• To compare structural changes in the brains of subjects receiving a 12-month course of Rosiglitazone XR to those receiving placebo, as assessed by changes in volumetric MRI from baseline. • To compare changes in cognitive performance in subjects receiving a 12-month course of Rosiglitazone XR to those receiving placebo, including the time course of any changes. • To relate changes in cerebral glucose metabolism, cognitive performance and brain structure. • To compare changes in peripheral glucose metabolism and insulin sensitivity in subjects receiving a 12-month course of Rosiglitazone XR to those receiving placebo, including the time course of any changes. • To compare changes in lipid levels in subjects receiving a 12-month course of Rosiglitazone XR to those receiving placebo, including the time course of any changes.
*See protocol for further secondary objectives |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study only if all of the following criteria apply: 1. Is male, or if female meets one or more of the following criteria: • Post-menopausal females defined as menopause is defined as >6 months without menstrual period with an appropriate clinical profile, e.g. age appropriate, history of vasomotor symptoms. However if indicated this should be confirmed by oestradiol and FSH levels consistent with menopause (according to local laboratory ranges). Women who are on HRT treatment, and have not been confirmed as post-menopausal should be advised to use contraception (See Appendix 4) • Pre-menopausal females with a documented (medical report verification) hysterectomy and/or bilateral oophorectomy only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. 2. Meets the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for Alzheimer's disease, regardless of date of diagnosis relative to study entry date (See Appendix 5). 3. Has an Alzheimer's disease status of mild to moderate, as classified by a Mini Mental State Examination (MMSE) score of 16 – 26 inclusive at screening. 4. Is aged 50 to 85 years. 5. Prior and current use of medication corresponds with the criteria listed in Appendix 3. 6. Has the ability to comply with requirements of cognitive and other testing. 7. Has a permanent 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. (Subjects living alone or in a nursing home are not eligible). 8. 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, provision of informed consent by cognitively intact legally acceptable representative . 9. Caregiver has provided full written informed consent prior to the performance of any protocol-specified procedure. |
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E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria apply: 1. Is unsuitable for MRI scanning as assessed by local pre-MRI questionnaire . 2. Has a history of or suffers from claustrophobia. 3. Is unable to lie comfortably on a bed inside a PET camera with their head in the field of view for at least 60 minutes as assesed by physical examination and medical history (e.g. back pain, arthritis). 4. Has a history or presence of other neurological or other medical conditions that may influence the outcome or analysis of the PET scan results. Examples of such conditions include, but are not limited to stroke, traumatic brain injury, epilepsy or space occupying lesions. 5. History of Type I or Type II diabetes mellitus. 6. Fasting plasma glucose level >126 mg/dL (>7.0 mmol/L) or HbA1c >6.2% 7. History or clinical/laboratory evidence of moderate congestive heart failure defined by the New York Heart Association criteria (class I-IV) (See Appendix 6). 8. Ejection fraction <40% determined by echocardiogram, or any other abnormality on echocardiography which in the view of the investigator required further investigation or intervention, or significant abnormalities on screening ECG (in accordance with the definitions below).
Significant ECG abnormalities for the purposes of this study. Detection of any of the following abnormalities renders the subject ineligible for the study. ECG abnormalities permitted at entry to this study. A subject will not be rendered ineligible by the presence of any of the following abnormalities. 1. ECG heart rate <50 and >100 bpm 2. Any previously unrecognised sustained or paroxysmal arrhythmia requiring further intervention e.g. anticoagulation, cardioversion, anti-arrhythmic agent, further investigation etc. 3. PR interval >0.3 s, 2nd or 3rd degree heart block, symptomatic bifascicular block, trifascicular block 4. Multifocal ventricular ectopy 5. Ventricular bigemini or couplets, triplets etc.
1. AF with a heart rate <=90 in subjects receiving appropriate anti-platelet or anticoagulant therapy 2. 1st degree heart block (PR<=0.3 s) 3. Subjects with a paced rhythm (further information required if subject has an Implantable Cardiac Defibrillator) 4. Atrial ectopic beats 5. Unifocal ventricular ectopic beats 6. Left or right bundle branch block 7. Asymptomatic bifascicular block 8. Left ventricular hypertrophy 9. Q waves present suggesting previous MI 10. Repolarisation abnormalities
9. History of new cardiovascular event within the last 6 months (i.e. intervention, percutaneous coronary intervention, vascular surgery, acute coronary syndrome [non Q-wave myocardial infarction, Q-wave myocardial infarction, unstable angina) or significant arrhythmia; or major intervention (e.g. cardiac surgery or angiography plus stenting) scheduled. 10. History or clinical laboratory evidence of cerebrovascular disease (stroke, transient ischaemic attack, haemorrhage), or diagnosis of possible, probable or definite vascular dementia in accordance with National Institute of Neurological Disorders and Stroke, and Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) criteria (See Appendix 8). 11. History or evidence of any other CNS disorder that could be interpreted as a cause of dementia: e.g. structural abnormality, epilepsy, infectious or inflammatory/demyelinating CNS conditions, Parkinson's disease. 12. Significant peripheral oedema at the time of screening as assessed by Clinical Evaluation of Oedema and/or Signs of Congestive Heart Failure (Appendix 14). 13. History of major psychiatric illness such as schizophrenia or bipolar affective disorder, or current depression (score on Hospital Anxiety and Depression Scale (HADS) depression questions >7, See Appendix 9). 14. Systolic blood pressure >165 mmHg or diastolic blood pressure >95 mmHg whilst receiving optimal antihypertensive therapy according to local practice. 15. Clinically significant anaemia (i.e. haemoglobin <11 g/dL for males or <10 g/dL for females) or presence of haemoglobinopathies which would prevent accurate assessment of HbA1c. 16. Renal dysfunction, defined as creatinine clearance <30 ml/min (calculated from serum creatinine using the Cockcroft-Gault formula, See Appendix 10). 17. ALT, AST, total bilirubin, or alkaline phosphatase >2.5 times the upper limit of normal laboratory range, or history of severe hepatobiliary disease (e.g. hepatitis B or C, or cirrhosis (Childs-Pugh classes B/C)) without enzyme elevation. 18. Fasting triglycerides >12 mmol/L. 19. Abnormal/positive result within the past 12 months or at screening for any of the following tests: vitamin B12 (<200 pg/mL), syphilis serology, thyroid stimulating hormone. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in global and regional cerebral glucose metabolism/Cerebral Metabolic Rate for glucose (CMRglu) between baseline and 12 months as measured by [18F]FDG uptake. |
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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 | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
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 | Yes |
E.7.1.3.1 | Other trial type description |
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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 | 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 | 8 |
E.8.5 | The trial involves multiple Member States | No |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
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 | 0 |
E.8.9.1 | In the Member State concerned months | 12 |
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 | 12 |
E.8.9.2 | In all countries concerned by the trial days | 0 |