Clinical trial NCT00265148: Brain Imaging Study Of Rosiglitazone Efficacy And Safety In Alzheimer's Disease
Official title: Effects of Avandia on Cognition and Cerebral Glucose Utilisation in Subjects With Mild to Moderate Alzheimer's Disease (AD).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alzheimer's Disease
Keywords: rosiglitazone
cognition
cerebral glucose metabolism
positron emission tomography (PET)
Alzheimer's Disease
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2005-12-14
Enrollment: 80
Sex: ALL
Minimum age (years): 50
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Primary outcomes:
measure: Change From Baseline (Day 1) in Global and Regional Indices of Cerebral Metabolic Rate of Glucose (CMRglu) at Month 12
timeFrame: Baseline (Day 1) and Month 12
Secondary outcomes:
measure: Change From Baseline (Day 1) in CMRGlu Indices at Months 1 and 6
timeFrame: Baseline (Day 1), Months 1, and 6
measure: Change From Baseline (Day 1) in Delayed Free Recall Words at Months 1, 6, and 12 by Buschke Selective Reminding (BSR) Test
timeFrame: Baseline (Day 1), and Months 1, 6, and 12
measure: Change From Baseline (Day 1) in Delayed Free Recall Items Over Period by Stroop Colour Word Interference (SCWI) at Months 1, 6 and 12
timeFrame: Baseline (Day 1), Months1, 6, and 12
measure: Change From Baseline (Day 1) in Simplified Spatial Paired Associate Learning (SSPAL) Response Over Period
timeFrame: Baseline (Day 1), Months 1, 6, and 12
measure: Change From Baseline (Day 1) in Accuracy by Choice Reaction Time (CRT) Test Over Period
timeFrame: Baseline (Day 1) and up to 12 months
measure: Change From Baseline in Cognitive Test by Simple Reaction Time (SRT) Method Over Period
timeFrame: Baseline (Day 1) and up to 12 months
measure: Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Scale (ADAS-COG) Total Score Over Period
timeFrame: Baseline (Day 1), and Months 1, 6, and 12
measure: Change From Baseline in Clinician Based Impression of Change-plus (CBIC +) Score Over Period
timeFrame: Baseline (Day 1) and Months 1, 6, and 12
measure: Change From Baseline in Neuropsychiatric Inventory Score Over Period
timeFrame: Baseline (Day 1), Months 1, 6 and 12
measure: Change From Baseline in Mini-mental State Examination (MMSE) Score Over Period
timeFrame: Baseline (Day 1), and up to Month 12
measure: Change From Baseline in Normalized Brain Volume Over Period
timeFrame: Baseline (Day 1), Month 6 and Month 12
measure: Percent Change From Baseline in Brain Volume Over Period
timeFrame: Baseline (Day 1), Month 6, and Month 12
measure: Change From Baseline in Fasting Plasma Glucose at Month 12
timeFrame: Baseline (Day 1) and Month 12
measure: Change From Baseline in Glycosylated Hemoglobin [HbA1C] at Month 12
timeFrame: Baseline (Day 1) and Month 12
measure: Change From Baseline in Lipid (Cholesterol) and Apo-lipoprotein Levels at Month 12
timeFrame: Baseline (Day 1) and Month 12
measure: Change From Baseline in Inflammatory Biomarkers (CD40, C-reactive Protein [CRP] , Interleukin [ IL ]-6, and Tumor Necrosing Factor [TNF]-Alpha)
timeFrame: Baseline (Day 1) and Month 12
measure: Change From Baseline in Insulin Sensitivity Measured by Homeostasis Model Assessment of Insulin Resistance (HOMA IR)
timeFrame: Baseline (Day 1) and Month 12
measure: Number of Participants by Apo-lipoprotein -e (APOE Epsilon)-4 Allele Subtype
timeFrame: Up to 12 months
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to 12 months
measure: Number of Participants With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Outside the Concern Range at Month 12
timeFrame: At Month 12
measure: Number of Participants With Heart Rate/ Pulse Rate Outside the Concern Range at Month 12
timeFrame: At Month 12
measure: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Parameters at Screening and Follow-up
timeFrame: At screening (within 1 month of Day 1) and follow-up period (within 2 weeks of final dose [12 months])
measure: Number of Participants With Body Weight and Height Outside the Clinical Concern at Month 12
timeFrame: At Month 12
measure: Global and Regional CMRglu Index by APOE Epsilon-4 Allele Subtype at 12 Month
timeFrame: At Month 12
measure: Number of Participants With Hematological Data of Potential Clinical Concern (PCC) at End of Treatment (Month 12)
timeFrame: At Month 12
measure: Number of Participants With Clinical Chemistry Data of PCC at End of the Treatment (Month 12)
timeFrame: At Month 12
Other outcomes:
Locations:
city: Litchfield Park
country: United States
facility: GSK Investigational Site
state: Arizona
city: Phoenix
country: United States
facility: GSK Investigational Site
state: Arizona
city: Scottsdale
country: United States
facility: GSK Investigational Site
state: Arizona
city: Sun City
country: United States
facility: GSK Investigational Site
state: Arizona
city: Tucson
country: United States
facility: GSK Investigational Site
state: Arizona
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: Belmont
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Ann Arbor
country: United States
facility: GSK Investigational Site
state: Michigan
city: Durham
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Liverpool
country: United Kingdom
facility: GSK Investigational Site
city: Manchester
country: United Kingdom
facility: GSK Investigational Site
city: Swindon
country: United Kingdom
facility: GSK Investigational Site
city: West End, Southampton
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Tzimopoulou S, Cunningham VJ, Nichols TE, Searle G, Bird NP, Mistry P, Dixon IJ, Hallett WA, Whitcher B, Brown AP, Zvartau-Hind M, Lotay N, Lai RY, Castiglia M, Jeter B, Matthews JC, Chen K, Bandy D, Reiman EM, Gold M, Rabiner EA, Matthews PM. A multi-center randomized proof-of-concept clinical trial applying [(1)(8)F]FDG-PET for evaluation of metabolic therapy with rosiglitazone XR in mild to moderate Alzheimer's disease. J Alzheimers Dis. 2010;22(4):1241-56. doi: 10.3233/JAD-2010-100939.