Brain Imaging Study Of Rosiglitazone Efficacy And Safety In Alzheimer's Disease

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00265148
• Collaborator: (none)
• Enrollment: 80
• Locations: 15
• Arms: 2
• Actual Duration (Months): 49.7
• Patients Per Site: 5.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Alzheimer's Disease	Drug: Rosiglitazone; Other: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 80 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Effects of Avandia on Cognition and Cerebral Glucose Utilisation in Subjects With Mild to Moderate Alzheimer's Disease (AD).
• Actual Study Start Date: May 18, 2004
• Actual Primary Completion Date: Jul 10, 2008
• Actual Study Completion Date: Jul 10, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rosiglitazone 4 mg once a day for 1 month increasing to 8 mg once a day (Extended Released Tablets)	Drug: Rosiglitazone; Extended Release Tablets
Other: Placebo Placebo dummy to match	Other: Placebo; Placebo dummy to match

Outcome Measures

Primary Outcome Measures

1. Change From Baseline (Day 1) in Global and Regional Indices of Cerebral Metabolic Rate of Glucose (CMRglu) at Month 12 [Baseline (Day 1) and Month 12]

   Global CMRGlu index was related to grey matter of brain. Regional CMRGlu index was related to assessment of different regions of brain namely posterior cingulate gyrus, frontal lobe, parietal lobe, posterior temporal lobe, cerebellum, and medial temporal lobe. Evaluation of medial temporal lobe CMRGlu included assessment of medial anterior temporal lobe, paraHippocampal Ambiens gyrus, amygdala, and hippocampus. The regional CMRGlu index is directly proportional to the true metabolic rate of glucose. Baseline was defined as Day 1 of the 12 months treatment period. Change from Baseline is the value at indicated time point minus the Baseline value. Data has been presented for arithmetic mean; however, statistical analysis has been presented for adjusted or least square (LS) mean.

Secondary Outcome Measures

1. Change From Baseline (Day 1) in CMRGlu Indices at Months 1 and 6 [Baseline (Day 1), Months 1, and 6]

   Global CMRGlu index was related to grey matter of brain. Baseline measurement was performed on Day 1. Change from Baseline is the value at indicated time point minus the Baseline value.

2. Change From Baseline (Day 1) in Delayed Free Recall Words at Months 1, 6, and 12 by Buschke Selective Reminding (BSR) Test [Baseline (Day 1), and Months 1, 6, and 12]

   The BSR test included evaluating short-term memory of a participant to remember a list of unrelated words, to learn the words over 8 trials and to remember these words over 8 trials, and to remember these words during a 20 minute delay. The number of words recalled in delayed free recalls were analyzed. Other parameters analyzed included number recalled Trial 1 immediate, number recalled Trial 8 immediate, total number for all 8 immediate trials, and total number of uncued words recalled. Higher number of words recalled indicated better short term memory and positive treatment differences in these number of words recalled were indicative of superiority of drug over placebo. Baseline measurement was performed on Day 1. Change from Baseline is the value at indicated time point minus the Baseline value. Statistical analysis is presented for difference of means.

3. Change From Baseline (Day 1) in Delayed Free Recall Items Over Period by Stroop Colour Word Interference (SCWI) at Months 1, 6 and 12 [Baseline (Day 1), Months1, 6, and 12]

   It is a measure of change from Baseline (Day 1) in clinical scale of AD status. A 3-card version test includes all card containing 50 items each. Participants were asked to complete all items and time in seconds was recorded. Participants first read color words printed in black, then named the printed color of the colored patches, and finally named the printed color of the colored words. The word condition was used to verify that participants were able to read colored words and time to perform color condition was considered as ' control'. The dependent variable was the time to complete the interference condition and the test could have presented in pencil and paper or on screen, both the ways. Change from Baseline is the value at indicated time point minus the Baseline value. Statistical analysis is presented for difference of means.

4. Change From Baseline (Day 1) in Simplified Spatial Paired Associate Learning (SSPAL) Response Over Period [Baseline (Day 1), Months 1, 6, and 12]

   Change from Baseline = value at the indicated time point minus the Baseline(Day1) value. SSPAL is a cognitive test that involves object-location memory and learning. It is used to examine cognitive deficits in AD. Participants were asked to sit 50 cm away from screen and different pictures (target and distracter) were shown on a monitor. Responses were acquired from response box. Participants were informed by visual feedback whether the response was correct or incorrect and the accuracy was collected automatically. SSPAL responses were captured as new accuracy and global accuracy. New accuracy was defined as proportion of accurate responses per participant for recall of any new item (picture). Global accuracy was defined as proportion of accurate responses per participant for recall of all new items and their displayed locations (i.e. right or left position on the screen). The possible range for new and global accuracy is 0(worst) to 1(best). Higher values indicate better performance.

5. Change From Baseline (Day 1) in Accuracy by Choice Reaction Time (CRT) Test Over Period [Baseline (Day 1) and up to 12 months]

   A motor reaction task was presented 4 runs of 50 trials each. In each trial, presentation of a central crosshair for 200 milliseconds (ms) was followed by display of a grey square for 800 ms. The square appeared in two of five possible positions relative to the crosshair (leftmost or rightmost). When the grey square became white, the participant was trained to press the a button. In each trial of the Simple Reaction Time Task, presentation of a central crosshair for 200 ms was followed by display of one square for 800 ms. For both simple and choice versions of the task, trial duration was 4000 ms maximum. The participant was immediately informed (by color changes of the white square) whether the response to each trial was correct or incorrect, and accuracy and reaction time (RT) are automatically calculated. Change from Baseline is the value at indicated time point minus the Baseline value.

6. Change From Baseline in Cognitive Test by Simple Reaction Time (SRT) Method Over Period [Baseline (Day 1) and up to 12 months]

   A motor reaction task was presented 4 runs of 50 trials each. In each trial, presentation of a central crosshair for 200 milliseconds (ms) was followed by display of a grey square for 800 ms. The square appeared in two of five possible positions relative to the crosshair (leftmost or rightmost). When the grey square became white, the participant was trained to press the a button. In each trial of the Simple Reaction Time Task, presentation of a central crosshair for 200 ms was followed by display of one square for 800 ms. For both simple and choice versions of the task, trial duration was 4000 ms maximum. The participant was immediately informed (by color changes of the white square) whether the response to each trial was correct or incorrect, and accuracy and reaction time (RT) are automatically calculated. Baseline measurement was performed on Day 1. Change from Baseline is the value at indicated time point minus the Baseline value.

7. Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Scale (ADAS-COG) Total Score Over Period [Baseline (Day 1), and Months 1, 6, and 12]

   Change from Baseline is the value at indicated time point minus the Baseline value. ADAS-COG is a 13 item, 11 questionnaire assessment of range of cognitive abilities including memory, comprehension, orientation in time and place, and spontaneous speech. The scale ranges from 0 to 70, with negative changes from Baseline indicating the improvement and positive changes indicating worsening of condition. Arithmetic means are presented as raw data; however, statistical analysis is based on LS means.

8. Change From Baseline in Clinician Based Impression of Change-plus (CBIC +) Score Over Period [Baseline (Day 1) and Months 1, 6, and 12]

   The CBIC+ assessment for global functioning consists of a 7 point rating scale of severity and change with 1 indicating marked improvement and 7 indicating marked worsening. This scale was used to analyze clinically relevant effect. This was supposed to be performed by an independent investigator who is not a part of the ongoing study. Change from Baseline is the value at indicated time point minus the Baseline value. This scale was used to decide clinical status of AD. Arithmetic means are presented as raw data; however, statistical analysis has been presented for LS means.

9. Change From Baseline in Neuropsychiatric Inventory Score Over Period [Baseline (Day 1), Months 1, 6 and 12]

   The NPI assesses the frequency and severity of behavioral disturbances in dementia across 10 domains. The total NPI score was calculated by adding all individual domains cores. The scale ranges from 0 to 120 , 0 indicating no / least burden and 120 indicating maximum burden. A negative change from Baseline indicated improvement. Baseline measurement was performed on Day 1. Change from Baseline is the value at indicated time point minus the Baseline value.

10. Change From Baseline in Mini-mental State Examination (MMSE) Score Over Period [Baseline (Day 1), and up to Month 12]

    The MMSE consists of 11 categories of orientation, memory (recent and immediate), concentration, language, and praxis. The scale ranges from 0 to 30 with lower scores indicating greater cognitive impairment. Negative changes from Baseline indicate improvement and positive changes indicate increasing symptoms. Change from Baseline is the value at indicated time point minus the Baseline value.

11. Change From Baseline in Normalized Brain Volume Over Period [Baseline (Day 1), Month 6 and Month 12]

    Normalized brain volume is a function of global changes in brain structure. Reduction in brain volume is indicative of reduction in Grey matter and thus the AD stage. The method used was structural magnetic resonance imaging (MRI). Change from Baseline is the value at indicated time point minus the Baseline value. Arithmetic means have been presented; however, statistical analysis is based upon the least square (LS) means.

12. Percent Change From Baseline in Brain Volume Over Period [Baseline (Day 1), Month 6, and Month 12]

    Percent volume change of brain is a function of global changes in brain structure. Reduction in brain volume is indicative of reduction in Grey matter and thus the AD stage. The method used was structural magnetic resonance imaging (MRI). Baseline value was recorded on Day 1. Change from Baseline is the value at indicated time point minus the Baseline value. Arithmetic means have been presented; however, statistical analysis is based upon the LS means.

13. Change From Baseline in Fasting Plasma Glucose at Month 12 [Baseline (Day 1) and Month 12]

    Fasting plasma glucose are indicative of Glucose metabolism. Baseline measurement was performed on Day 1. Change from Baseline is the value at indicated time point minus the Baseline value.

14. Change From Baseline in Glycosylated Hemoglobin [HbA1C] at Month 12 [Baseline (Day 1) and Month 12]

    HbA1c levels are measure of glucose metabolism in body. Baseline value measurement was performed on Day 1. Change from Baseline is the value at indicated time point minus the Baseline value.

15. Change From Baseline in Lipid (Cholesterol) and Apo-lipoprotein Levels at Month 12 [Baseline (Day 1) and Month 12]

    Lipid (cholesterol) and apo-lipoprotein (A and B) are biomarkers of glucose metabolism in blood. The method used for analyzes was positron emission tomography (PET) using radiolabelled [18F] -fluoro-deoxy-glucose (FDG). Baseline measurement was performed on Day 1. Change from baseline is the value at indicated time point minus the Baseline value.

16. Change From Baseline in Inflammatory Biomarkers (CD40, C-reactive Protein [CRP] , Interleukin [ IL ]-6, and Tumor Necrosing Factor [TNF]-Alpha) [Baseline (Day 1) and Month 12]

    The inflammatory biomarkers namely CD40, C-reactive protein (CRP) , interleukin (IL)-6, and tumor necrosing factor (TNF)-alpha) were analyzed. Baseline measurement was performed on Day 1. Change from Baseline is the value at indicated time point minus the Baseline value.

17. Change From Baseline in Insulin Sensitivity Measured by Homeostasis Model Assessment of Insulin Resistance (HOMA IR) [Baseline (Day 1) and Month 12]

    This is a measure of assessing insulin sensitivity. HOMA IR was calculated by multiplying fasting insulin by fasting plasma glucose and dividing the multiplied digit by 22.5. All samples were collected under fasting condition. Baseline measurement was performed on Day 1. Change from Baseline is the value at indicated time point minus the Baseline value.

18. Number of Participants by Apo-lipoprotein -e (APOE Epsilon)-4 Allele Subtype [Up to 12 months]

    Participants were categorized into two major types namely those with APOE4 genotype and without APOE4 genotype. Further, 6 subtypes/ alleles of APOE4 gene (as mentioned in the categories below) were analyzed. Participants were also classified as having 0 or 1 or 2 copies of this gene.

19. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [Up to 12 months]

    Adverse event (AE) is an unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a certain time period after the study has ended. This change may or may not be caused by the intervention being studied. Serious adverse event (SAE) is an adverse event that results in death, is life-threatening, requires inpatient hospitalization or extends a current hospital stay, results in an ongoing or significant incapacity or interferes substantially with normal life functions, or causes a congenital anomaly or birth defect. Medical events that do not result in death, are not life-threatening, or do not require hospitalization may be considered serious adverse events if they put the participant in danger or require medical or surgical intervention to prevent one of the results listed above.

20. Number of Participants With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Outside the Concern Range at Month 12 [At Month 12]

    Number of participants with SBP or DBP outside the defined range of clinical concern were collectively presented for any time on-treatment period. SBP of <90 millimeters of mercury (mmHg) and >140 mmHg was considered as of clinical concern. DBP of <50 and >90 mmHg was considered as of clinical concern. Increase in SBP from Baseline of >=40 mmHg and Decrease of >=30 mmHg was also recorded. Increase in DBP from Baseline of >=30 mmHg and Decrease of >=20 mmHg was also recorded.

21. Number of Participants With Heart Rate/ Pulse Rate Outside the Concern Range at Month 12 [At Month 12]

    Heart rate was measured in supine position. Number of participants with any time on-treatment values of heart rate values outside the clinical concern were presented. Heart rate values of >100 or <50 were considered as of clinical concern. Increase in heart rate from Baseline of >=30 beats per minute (bpm) and decrease in heart rate from Baseline of >=30 bpm was also recorded and presented.

22. Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Parameters at Screening and Follow-up [At screening (within 1 month of Day 1) and follow-up period (within 2 weeks of final dose [12 months])]

    Two screening visits were arranged within 30 days of Day 1 of screening period and within 7 to 10 days of Day 1 of screening period. Follow-up period was arranged within 14 days of the last dose (post 12 months) of the study drug. Data for only the participants with abnormal ECG values has been presented.

23. Number of Participants With Body Weight and Height Outside the Clinical Concern at Month 12 [At Month 12]

    Body weight and height are the parameters of physical examination. Body weight is also a measure of fluid retention. Body weight increase or decrease of >= 7 % was considered as of clinical concern. Since there would be no or negligible (insignificant) change in height of a participant, no data has been presented for change from Baseline in height of participants after exposure to the study drug.

24. Global and Regional CMRglu Index by APOE Epsilon-4 Allele Subtype at 12 Month [At Month 12]

    The CMRglu was analyzed based on the APOE Epsilon-4 gene allele, whether it was present (positive) or was missing (negative) among the participants. The data has been presented for Month 12. Data has been presented for arithmetic mean; however, statistical analysis presented is based on LS means.

25. Number of Participants With Hematological Data of Potential Clinical Concern (PCC) at End of Treatment (Month 12) [At Month 12]

    Participants were analyzed for any abnormality in basophils, eosinophils, hemoglobin, lymphocytes, monocytes, neutrophils, segmented neutrophils, platelets, red blood cells, and white blood cells with data outside the respective reference ranges. The values higher (H) or lower (L) than the reference range were analyzed at each month. The parameter has not been presented for participants who did not have any abnormality.

26. Number of Participants With Clinical Chemistry Data of PCC at End of the Treatment (Month 12) [At Month 12]

    Participants were analyzed for any abnormality in albumin, alanine aminotransferases, alkaline phosphatase, apolipoprotein A, apolipoprotein B, aspartate aminotransferases, Vitamin B12, direct bilirubin, indirect bilirubin, total bilirubin, cholesterol, creatinine, C-reactive protein, serum glucose, and non-fasting glucose, with data of PCC range. The values higher (H) or lower (L) than the reference range were analyzed at each month. The parameter has not been presented for participants who did not have any abnormality.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Litchfield Park	Arizona	United States	85340
2	GSK Investigational Site	Phoenix	Arizona	United States	85006
3	GSK Investigational Site	Scottsdale	Arizona	United States	85259
4	GSK Investigational Site	Sun City	Arizona	United States	85351
5	GSK Investigational Site	Tucson	Arizona	United States	85724
6	GSK Investigational Site	Los Angeles	California	United States	90024
7	GSK Investigational Site	Belmont	Massachusetts	United States	02478
8	GSK Investigational Site	Ann Arbor	Michigan	United States	48109
9	GSK Investigational Site	Durham	North Carolina	United States	27705
10	GSK Investigational Site	Montreal	Quebec	Canada	H3T 1E2
11	GSK Investigational Site	Montreal	Quebec	Canada	H4H 1R3
12	GSK Investigational Site	Liverpool		United Kingdom	L9 7LJ
13	GSK Investigational Site	Manchester		United Kingdom	M20 3LJ
14	GSK Investigational Site	Swindon		United Kingdom	SN1 4HZ
15	GSK Investigational Site	West End, Southampton		United Kingdom	SO30 3JB

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT00265148
• Other Study ID Numbers: BRL-49653/461; 2005-005089-34
• First Posted: Dec 14, 2005
• Last Update Posted: Nov 18, 2020
• Last Verified: Oct 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by GlaxoSmithKline: rosiglitazone; cognition; cerebral glucose metabolism; positron emission tomography (PET); Alzheimer's Disease
• Additional relevant MeSH terms: Alzheimer Disease; Rosiglitazone

Study Results

Participant Flow

Recruitment Details	This study was conducted from 18 May 2004 to 10 July 2008 at centers across Canada, the United States (US), and the United Kingdom (UK). A total of 80 participants with mild to moderate Alzheimer's disease were planned to be enrolled.
Pre-assignment Detail	A total of 135 participants were screened of which 80 participants were randomized, during which they received oral Rosiglitazone-extended (RSG-XR) release 4 milligrams (mg) once daily. Intent- to-treat (ITT) population included 78 participants who had more than or equal to 1 efficacy, pharmacokinetic, pharmacodynamics, or genetic assessment.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 milligrams (mg) for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligibale participants received unit oral Rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Period Title: Overall Study
STARTED	40	40
COMPLETED	31	31
NOT COMPLETED	9	9

Baseline Characteristics

Arm/Group Title	Placebo	Rosiglitazone	Total
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 milligrams (mg) for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.	Total of all reporting groups
Overall Participants	39	39	78
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	70.2 (9.28)	72.5 (9.60)	71.4 (9.45)
Sex: Female, Male (Count of Participants)
Female	19 48.7%	17 43.6%	36 46.2%
Male	20 51.3%	22 56.4%	42 53.8%
Race/Ethnicity, Customized (Count of Participants)
American hispanic	1 2.6%	1 2.6%	2 2.6%
Black	1 2.6%	0 0%	1 1.3%
White/Caucasian	37 94.9%	37 94.9%	74 94.9%
Other Caucasiann/ Japanese	0 0%	1 2.6%	1 1.3%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline (Day 1) in Global and Regional Indices of Cerebral Metabolic Rate of Glucose (CMRglu) at Month 12
Description	Global CMRGlu index was related to grey matter of brain. Regional CMRGlu index was related to assessment of different regions of brain namely posterior cingulate gyrus, frontal lobe, parietal lobe, posterior temporal lobe, cerebellum, and medial temporal lobe. Evaluation of medial temporal lobe CMRGlu included assessment of medial anterior temporal lobe, paraHippocampal Ambiens gyrus, amygdala, and hippocampus. The regional CMRGlu index is directly proportional to the true metabolic rate of glucose. Baseline was defined as Day 1 of the 12 months treatment period. Change from Baseline is the value at indicated time point minus the Baseline value. Data has been presented for arithmetic mean; however, statistical analysis has been presented for adjusted or least square (LS) mean.
Time Frame	Baseline (Day 1) and Month 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population included all participants from all subjects population who had at least one or more than one post-baseline pharmacodynamic (PD) or biomarker, efficacy, or pharmacogenetic (PGx) assessment. Only those participants available at the time of assessment were analyzed.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	39	39
Grey matter	-0.2793 (0.48541)	-0.0887 (0.34985)
Posterior cingulate gyrus	-0.3143 (0.57567)	-0.0786 (0.36019)
Frontal lobe	-0.3087 (0.55631)	-0.1131 (0.36876)
Parietal lobe	-0.3081 (0.50596)	-0.1175 (0.33335)
Posterior temporal lobe	-0.2771 (0.40458)	-0.1122 (0.32346)
Cerebellum	-0.2523 (0.46730)	-0.0248 (0.38874)
Medial temporal lobe	-0.1950 (0.33360)	-0.0349 (0.32429)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For Grey matter
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1695
	Comments
	Method	Mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1334
	Confidence Interval	(2-Sided) 95%; -0.0583 to 0.3251
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For posterior cingulate Gyrus
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1057
	Comments
	Method	Mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1750
	Confidence Interval	(2-Sided) 95%; -0.0380 to 0.3880
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For Frontal lobe
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1833
	Comments
	Method	Mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1426
	Confidence Interval	(2-Sided) 95%; -0.0691 to 0.3543
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For parietal lobe
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1644
	Comments
	Method	Mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1366
	Confidence Interval	(2-Sided) 95%; -0.0574 to 0.3307
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For Posterior temporal lobe
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1509
	Comments
	Method	Mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1259
	Confidence Interval	(2-Sided) 95%; -0.0471 to 0.2989
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For cerebellum
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2041
	Comments
	Method	Mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1339
	Confidence Interval	(2-Sided) 95%; -0.0747 to 0.3424
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For medial temporal lobe
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1445
	Comments
	Method	Mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1094
	Confidence Interval	(2-Sided) 95%; -0.0385 to 0.2572
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline (Day 1) in CMRGlu Indices at Months 1 and 6
Description	Global CMRGlu index was related to grey matter of brain. Baseline measurement was performed on Day 1. Change from Baseline is the value at indicated time point minus the Baseline value.
Time Frame	Baseline (Day 1), Months 1, and 6

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants available at the time of assessment were analyzed

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	39	39
Month 1	-0.1049 (0.39301)	0.0475 (0.46904)
Month 6	-0.1556 (0.36397)	-0.0269 (0.35311)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	At Month 1
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2251
	Comments
	Method	Mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1211
	Confidence Interval	(2-Sided) 95%; -0.0763 to 0.3185
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For Month 6
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2497
	Comments
	Method	Mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.0893
	Confidence Interval	(2-Sided) 95%; -0.0643 to 0.2430
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline (Day 1) in Delayed Free Recall Words at Months 1, 6, and 12 by Buschke Selective Reminding (BSR) Test
Description	The BSR test included evaluating short-term memory of a participant to remember a list of unrelated words, to learn the words over 8 trials and to remember these words over 8 trials, and to remember these words during a 20 minute delay. The number of words recalled in delayed free recalls were analyzed. Other parameters analyzed included number recalled Trial 1 immediate, number recalled Trial 8 immediate, total number for all 8 immediate trials, and total number of uncued words recalled. Higher number of words recalled indicated better short term memory and positive treatment differences in these number of words recalled were indicative of superiority of drug over placebo. Baseline measurement was performed on Day 1. Change from Baseline is the value at indicated time point minus the Baseline value. Statistical analysis is presented for difference of means.
Time Frame	Baseline (Day 1), and Months 1, 6, and 12

Outcome Measure Data

Analysis Population Description

ITT population. Only the participants available at the time of assessment were analyzed.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	39	39
Delayed free recall, Month 1	0.1 (1.72)	0.2 (1.23)
Delayed free recall, Month 6	-0.1 (1.56)	0.0 (1.21)
Delayed free recall, Month 12	-0.4 (1.32)	-0.4 (1.53)
Trial 1 immediate, Month 1	0.2 (1.30)	-0.1 (1.13)
Trial 1 immediate, Month 6	-0.2 (1.69)	-0.1 (1.42)
Trial 1 immediate, Month 12	-0.6 (1.32)	-0.5 (1.27)
Trial 8 immediate, Month 1	-0.2 (1.82)	0.0 (1.45)
Trial 8 immediate, Month 6	-0.3 (1.29)	-0.2 (1.21)
Trial 8 immediate, Month 12	-0.9 (1.32)	-0.2 (1.03)
For all 8 immediate trial, Month 1	-1.4 (7.27)	0.9 (5.51)
For all 8 immediate trial, Month 6	-3.0 (7.31)	0.4 (5.85)
For all 8 immediate trial, Month 12	-5.8 (7.95)	-0.9 (5.27)
Uncued words recalled, Month 1	-1.7 (8.56)	0.9 (5.43)
Uncued words recalled, Month 6	-3.2 (7.92)	0.9 (7.55)
Uncued words recalled, Month 12	-7.0 (9.91)	-2.0 (8.59)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For BSR test , Month 1
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.7618
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; -0.59 to 0.80
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For BSR test, Month 6
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.8350
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95%; -0.53 to 0.66
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For BSR test, Month 12
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.6735
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95%; -0.78 to 0.51
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline (Day 1) in Delayed Free Recall Items Over Period by Stroop Colour Word Interference (SCWI) at Months 1, 6 and 12
Description	It is a measure of change from Baseline (Day 1) in clinical scale of AD status. A 3-card version test includes all card containing 50 items each. Participants were asked to complete all items and time in seconds was recorded. Participants first read color words printed in black, then named the printed color of the colored patches, and finally named the printed color of the colored words. The word condition was used to verify that participants were able to read colored words and time to perform color condition was considered as ' control'. The dependent variable was the time to complete the interference condition and the test could have presented in pencil and paper or on screen, both the ways. Change from Baseline is the value at indicated time point minus the Baseline value. Statistical analysis is presented for difference of means.
Time Frame	Baseline (Day 1), Months1, 6, and 12

Outcome Measure Data

Analysis Population Description

ITT population. Only the participants available at the time of assessment were analyzed.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	39	39
Month 1	-0.0 (0.88)	-0.4 (1.33)
Month 6	0.1 (0.97)	-0.2 (1.06)
Month 12	0.5 (1.09)	-0.3 (1.78)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For Month 1
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.7045
	Comments
	Method	Repetaed measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 95%; -0.44 to 0.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For Month 6
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.8181
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.40 to 0.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	AT Month 12
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.7688
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.71 to 0.53
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	Overall
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.6810
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 95%; -0.40 to 0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline (Day 1) in Simplified Spatial Paired Associate Learning (SSPAL) Response Over Period
Description	Change from Baseline = value at the indicated time point minus the Baseline(Day1) value. SSPAL is a cognitive test that involves object-location memory and learning. It is used to examine cognitive deficits in AD. Participants were asked to sit 50 cm away from screen and different pictures (target and distracter) were shown on a monitor. Responses were acquired from response box. Participants were informed by visual feedback whether the response was correct or incorrect and the accuracy was collected automatically. SSPAL responses were captured as new accuracy and global accuracy. New accuracy was defined as proportion of accurate responses per participant for recall of any new item (picture). Global accuracy was defined as proportion of accurate responses per participant for recall of all new items and their displayed locations (i.e. right or left position on the screen). The possible range for new and global accuracy is 0(worst) to 1(best). Higher values indicate better performance.
Time Frame	Baseline (Day 1), Months 1, 6, and 12

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants available at the time of assessment were analyzed.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	39	39
Global accuracy, Month 1	-0.0 (0.16)	0.0 (0.06)
Global accuracy, Month 6	-0.0 (0.14)	-0.0 (0.12)
Global accuracy, Month 12	-0.0 (0.15)	0.0 (0.12)
New accuracy, Month 1	0.1 (0.22)	0.0 (0.17)
New accuracy, Month 6	0.0 (0.19)	-0.0 (0.29)
New accuracy, Month 12	-0.0 (0.22)	-0.1 (0.22)

6. Secondary Outcome

Title	Change From Baseline (Day 1) in Accuracy by Choice Reaction Time (CRT) Test Over Period
Description	A motor reaction task was presented 4 runs of 50 trials each. In each trial, presentation of a central crosshair for 200 milliseconds (ms) was followed by display of a grey square for 800 ms. The square appeared in two of five possible positions relative to the crosshair (leftmost or rightmost). When the grey square became white, the participant was trained to press the a button. In each trial of the Simple Reaction Time Task, presentation of a central crosshair for 200 ms was followed by display of one square for 800 ms. For both simple and choice versions of the task, trial duration was 4000 ms maximum. The participant was immediately informed (by color changes of the white square) whether the response to each trial was correct or incorrect, and accuracy and reaction time (RT) are automatically calculated. Change from Baseline is the value at indicated time point minus the Baseline value.
Time Frame	Baseline (Day 1) and up to 12 months

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants available at the time of assessment were analyzed.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	39	39
Accuracy, Left, Month 1	-0.0 (0.04)	0.0 (0.15)
Accuracy, Left, Month 6	-0.1 (0.16)	0.0 (0.14)
Accuracy, Left, Month 12	-0.1 (0.14)	0.0 (0.12)
Accuracy, Right, Month 1	0.0 (0.02)	0.0 (0.15)
Accuracy, Right, Month 6	-0.0 (0.02)	0.0 (0.15)
Accuracy, Right, Month 12	-0.0 (0.13)	0.0 (0.14)

7. Secondary Outcome

Title	Change From Baseline in Cognitive Test by Simple Reaction Time (SRT) Method Over Period
Description	A motor reaction task was presented 4 runs of 50 trials each. In each trial, presentation of a central crosshair for 200 milliseconds (ms) was followed by display of a grey square for 800 ms. The square appeared in two of five possible positions relative to the crosshair (leftmost or rightmost). When the grey square became white, the participant was trained to press the a button. In each trial of the Simple Reaction Time Task, presentation of a central crosshair for 200 ms was followed by display of one square for 800 ms. For both simple and choice versions of the task, trial duration was 4000 ms maximum. The participant was immediately informed (by color changes of the white square) whether the response to each trial was correct or incorrect, and accuracy and reaction time (RT) are automatically calculated. Baseline measurement was performed on Day 1. Change from Baseline is the value at indicated time point minus the Baseline value.
Time Frame	Baseline (Day 1) and up to 12 months

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants available at the time of assessment were analyzed.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	39	39
Month 1	-17.1 (161.70)	36.5 (162.72)
Month 6	37.8 (170.67)	59.3 (158.32)
Month 12	177.7 (359.91)	76.4 (179.78)

8. Secondary Outcome

Title	Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Scale (ADAS-COG) Total Score Over Period
Description	Change from Baseline is the value at indicated time point minus the Baseline value. ADAS-COG is a 13 item, 11 questionnaire assessment of range of cognitive abilities including memory, comprehension, orientation in time and place, and spontaneous speech. The scale ranges from 0 to 70, with negative changes from Baseline indicating the improvement and positive changes indicating worsening of condition. Arithmetic means are presented as raw data; however, statistical analysis is based on LS means.
Time Frame	Baseline (Day 1), and Months 1, 6, and 12

Outcome Measure Data

Analysis Population Description

ITT population. Only the participants available at the time of assessment were analyzed.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	39	39
Month 1	-0. (5.38)	-0.5 (4.84)
Month 6	1.7 (6.73)	3.2 (5.58)
Month 12	5.7 (7.52)	6.6 (7.80)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	At Month 1
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.8593
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.20
	Confidence Interval	(2-Sided) 95%; -2.38 to 1.99
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	At Month 6
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3201
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.44
	Confidence Interval	(2-Sided) 95%; -1.43 to 4.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	At Month 12
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2627
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.18
	Confidence Interval	(2-Sided) 95%; -1.68 to 6.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For overall period
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3633
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95%; -1.35 to 3.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline in Clinician Based Impression of Change-plus (CBIC +) Score Over Period
Description	The CBIC+ assessment for global functioning consists of a 7 point rating scale of severity and change with 1 indicating marked improvement and 7 indicating marked worsening. This scale was used to analyze clinically relevant effect. This was supposed to be performed by an independent investigator who is not a part of the ongoing study. Change from Baseline is the value at indicated time point minus the Baseline value. This scale was used to decide clinical status of AD. Arithmetic means are presented as raw data; however, statistical analysis has been presented for LS means.
Time Frame	Baseline (Day 1) and Months 1, 6, and 12

Outcome Measure Data

Analysis Population Description

ITT population. Only the participants available at the time of assessment were analyzed.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	39	39
Month 1	3.9 (1.08)	3.9 (0.95)
Month 6	4.7 (0.93)	4.5 (1.22)
Month 12	4.9 (1.03)	4.8 (1.38)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For overall period
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.5647
	Comments
	Method	Repetaed measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.11
	Confidence Interval	(2-Sided) 95%; -0.48 to 0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For Month 1
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.9935
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.00
	Confidence Interval	(2-Sided) 95%; -0.46 to 0.46
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	At Month 6
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3794
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.22
	Confidence Interval	(2-Sided) 95%; -0.72 to 0.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	At Month 12
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.7357
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.70 to 0.49
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Change From Baseline in Neuropsychiatric Inventory Score Over Period
Description	The NPI assesses the frequency and severity of behavioral disturbances in dementia across 10 domains. The total NPI score was calculated by adding all individual domains cores. The scale ranges from 0 to 120 , 0 indicating no / least burden and 120 indicating maximum burden. A negative change from Baseline indicated improvement. Baseline measurement was performed on Day 1. Change from Baseline is the value at indicated time point minus the Baseline value.
Time Frame	Baseline (Day 1), Months 1, 6 and 12

Outcome Measure Data

Analysis Population Description

ITT population. Only the participants available at the time of assessment were analyzed.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	39	39
Month 1	-1.6 (6.30)	-2.6 (6.82)
Month 6	2.1 (8.63)	-0.8 (11.59)
Month 12	0.9 (8.39)	1.8 (13.84)

11. Secondary Outcome

Title	Change From Baseline in Mini-mental State Examination (MMSE) Score Over Period
Description	The MMSE consists of 11 categories of orientation, memory (recent and immediate), concentration, language, and praxis. The scale ranges from 0 to 30 with lower scores indicating greater cognitive impairment. Negative changes from Baseline indicate improvement and positive changes indicate increasing symptoms. Change from Baseline is the value at indicated time point minus the Baseline value.
Time Frame	Baseline (Day 1), and up to Month 12

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants available at the time of assessment were analyzed.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	30	30
Mean (Standard Deviation) [Scores on a scale]	-3.3 (4.09)	-2.6 (3.27)

12. Secondary Outcome

Title	Change From Baseline in Normalized Brain Volume Over Period
Description	Normalized brain volume is a function of global changes in brain structure. Reduction in brain volume is indicative of reduction in Grey matter and thus the AD stage. The method used was structural magnetic resonance imaging (MRI). Change from Baseline is the value at indicated time point minus the Baseline value. Arithmetic means have been presented; however, statistical analysis is based upon the least square (LS) means.
Time Frame	Baseline (Day 1), Month 6 and Month 12

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants available at the time of assessment were analyzed.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	39	39
Month 6	-4553.1 (43069.12)	-15995.6 (41075.95)
Month 12	-16599.9 (47173.85)	-13929.6 (31031.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	At Month 6
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.6299
	Comments
	Method	Repeated measure mixed model
	Comments	Arithmetic means have been presented; however, statistical analysis is based upon the least square (LS) means
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-4971.6
	Confidence Interval	(2-Sided) 95%; -255515.6 to 15572.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	At Month 12
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2184
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	12223.0
	Confidence Interval	(2-Sided) 95%; -7450.6 to 31896.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Percent Change From Baseline in Brain Volume Over Period
Description	Percent volume change of brain is a function of global changes in brain structure. Reduction in brain volume is indicative of reduction in Grey matter and thus the AD stage. The method used was structural magnetic resonance imaging (MRI). Baseline value was recorded on Day 1. Change from Baseline is the value at indicated time point minus the Baseline value. Arithmetic means have been presented; however, statistical analysis is based upon the LS means.
Time Frame	Baseline (Day 1), Month 6, and Month 12

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants available at the time of assessment were analyzed.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	39	39
Month 6	-0.9 (0.62)	-1.4 (0.94)
Month 12	-2.4 (1.40)	-2.6 (1.48)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For Month 6
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0129
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95%; -1.0 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For Month 12
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.5607
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -1.0 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose at Month 12
Description	Fasting plasma glucose are indicative of Glucose metabolism. Baseline measurement was performed on Day 1. Change from Baseline is the value at indicated time point minus the Baseline value.
Time Frame	Baseline (Day 1) and Month 12

Outcome Measure Data

Analysis Population Description

ITT population. Only the participants available at the time of assessment were analyzed.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	27	28
Mean (Standard Deviation) [Millimoles per Liter]	0.2556 (0.99974)	-0.1750 (0.48810)

15. Secondary Outcome

Title	Change From Baseline in Glycosylated Hemoglobin [HbA1C] at Month 12
Description	HbA1c levels are measure of glucose metabolism in body. Baseline value measurement was performed on Day 1. Change from Baseline is the value at indicated time point minus the Baseline value.
Time Frame	Baseline (Day 1) and Month 12

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants available at the time of assessment were analyzed.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	32	31
Mean (Standard Deviation) [Percentage of HbA1c]	0.0625 (0.43533)	0.3871 (0.49514)

16. Secondary Outcome

Title	Change From Baseline in Lipid (Cholesterol) and Apo-lipoprotein Levels at Month 12
Description	Lipid (cholesterol) and apo-lipoprotein (A and B) are biomarkers of glucose metabolism in blood. The method used for analyzes was positron emission tomography (PET) using radiolabelled [18F] -fluoro-deoxy-glucose (FDG). Baseline measurement was performed on Day 1. Change from baseline is the value at indicated time point minus the Baseline value.
Time Frame	Baseline (Day 1) and Month 12

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants available at the time of assessment were analyzed.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	39	39
Apolipoprotein A	-0.0478 (0.29284)	-0.2058 (0.27424)
Apolipoprotein B	-0.0191 (0.18714)	-0.0006 (0.25070)
Cholesterol	-0.2556 (0.69756)	0.1340 (1.09229)

17. Secondary Outcome

Title	Change From Baseline in Inflammatory Biomarkers (CD40, C-reactive Protein [CRP] , Interleukin [ IL ]-6, and Tumor Necrosing Factor [TNF]-Alpha)
Description	The inflammatory biomarkers namely CD40, C-reactive protein (CRP) , interleukin (IL)-6, and tumor necrosing factor (TNF)-alpha) were analyzed. Baseline measurement was performed on Day 1. Change from Baseline is the value at indicated time point minus the Baseline value.
Time Frame	Baseline (Day 1) and Month 12

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants available at the time of assessment were analyzed.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	39	39
CD40	-236.79 (2500.30)	130.543 (2580.16)
CRP	0.8161 (5.94099)	-1.4800 (4.63565)
IL-6	6.3390 (22.5103)	2.6370 (11.1159)
TNF-alpha	16.7893 (53.0817)	3.8407 (15.9970)

18. Secondary Outcome

Title	Change From Baseline in Insulin Sensitivity Measured by Homeostasis Model Assessment of Insulin Resistance (HOMA IR)
Description	This is a measure of assessing insulin sensitivity. HOMA IR was calculated by multiplying fasting insulin by fasting plasma glucose and dividing the multiplied digit by 22.5. All samples were collected under fasting condition. Baseline measurement was performed on Day 1. Change from Baseline is the value at indicated time point minus the Baseline value.
Time Frame	Baseline (Day 1) and Month 12

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants available at the time of assessment were analyzed.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	31	31
Mean (Standard Deviation) [HOMA IR score]	-0.2703 (12.6037)	-5.9910 (9.79511)

19. Secondary Outcome

Title	Number of Participants by Apo-lipoprotein -e (APOE Epsilon)-4 Allele Subtype
Description	Participants were categorized into two major types namely those with APOE4 genotype and without APOE4 genotype. Further, 6 subtypes/ alleles of APOE4 gene (as mentioned in the categories below) were analyzed. Participants were also classified as having 0 or 1 or 2 copies of this gene.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

PGx population included all ITT participants with evaluable PGx data (had consented to genotyping, provided and identified blood sample for genotyping and were successfully genotyped for at least one of the genetic markers under study). Only those participants available at time of assessment were analyzed.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	30	29
With APOE4 gene	24 61.5%	15 38.5%
Without APOE4 gene	6 15.4%	14 35.9%
With E4E4 allele	7 17.9%	6 15.4%
With E3E4 allele	17 43.6%	8 20.5%
With E2E4 allele	0 0%	1 2.6%
With E3E3 allele	5 12.8%	12 30.8%
With E2E3 allele	1 2.6%	1 2.6%
With E2E2 allele	0 0%	1 2.6%
2 copies of APOE4 gene	7 17.9%	6 15.4%
1 copies of APOE4 gene	17 43.6%	9 23.1%
0 copies of APOE4 gene	6 15.4%	14 35.9%

20. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	Adverse event (AE) is an unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a certain time period after the study has ended. This change may or may not be caused by the intervention being studied. Serious adverse event (SAE) is an adverse event that results in death, is life-threatening, requires inpatient hospitalization or extends a current hospital stay, results in an ongoing or significant incapacity or interferes substantially with normal life functions, or causes a congenital anomaly or birth defect. Medical events that do not result in death, are not life-threatening, or do not require hospitalization may be considered serious adverse events if they put the participant in danger or require medical or surgical intervention to prevent one of the results listed above.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

All subjects population included all randomized subjects who receive at least one dose of study drug.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	40	40
Any AE	32 82.1%	33 84.6%
Any SAE	6 15.4%	4 10.3%

21. Secondary Outcome

Title	Number of Participants With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Outside the Concern Range at Month 12
Description	Number of participants with SBP or DBP outside the defined range of clinical concern were collectively presented for any time on-treatment period. SBP of <90 millimeters of mercury (mmHg) and >140 mmHg was considered as of clinical concern. DBP of <50 and >90 mmHg was considered as of clinical concern. Increase in SBP from Baseline of >=40 mmHg and Decrease of >=30 mmHg was also recorded. Increase in DBP from Baseline of >=30 mmHg and Decrease of >=20 mmHg was also recorded.
Time Frame	At Month 12

Outcome Measure Data

Analysis Population Description

All subjects population. Only the participants available at the time of assessment were analyzed.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	39	40
SBP, >140 or <90	20 51.3%	23 59%
SBP, Increase from Baseline>=40	1 2.6%	3 7.7%
SBP, Decrease from Baseline>=30	12 30.8%	13 33.3%
DBP, >90 or <50	5 12.8%	2 5.1%
DBP, Increase from Baseline>=30	1 2.6%	1 2.6%
DBP, Decrease from Baseline>=20	3 7.7%	7 17.9%

22. Secondary Outcome

Title	Number of Participants With Heart Rate/ Pulse Rate Outside the Concern Range at Month 12
Description	Heart rate was measured in supine position. Number of participants with any time on-treatment values of heart rate values outside the clinical concern were presented. Heart rate values of >100 or <50 were considered as of clinical concern. Increase in heart rate from Baseline of >=30 beats per minute (bpm) and decrease in heart rate from Baseline of >=30 bpm was also recorded and presented.
Time Frame	At Month 12

Outcome Measure Data

Analysis Population Description

All subjects population. Only those participants available at the time of assessment were analyzed.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.
Measure Participants	39	40
Heart rate >100 or <50	4 10.3%	3 7.7%
Increase in heart rate from Baseline of >=30	2 5.1%	4 10.3%
Dncrease in heart rate from Baseline of >=30	0 0%	0 0%

23. Secondary Outcome

Title	Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Parameters at Screening and Follow-up
Description	Two screening visits were arranged within 30 days of Day 1 of screening period and within 7 to 10 days of Day 1 of screening period. Follow-up period was arranged within 14 days of the last dose (post 12 months) of the study drug. Data for only the participants with abnormal ECG values has been presented.
Time Frame	At screening (within 1 month of Day 1) and follow-up period (within 2 weeks of final dose [12 months])

Outcome Measure Data

Analysis Population Description

All subjects population.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	40	40
At screening	18 46.2%	18 46.2%
At follow-up	5 12.8%	10 25.6%

24. Secondary Outcome

Title	Number of Participants With Body Weight and Height Outside the Clinical Concern at Month 12
Description	Body weight and height are the parameters of physical examination. Body weight is also a measure of fluid retention. Body weight increase or decrease of >= 7 % was considered as of clinical concern. Since there would be no or negligible (insignificant) change in height of a participant, no data has been presented for change from Baseline in height of participants after exposure to the study drug.
Time Frame	At Month 12

Outcome Measure Data

Analysis Population Description

All subjects population. Only those participants available at the time of assessment were analyzed.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	33	31
Increase from Baseline >=7%	2 5.1%	5 12.8%
Decrease from Baseline >=7%	2 5.1%	2 5.1%

25. Secondary Outcome

Title	Global and Regional CMRglu Index by APOE Epsilon-4 Allele Subtype at 12 Month
Description	The CMRglu was analyzed based on the APOE Epsilon-4 gene allele, whether it was present (positive) or was missing (negative) among the participants. The data has been presented for Month 12. Data has been presented for arithmetic mean; however, statistical analysis presented is based on LS means.
Time Frame	At Month 12

Outcome Measure Data

Analysis Population Description

PGx ITT population included all participants in ITT population who had evaluable PGx data (who consented to genotyping, provided an identified blood sample for genotyping and were successfully genotyped for at least one of the genetic markers under study. Only the participants available at the time of assessment were analyzed.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	40	40
Grey matter, APOE positive	-0.2649 (0.58442)	-0.0903 (0.44270)
Posterior cingulate gyrus, APOE positive	-0.2728 (0.69449)	-0.0987 (0.43553)
Frontal lobe, APOE positive	-0.2939 (0.66878)	-0.1046 (0.45385)
Parietal lobe, APOE positive	-0.2919 (0.60832)	-0.1404 (0.42635)
Posterior temporal lobe, APOE positive	-0.2722 (0.48425)	-0.1175 (0.42617)
Cerebellum, APOE positive	-0.2280 (0.54477)	-0.0375 (0.49150)
Medial temporal lobe, APOE positive	-0.1647 (0.39800)	-0.0004 (0.43929)
Grey matter, APOE negative	-0.1577 (0.06551)	-0.0107 (0.16654)
Posterior cingulate gyrus, APOE negative	-0.2655 (0.11854)	0.0141 (0.17927)
Frontal lobe, APOE negative	-0.1967 (0.09081)	-0.0323 (0.17438)
Parietal lobe, APOE negative	-0.1549 (0.08056)	-0.0362 (0.17425)
Posterior temporal lobe, APOE negative	-0.1391 (0.11660)	-0.0443 (0.16786)
Cerebellum, APOE negative	-0.1732 (0.05698)	0.0742 (0.15230)
Medial temporal lobe, APOE negative	-0.1134 (0.06707)	0.0026 (0.14382)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For Grey matter, APOE Epsilon-4 status positive
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2800
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1154
	Confidence Interval	(2-Sided) 95%; -0.0967 to 0.3275
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For Grey matter, APOE Epsilon-4 status negative
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.4159
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1337
	Confidence Interval	() 95%; -0.1931 to 0.4605
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For posterior cingulate gyrus, APOE Epsilon-4 status positive
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2158
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1491
	Confidence Interval	(2-Sided) 95%; -0.0897 to 0.3878
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For posterior cingulate gyrus, APOE Epsilon-4 status negative
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2087
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.2346
	Confidence Interval	(2-Sided) 95%; -0.1350 to 0.6042
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For Frontal lobe, APOE Epsilon-4 status positive
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3064
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1233
	Confidence Interval	(2-Sided) 95%; -0.1162 to 0.3628
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For Frontal lobe APOE Epsilon-4 status negative
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3500
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1734
	Confidence Interval	(2-Sided) 95%; -0.1952 to 0.5420
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For parietal lobe, APOE Epsilon-4 status positive
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2487
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1300
	Confidence Interval	(2-Sided) 95%; -0.0937 to 0.3538
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For parietal lobe, APOE Epsilon-4 status negative
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.5521
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1038
	Confidence Interval	(2-Sided) 95%; -0.2440 to 0.4516
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For posterior temporal lobe, APOE Epsilon-4 status positive
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1760
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1384
	Confidence Interval	(2-Sided) 95%; -0.0640 to 0.3409
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For posterior temporal lobe, APOE Epsilon-4 status negative
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.5952
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.0837
	Confidence Interval	(2-Sided) 95%; -0.2303 to 0.3978
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For Cerebellum, APOE Epsilon-4 status positive
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.4025
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.0847
	Confidence Interval	(2-Sided) 95%; -0.1169 to 0.2863
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For Cerebellum, APOE Epsilon-4 status negative
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3081
	Comments
	Method	Repeated measure mixed model95
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1536
	Confidence Interval	(2-Sided) 95%; -0.1458 to 0.4530
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For medial temporal lobe, APOE Epsilon-4 status positive
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2964
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.0839
	Confidence Interval	(2-Sided) 95%; -0.0758 to 0.2436
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Placebo, Rosiglitazone
	Comments	For medial temporal lobe, APOE Epsilon-4 status negative
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2101
	Comments
	Method	Repeated measure mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1536
	Confidence Interval	(2-Sided) 95%; -0.0892 to 0.3963
	Parameter Dispersion	Type: Value:
	Estimation Comments

26. Secondary Outcome

Title	Number of Participants With Hematological Data of Potential Clinical Concern (PCC) at End of Treatment (Month 12)
Description	Participants were analyzed for any abnormality in basophils, eosinophils, hemoglobin, lymphocytes, monocytes, neutrophils, segmented neutrophils, platelets, red blood cells, and white blood cells with data outside the respective reference ranges. The values higher (H) or lower (L) than the reference range were analyzed at each month. The parameter has not been presented for participants who did not have any abnormality.
Time Frame	At Month 12

Outcome Measure Data

Analysis Population Description

All subjects population. Only the participants available at the time of assessment were analyzed.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	40	40
Hemoglobin, Month 12, L	0 0%	1 2.6%
Neutrophils, Month 12, L	0 0%	1 2.6%
Platelets, Month 12, L	0 0%	1 2.6%
White cells, Month 12, L	1 2.6%	1 2.6%
Lymphoctes percentage, Month 12, L	1 2.6%	0 0%

27. Secondary Outcome

Title	Number of Participants With Clinical Chemistry Data of PCC at End of the Treatment (Month 12)
Description	Participants were analyzed for any abnormality in albumin, alanine aminotransferases, alkaline phosphatase, apolipoprotein A, apolipoprotein B, aspartate aminotransferases, Vitamin B12, direct bilirubin, indirect bilirubin, total bilirubin, cholesterol, creatinine, C-reactive protein, serum glucose, and non-fasting glucose, with data of PCC range. The values higher (H) or lower (L) than the reference range were analyzed at each month. The parameter has not been presented for participants who did not have any abnormality.
Time Frame	At Month 12

Outcome Measure Data

Analysis Population Description

All subjects population. Only the participants available at the time of assessment were analyzed.

Arm/Group Title	Placebo	Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.	Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
Measure Participants	40	40
Direct bilirubin, H	1 2.6%	0 0%
Cholesterol, H	1 2.6%	0 0%
Glucose, H	1 2.6%	0 0%
Low density lipoprotein cholesterol, H	2 5.1%	5 12.8%

Adverse Events

Time Frame	Up to 13 months
Adverse Event Reporting Description	All subjects population was used to report AEs and SAEs.
Arm/Group Title	Placebo		Rosiglitazone
Arm/Group Description	Eligible participants received unit oral dose of visually matching Placebo 4 mg for one month. Participants received escalated dose of 8 mg matching placebo for next 12 months and were followed-up to 30 days.		Eligible participants received unit oral rosiglitazone extended release (RSG XR) 4 mg for one month with or without food. Participants received escalated dose of rosiglitazone-XR for next 12 months and were followed-up to 30 days.
All Cause Mortality
	Placebo		Rosiglitazone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0%)		0/40 (0%)
Serious Adverse Events
	Placebo		Rosiglitazone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/40 (15%)		4/40 (10%)
Cardiac disorders
MYOCARDIAL INFARCTION	1/40 (2.5%)		0/40 (0%)
Gastrointestinal disorders
ABDOMINAL PAIN	1/40 (2.5%)		0/40 (0%)
FAECALOMA	0/40 (0%)		1/40 (2.5%)
Infections and infestations
LABYRINTHITIS	1/40 (2.5%)		0/40 (0%)
PNEUMONIA	1/40 (2.5%)		0/40 (0%)
UROSEPSIS	1/40 (2.5%)		0/40 (0%)
Injury, poisoning and procedural complications
COMPRESSION FRACTURE	1/40 (2.5%)		0/40 (0%)
PELVIC FRACTURE	0/40 (0%)		1/40 (2.5%)
Metabolism and nutrition disorders
HYPONATRAEMIA	1/40 (2.5%)		0/40 (0%)
Psychiatric disorders
ABNORMAL BEHAVIOUR	0/40 (0%)		1/40 (2.5%)
Respiratory, thoracic and mediastinal disorders
INTERSTITIAL LUNG DISEASE	1/40 (2.5%)		0/40 (0%)
PULMONARY EMBOLISM	0/40 (0%)		1/40 (2.5%)
Other (Not Including Serious) Adverse Events
	Placebo		Rosiglitazone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/40 (80%)		33/40 (82.5%)
Gastrointestinal disorders
Diarrhea	3/40 (7.5%)		1/40 (2.5%)
Nausea	3/40 (7.5%)		1/40 (2.5%)
Vomiting	3/40 (7.5%)		0/40 (0%)
Frequent bowel movements	2/40 (5%)		0/40 (0%)
General disorders
Edema peripheral	0/40 (0%)		3/40 (7.5%)
Fatigue	1/40 (2.5%)		2/40 (5%)
Gait disturbance	0/40 (0%)		2/40 (5%)
Infections and infestations
Upper respiratory tract infection	3/40 (7.5%)		4/40 (10%)
Herpes zoster	1/40 (2.5%)		3/40 (7.5%)
Urinary tract infection	2/40 (5%)		3/40 (7.5%)
Pneumonia	2/40 (5%)		1/40 (2.5%)
Injury, poisoning and procedural complications
Fall	5/40 (12.5%)		2/40 (5%)
Joint sprain	0/40 (0%)		2/40 (5%)
Procedural pain	0/40 (0%)		2/40 (5%)
Excoriation	2/40 (5%)		0/40 (0%)
Investigations
Blood pressure increased	2/40 (5%)		0/40 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/40 (2.5%)		2/40 (5%)
Muscle Spasms	2/40 (5%)		1/40 (2.5%)
Intervertebral disc protrusion	2/40 (5%)		0/40 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	3/40 (7.5%)		1/40 (2.5%)
Nervous system disorders
Dizziness	3/40 (7.5%)		3/40 (7.5%)
Dementia Alzheimer's type	0/40 (0%)		2/40 (5%)
Headache	0/40 (0%)		2/40 (5%)
Psychiatric disorders
Depression	1/40 (2.5%)		2/40 (5%)
Agitation	2/40 (5%)		0/40 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	3/40 (7.5%)		1/40 (2.5%)
Skin and subcutaneous tissue disorders
Rash	3/40 (7.5%)		0/40 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.