Brain Imaging Study Of Rosiglitazone Efficacy And Safety In Alzheimer's Disease
Condition: Alzheimer's Disease
MeSH terms: Alzheimer Disease
Intervention: Rosiglitazone; Placebo
Intervention description: Extended Release Tablets; Placebo dummy to match
Intervention MeSH terms: Rosiglitazone
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 80.0
Sex: All
Minimum age: 50 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: rosiglitazone; cognition; cerebral glucose metabolism; positron emission tomography (PET); Alzheimer's Disease

Summary:

      This is a placebo-controlled study evaluating the effects of rosiglitazone on functional
      brain activity and cognition in patients with mild to moderate Alzheimer's Disease (AD).
    

Eligibility criteria:

        Inclusion criteria:

          -  Is male, or if female meets one or more of the following criteria:

          -  Post-menopausal females defined as menopause is defined as>6months 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.

          -  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) 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.

        Is aged >/= 50 to </= 85 years Prior and current use of medication corresponds with
        criteria listed in Appendix 3.

          -  Has the ability to comply with requirements of cognitive and other testing.

          -  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).

          -  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 (Where this is in accordance with local laws, regulations
             and ethics committee policy.) Caregiver has provided full written informed consent
             prior to the performance of any protocol-specified procedure.

        Exclusion criteria:

          -  Is unsuitable for MRI scanning as assessed by local pre-MRI questionnaire (GSK to
             review.)

          -  Has a history of or suffers from claustrophobia.

          -  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 assessed by physical examination and medical
             history (e.g. back pain, arthritis).

          -  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.

          -  History of Type I or Type II diabetes mellitus.

          -  Fasting plasma glucose level>126mg/dL (>7.0mmol/L) or HbA1c>6.2%.

          -  History or clinical/laboratory evidence of moderate congestive heart failure defined
             by the New York Heart Association criteria (class I-IV)(See Appendix 6).

        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: 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. 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. 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. Asymptomatice bifascicular block. 8. Left ventricular
        hypertrophy. 9. Q waves present suggesting previous MI. 10. Repolarisation abnormalities
        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.

          -  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).

          -  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.

        Significant peripheral oedema at the time of screening as assessed by Clinical Evaluation
        of Oedema and/or Signs of Congestive Heart Failure (Appendix 14)

          -  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).

        Systolic blood pressure >165 mmHg or diastolic blood pressure >95 mmHG whilst receiving
        optimal antihypertensive therapy according to local practice.

        Clinically significant anaemia (i.e.haemoglobin <11g/dL for males or <10 g/dL for females)
        or presence of haemoglobinopathies which would prevent accurate assessment of HbA1c.

        Renal dysfunction, defined as creatinine clearance <30 ml/min (calculated from serum
        creatinine using the Cockcroft-Gault formula, See Appendix 10).

        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.

          -  Fasting triglycerides >12mmol/L Abnormal/positive result within the past 12 months or
             at screening for any of the following tests: vitamin B12 (</=200pg/mL), syphilis
             serology, thyroid stimulating hormone.

          -  History or presence of gastro-intestinal, hepatic or renal disease or other condition
             known to interfere with absorption, distribution, metabolism or excretion of drugs.

        any clinically relevant abnormality, medical or psychiatric condition, which, in the
        opinion of the investigator, makes the subject unsuitable for inclusion in the study.

          -  Has donated >/= ml of blood within the past 2 months. Use of any other investigational
             agent within 30 days or 5 half-lives (whichever is longer) prior to the screening
             visit.

        History of alcohol abuse, or of drug abuse within the past 6 months (or has tested positive
        for drugs of abuse at screening).

        Subject is unable (with assistance, if appropriate) to take study medication as prescribed
        throughout the study.

          -  History of non-compliance with prescribed medication, or risk of non-compliance with
             study medication or procedures.

        Subject is an immediate family member or employee of the participating investigator or of
        any of the participating site staff.

        Shows any neurological abnormality by MRI, which in the opinion of the Principal
        Investigator would introduce additional risk factors, study procedures or effect endpoint
        data. MRI scanning will only be conducted on subjects who satisfy all other eligibility
        criteria.

          -  History of bone marrow transplant Exhibits screening/baseline results not consistent
             with AD e.g. radiological findings, or results on cognitive tests.

        Use of tacrine within 30 days prior to the screening visit.