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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT00348140




Trial ID
NCT00348140
Ethics application status
Date submitted
30/06/2006
Date registered
30/06/2006
Date last updated
3/08/2017

Titles & IDs
Public title
Rosiglitazone (Extended Release Tablets) As Adjunctive Therapy In Subjects With Mild To Moderate Alzheimer's Disease
Scientific title
A 54 Week, Double-blind, Randomised, Placebo-controlled, Parallel Group Study to Investigate the Effects of Rosiglitazone (Extended Release Tablets) as Adjunctive Therapy to Acetylcholinesterase Inhibitors on Cognition and Overall Clinical Response in APOE4-stratified Subjects With Mild to Moderate Alzheimer's Disease
Secondary ID [1] 0 0
AVA102670
Universal Trial Number (UTN)
Trial acronym
REFLECT-3
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Alzheimer's Disease 0 0
Condition category
Condition code
Neurological 0 0 0 0
Alzheimer's disease
Neurological 0 0 0 0
Dementias

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Rosiglitazone Extended Release 2mg
Treatment: Drugs - Rosiglitazone Extended Release 8mg
Other interventions - Placebo

Experimental: Arm 1 - Rosiglitazone Extended Release 2mg OD

Experimental: Arm 2 - Rosiglitazone Extended Release 8mg OD

Placebo Comparator: Arm 3 - Placebo


Treatment: Drugs: Rosiglitazone Extended Release 2mg
Rosiglitazone Extended Release 2mg OD

Treatment: Drugs: Rosiglitazone Extended Release 8mg
Rosiglitazone Extended Release 8mg OD

Other interventions: Placebo
Placebo

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score at Week 48, as a Function of APOE e4 Status in APOE4 Negatives Cohort - The 11-item ADAS-Cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Most items were evaluated by tests, but some were dependent on clinician ratings on a five point scale. Scores range from 0 to 70 with higher scores indicating greater dysfunction. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at Week 0. Estimated value was calculated by Active treatment minus Placebo. The adjusted means were presented. A hierarchical testing procedure was used to control for statistical tests in the two RSG dose groups and the genetic subgroups.
Timepoint [1] 0 0
Baseline (Week 0) and Week 48
Primary outcome [2] 0 0
Change From Baseline in ADAS-Cog Total Score at Week 48, as a Function of APOE e4 Status in All Except E4/E4s Cohort - The 11-item ADAS-Cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Most items were evaluated by tests, but some were dependent on clinician ratings on a five point scale. Scores range from 0 to 70 with higher scores indicating greater dysfunction. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value a t Week 0. Estimated value was calculated by Active treatment minus Placebo. The adjusted means were presented. A hierarchical testing procedure was used to control for statistical tests in the two RSG dose groups and the genetic subgroups.
Timepoint [2] 0 0
Baseline (Week 0) and Week 48
Primary outcome [3] 0 0
Change From Baseline in ADAS-Cog Total Score at Week 48, as a Function of APOE e4 Status in Full Population Cohort - The 11-item ADAS-Cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Most items were evaluated by tests, but some were dependent on clinician ratings on a five point scale. Scores range from 0 to 70 with higher scores indicating greater dysfunction. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value a t Week 0. Estimated value was calculated by Active treatment minus Placebo. The adjusted means were presented. A hierarchical testing procedure was used to control for statistical tests in the two RSG dose groups and the genetic subgroups.
Timepoint [3] 0 0
Baseline (Week 0) and Week 48
Primary outcome [4] 0 0
Change From Baseline in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) Score at Week 48, as a Function of APOE e4 Status in APOE4 Negatives Cohort - The CDR-SB was a validated clinical assessment of global function in patients with AD. Impairment was scored in each of 6 cognitive categories on a scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2, and severe = 3. The 6 individual category ratings, or "box scores", can be added together to give the CDR-Sum of Boxes which ranges from 0 to 18 (severe impairment). Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value a t Week 0. Estimated value was calculated by Active treatment minus Placebo. The adjusted means were presented. Primary inference will be based on the week 48 treatment differences obtained from the MMRM model. A hierarchical testing procedure was used to control for statistical tests in the two RSG dose groups and the genetic subgroups.
Timepoint [4] 0 0
Baseline (Week 0) and Week 48
Primary outcome [5] 0 0
Change From Baseline in CDR-SB Score at Week 48, as a Function of APOE e4 Status in All Except E4/E4s Cohort - The CDR-SB was a validated clinical assessment of global function in patients with AD. Impairment was scored in each of 6 cognitive categories on a scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2, and severe = 3. The 6 individual category ratings, or "box scores", can be added together to give the CDR-Sum of Boxes which ranges from 0 to 18 (severe impairment). Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value a t Week 0. Estimated value was calculated by Active treatment minus Placebo. The adjusted means were presented. Primary inference will be based on the week 48 treatment differences obtained from the MMRM model. A hierarchical testing procedure was used to control for statistical tests in the two RSG dose groups and the genetic subgroups.
Timepoint [5] 0 0
Baseline (Week 0) and Week 48
Primary outcome [6] 0 0
Change From Baseline in CDR-SB Score at Week 48, as a Function of APOE e4 Status in Full Population Cohort - The CDR-SB was a validated clinical assessment of global function in patients with AD. Impairment was scored in each of 6 cognitive categories on a scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2, and severe = 3. The 6 individual category ratings, or "box scores", can be added together to give the CDR-Sum of Boxes which ranges from 0 to 18 (severe impairment). Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value a t Week 0. Estimated value was calculated by Active treatment minus Placebo. The adjusted means were presented. Primary inference will be based on the week 48 treatment differences obtained from the MMRM model. A hierarchical testing procedure was used to control for statistical tests in the two RSG dose groups and the genetic subgroups.
Timepoint [6] 0 0
Baseline (Week 0) and Week 48
Secondary outcome [1] 0 0
Change From Baseline in ADAS-Cog Total Score at Weeks 8, 16, 24 and 36 - The 11-item ADAS-Cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Most items were evaluated by tests, but some were dependent on clinician ratings on a five point scale. Scores range from 0 to 70 with higher scores indicating greater dysfunction. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value a t Week 0. It was calculated at Weeks 8, 16, 24 and 36. Full population data was presented.
Timepoint [1] 0 0
Baseline (Week 0) and Week 8, 16, 24, 36
Secondary outcome [2] 0 0
Change From Baseline in CDR-SB Score at Weeks 12, 24 and 36 - The CDR-SB was a validated clinical assessment of global function in patients with AD. Impairment was scored in each of 6 cognitive categories on a scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2, and severe = 3. The 6 individual category ratings, or "box scores", can be added together to give the CDR-Sum of Boxes which ranges from 0 to 18 (severe impairment). Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value a t Week 0. Estimated value was calculated by Active treatment minus Placebo. The adjusted means were presented. It was calculated at Weeks 12, 24 and 36. Full population data was presented.
Timepoint [2] 0 0
Baseline (Week 0) and Week 12, 24, 36
Secondary outcome [3] 0 0
Change From Screening in Mini Mental State Examination (MMSE) Total Score - The MMSE consists of 11 tests of orientation, memory (recent and immediate), concentration, language and praxis. Scores range from 0 to 30, with lower scores indicating greater cognitive impairment. The scale is completed by the investigator, based on the performance of the participant. Change from screening was calculated as value at scheduled time point minus screening value. Baseline was defined as value a t Week 0. Estimated value was calculated by Active treatment minus Placebo. The adjusted means were presented. Full population data was presented.
Timepoint [3] 0 0
Screening (Week -4) and Week 48
Secondary outcome [4] 0 0
Change From Baseline in Disability Assessment for Dementia (DAD) Total Score - The DAD assessed the ability of a participant to execute basic and instrumental activities of daily living (ADL) and leisure activities. The scale consists of 40 questions assessing basic and instrumental ADLs. This scale assessed a participants' ability to initiate, plan, and perform activities related to hygiene, dressing, continence, eating, meal preparation, telephoning, going on an outing, finance and correspondence, medications, leisure, and housework. Each item was scored as yes: 1, no: 0 and N/A: not applicable. Higher scores indicate less disability with a score of 100 indicating no disability and 0 indicating no functional ability. The percentage score was calculated as (DAD Total score /Total number of applicable items) multiplied by 100. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at Week 0. Full population data was presented.
Timepoint [4] 0 0
Baseline (Week 0) and Week 8, 16, 24, 48
Secondary outcome [5] 0 0
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score - NPI is an assessment of frequency and severity of behavioral disturbances in dementia that comprised of 10 dimensions: delusions, hallucinations, dysphoria, apathy, euphoria, disinhibition, aggressiveness and agitation, irritability, anxiety, aberrant motor activity. Participant's caregiver asked about behavior in participant. If "Yes", informant then rated both severity on a 3-point scale, 1-mild to 3-severe (total range: 0-36) and frequency using a 4-point scale, 1-occasionally to 4-very frequently. Total score was frequency × severity. Distress was scored on 5-point scale, 0-no distress to 5-very severe or extreme. Total NPI score was calculated by adding all domain scores; NPI total score: 0-144 and NPI distress score: 0-60, higher scores indicated more severe behavioral disturbance. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at Week 0. Adjusted means were presented. Full population data was presented.
Timepoint [5] 0 0
Baseline (Week 0) and Week 8, 16, 24, 48
Secondary outcome [6] 0 0
Change From Baseline in Domains of the Resource Utilization in Dementia Scale (RUD)- Q1 and Q2 Caregiver Hours - The RUD instrument was developed as a comprehensive tool to assess the amount of resource use among demented patients. RUD assessd both formal and informal resource use of the patient and the primary caregiver, making it possible to calculate costs from a societal perspective. Q1 corresponds to the number of hours during the last month the caregiver spent assisting the patient with toilet visits, eating, dressing, grooming, walking and bathing and Q2 corresponds to the number of hours during the last month the caregiver spent assisting the patient with shopping, food preparation, housekeeping, laundry, transportation, taking medication and managing financial matters. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at Week 0. Estimated value was calculated by Active treatment minus Placebo. The adjusted means were presented. Full population data was presented.
Timepoint [6] 0 0
Baseline (Week 0) and Week 12, 24, 36, 48
Secondary outcome [7] 0 0
Change From Baseline in European Quality of Life -5 Dimensions (EQ-5D) Scale Total Score- Thermometer Score - The EQ-5D Proxy is an assessment of quality of life and utility benefit. The EQ-5D Proxy is composed of two parts: part two is the visual analogue scale 'Thermometer'. Caregivers are asked to respond as they feel the participant would on dimensions of mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The 'Thermometer' has endpoints of 100 (best imaginable health state) and 0 (worst imaginable health state). Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value a t Week 0. Estimated value was calculated by Active treatment minus Placebo. The adjusted means were presented. Full population data was presented.
Timepoint [7] 0 0
Baseline (Week 0) and Week 12, 36, 48
Secondary outcome [8] 0 0
Change From Baseline in EQ-5D Scale Total Score- Utility Score - The EQ-5D Proxy is an assessment of quality of life and utility benefit. The EQ-5D Proxy is composed of two parts: part one is the five dimensional Health State Classification. The Utility score is a caregiver rating of health status on dimensions of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Answers to each question were responded to on a 3-point scale which indicates the level of impairment (level 1= no problem; level 2=some or moderate problem(s) and level 3=unable, or extreme problem with higher scores indicating greater dysfunction. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value a t Week 0. Estimated value was calculated by Active treatment minus Placebo. The adjusted means were presented. Full population data was presented.
Timepoint [8] 0 0
Baseline (Week 0) and Week 12, 36, 48
Secondary outcome [9] 0 0
Change From Baseline in Alzheimer's Carer's Quality of Life Instrument (ACQLI) Score - The ACQLI is an assessment of caregiver quality of life. This instrument consisted of 30 questions exploring various aspects of carer's quality of life. Each of the questions had two point response, and the 30 questions were summed to provide a total score. Items were assumed to be unidimensional (i.e., represent a single variable) and were scored 0/1 (false/true) before summation into a total score with a 0-30 range. To ease comparisons between scales, ACQLI scores were transformed to range between 0-100 (100: worse). Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value a t Week 0. Estimated value was calculated by Active treatment minus Placebo. The adjusted means were presented. Full population data was presented.
Timepoint [9] 0 0
Baseline (Week 0) and Week 12, 36, 48
Secondary outcome [10] 0 0
Change in ADAS-Cog Total Score for Observed Cases at Week 54 Compared to Week 48 - The 11-item ADAS-Cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Most items were evaluated by tests, but some were dependent on clinician ratings on a five point scale. Scores range from 0 to 70 with higher scores indicating greater dysfunction. It was of interest to compare the single blind phase data between the treatment groups defined based on the double blind treatment group. This analysis only included participants who received at least one dose of single-blind medication. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at Week 0. Full population data was presented.
Timepoint [10] 0 0
Week 48 and Week 54
Secondary outcome [11] 0 0
Change in CDR-SB Total Score for Observed Cases at Week 54 Compared to Week 48 - The CDR-SB was a validated clinical assessment of global function in participants with AD. Impairment was scored in each of 6 cognitive categories on a scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2, and severe = 3. The 6 individual category ratings, or "box scores", can be added together to give the CDR-Sum of Boxes which ranges from 0 to 18 (severe impairment). It was of interest to compare the single blind phase data between the treatment groups defined based on the double blind treatment group. This analysis only included participants who received at least one dose of single-blind medication. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at Week 0. Full population data was presented.
Timepoint [11] 0 0
Week 48 and Week 54
Secondary outcome [12] 0 0
Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 48 - Blood samples were collected for assessments of HbA1c levels at Baseline and up to Week 48. Change from Baseline was calculated as value at scheduled time point minus Baseline value . Baseline was defined as value at Week 0. Endpoint treatment differences which were adjusted to take account of missing data are derived. Full population data was presented.
Timepoint [12] 0 0
Baseline (Week 0) and Week 48
Secondary outcome [13] 0 0
Number of Participants With On-treatment Adverse Events (AEs), Serious Adverse Events (SAEs) and Severity of AEs - AE was defined as any untoward medical occurrence in a participant temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE was any untoward medical occurrence that, at any dose results in death, was life threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity, was a congenital anomaly/birth defect or was considered as medically significant.
Timepoint [13] 0 0
Upto Week 48
Secondary outcome [14] 0 0
Number of Participants With Change From Baseline in Vital Signs of Clinical Concern at Any Time on Treatment- Weight - Body weight was measured at all visits, without shoes and wearing light clothing. The assessment was performed a t Baseline and up to Week 54. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at Week 0. Full population data was presented.
Timepoint [14] 0 0
Upto Week 54
Secondary outcome [15] 0 0
Number of Participants With Change From Baseline in Vital Signs of Clinical Concern at Any Time on Treatment- Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) - SBP and DBP of participants were recorded in sitting posture as vital sign at each visit. The blood pressure (BP) values were identified as of potential clinical concern if the values were out of the reference range (for SBP, 90 to 140 mmHg and DBP, 50 to 90 mmHg) or meet a change from baseline criterion. The change from baseline criterion for SBP, was increase from Baseline (high) if increased by more than or equal to (>=) 40 mm Hg from Baseline; decrease from Baseline (low) if decreased by >= 30 mmHg from Baseline. For DBP, increase from baseline (high) if increased by >=30 mmHg from baseline; decrease from Baseline (low) if decreased by >= 20 mmHg from Baseline. Baseline was defined as value at Week 0.
Timepoint [15] 0 0
Upto Week 54
Secondary outcome [16] 0 0
Number of Participants With Change From Baseline in Vital Signs of Clinical Concern at Any Time on Treatment- Heart Rate (HR) - HR of participants were recorded in sitting posture as vital sign at each visit. The HR values were identified as of potential clinical concern if the values were out of the reference range (50 to 100 beats per minute) or meet a change from baseline criterion. The change from baseline criterion for HR, was increase from Baseline (high) if increased by more than or equal to (>=) 30 from Baseline; decrease from Baseline (low) if decreased by >= 30 from Baseline. Baseline was defined as value at Week 0. Full population data was presented.
Timepoint [16] 0 0
Upto Week 54
Secondary outcome [17] 0 0
Change From Baseline in Weight - Body weight was measured at all visits, without shoes and wearing light clothing. The assessment was performed at Baseline, Weeks 4, 8, 12, 16, 24, 36, 48, 54. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at Week 0. Full population data was presented.
Timepoint [17] 0 0
Baseline (Week 0) and Weeks 4, 8, 12, 16, 24, 36, 48, 54
Secondary outcome [18] 0 0
Change From Baseline in Hemoglobin - Hematology parameters were assessed at Baseline, Weeks 4, 16, 36, 48. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at Week 0. Full population data was presented.
Timepoint [18] 0 0
Baseline (Week 0) and Weeks 4, 16, 36, 48
Secondary outcome [19] 0 0
Change From Baseline in Hematocrit - Hematology parameters were assessed at Baseline and up to Week 48. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at Week 0.
Timepoint [19] 0 0
Baseline (Week 0) and Weeks 4, 16, 36, 48
Secondary outcome [20] 0 0
Any Time on Treatment Differences in Frequencies of Hematology Data Outside the Reference Range - Haematology parameters were identified as of PCC (high [H], low [L]), if the values were out of the reference range (RR). The range for parameters was: platelet (100AV-500AV), red blood cell (RBC , 0.8-1.2), hemoglobin (L: female [F]:10, male [M]:11; H: F:16.5-AV, M:18), hematocrit (0.8-1.2), white blood cell (WBC, 3-15), Total neutrophils (ANC- absolute Neutrophil count) (0.75-1.5), lymphocytes (0.75-1.5), monocyte s (0.75-2), eosinophils (none -2), basophils (none -2), mean corpuscle volume (MCV, 0.8-1.2), mean corpuscular hemoglobin (MCH, 0.8-1.2), mean corpuscular hemoglobin concentration (MCHC , 0.8-1.2), red cell distribution width (RDW, 0.8-1.2), Neutrophil bands (none-1) and segmented neutrophils (0.75-1.3). Full population data was presented.
Timepoint [20] 0 0
Up to Week 48
Secondary outcome [21] 0 0
Any Time on Treatment Differences in Frequencies of Clinical Chemistry Data Outside the Reference Range - Clinical chemistry parameters were identified as of PCC (High, Low), if values were out of RR: Alanine amino transferase (ALT,none-120 [250percent upper limit of RR, ULRR ]),Album in (0.75-2),Aldolase(1.1-1.1),Aspartate amino transferase (AST,none-105 (3-64y),137.5(65+y),>250 percent ULRR), Alkaline phosphatase(ALP,none-312.5 (20+y),>250percent ULRR),blood urea nitrogen(BUN)/Creatinine ratio(none-1.25),BUN(none-11),Chloride(80-115),Calcium (0.75-1.25),Carbon dioxide(CO2,15-40) content,Creatinine (22,<50percent lower limit of RR [LLRR ]-155, >125percent ULRR),Creatine phosphokinase(CPK,none-1.25),Gamma glutamyl transferase(GGT,none-2.5),Glucose (3.6-7.8),HbA1C, High density lipoprotein (HDL,0.65-none),Lactate dehydrogenase (LDH,none -2), Low density lipoprotein(LDL,none-1.25),Magnesium (0.5-2),Potassium (3-5.5),Phosphorus inorganic(0.5-1.5), Sodium (130-150), Total protein (0.8-1.5),Total cholesterol(none -1.5),Direct Billirubin.
Timepoint [21] 0 0
Upto Week 48
Secondary outcome [22] 0 0
Changes From Baseline in Electrocardiogram (ECG) Parameters- HR - Triplicate 12-lead ECG measures was obtained digitally, approximately one minute apart after the participant had rested in the supine position in a quiet room (no TV, minimal talking) for atleast 10 minutes. The ECG parameters includes HR. The assessments were performed at Baseline and up to Week 54. Change from Baseline was calculated as value at scheduled time point minus Baseline value . Baseline was defined as value at Week 0. Full population data was presented.
Timepoint [22] 0 0
Baseline (Week 0) and Weeks 4, 8, 16, 24, 36, 48, 54
Secondary outcome [23] 0 0
Changes From Baseline in ECG Parameters- RR Interval, QT Interval, QTcB, QTcF, PR Interval and QRS Duration - Triplicate 12-lead ECG measures was obtained digitally, approximately one minute apart after the participant had rested in the supine position in a quiet room (no TV, minimal talking) for atleast 10 minutes. The ECG parameters includes PR interval, QRS duration, QT - uncorrected interval, QTc Bazett (QTcB), QTc Fridericia (QTcF) and RR interval. The assessments were performed at Baseline and up to Week 54. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at Week 0. Full population data was presented.
Timepoint [23] 0 0
Baseline (Week 0) and Weeks 4, 8, 16, 24, 36, 48, 54
Secondary outcome [24] 0 0
Change From Baseline in HbA1c up to Week 54 - Blood samples were collected for assessments of HbA1c levels at Baseline, Weeks 12, 24, 36, 48, 54. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at Week 0.
Timepoint [24] 0 0
Baseline (Week 0) and Weeks 12, 24, 36, 48, 54
Secondary outcome [25] 0 0
Change From Baseline in Short Term Memory Assessment - The 11-item ADAS-Cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Most items were evaluated by tests, but some were dependent on clinician ratings on a five point scale. Scores range from 0 to 70 with higher scores indicating greater dysfunction. Questions 1 (word recall) and 7 (word recognition) of ADAS-Cog questionnaire was summed to get a short term memory assessment. The score for Question 1 was calculated as the mean number of words not recalled over the trials for which data was available. If data for all three trials was missing, or if the score for Question 7 was missing then the short term memory score will also be set to missing. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value a t Week 0. Estimated value was calculated by Active treatment minus Placebo. The adjusted means were presented.
Timepoint [25] 0 0
Baseline (Week 0) and upto Week 48

Eligibility
Key inclusion criteria
A subject will be eligible for inclusion in this study only if all of the following
criteria apply:

- Male or female subject with a clinical diagnosis of probable Alzheimer's disease in
accordance with NINCDS-ADRDA criteria (Appendix 2).

(Note: National Institute of Neurological and Communicative Disorders and Stroke (NINCDS)
and Alzheimer's Disease and Related Disorders Association (ADRDA).)

- Subject has mild to moderate Alzheimer's disease as defined by a MMSE score 10 to 26
inclusive at Screening.

- Hachinski Ischemia Score = 4 at Screening (See Appendix 3).

- Age =50 and =90 years.

- At least 6 months of ongoing acetylcholinesterase inhibitor therapy for Alzheimer's
disease, with stable dosing for at least the last 2 months (and with no intent to
change for the duration of the study).

- Current use of medication is in accordance with the criteria listed in Table 2
(Permitted Medications, Section 8.1).

- Female subjects must be post-menopausal (i.e. >1 year without menstrual period),
surgically sterile, or agree to use adequate method of contraception (Appendix 4) for
the duration of the study. Female subjects who are pre-menopausal or who have been
post-menopausal for <1 year must undertake pregnancy testing (urine test) at Visit 1,
which must be negative.

- Brain CT or MRI scan performed within the past 12 months or at Screening, showing no
evidence of any other potential cause of dementia other than Alzheimer's disease.

(Note: Questionable CT or MRI scans should be discussed with the medical monitor, using
central imaging guidelines.)

- Neurological exam without focal changes (excluding changes attributable to AD or
peripheral trauma).

- Subject has the ability to comply with procedures for cognitive and other testing.

- Subject lives with (or has substantial periods of contact with) a regular 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.

(Note: A non-cohabiting caregiver must spend sufficient time with the subject so that, in
the opinion of the Investigator, the caregiver can reliably assess cognitive function,
activities and behavior, and report on the subject's compliance and health. As caregiver
time spent with a potential subject is anticipated to be highly variable across countries
and cultures, GSK will consider a variety of different measures by which this stipulation
may be met, and GSK should be consulted if adequacy of a caregiver situation is in doubt.
However, as guidance, the ability for a caregiver to meet his/her expected responsibilities
for this study would normally be possible when the caregiver spends no less than 10 hours
per week with the subject, divided over multiple days.)

- Subject 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, full written informed consent on behalf of the subject has been
provided by a legally acceptable representative.

(Note: Consent by legally acceptable representative is allowed where this is in accordance
with local laws, regulations and ethics committee policy.)

- Caregiver has provided full written informed consent on his/her own behalf prior to
the performance of any protocol-specified procedure.

- Subjects considered for enrolment must have a QTc (either QTc B (Bazett's correction)
or QTc F (Fridericia's correction)) <450msec at Visit 1, with the exception of
subjects with bundle branch block (for whom either QTc B or QTc F must be <480msec).

(Note: For the purposes of these criteria, QTc B is defined as (QT interval [msec]) /
(square root of RR interval [seconds]); and QTc F is defined as (QT interval [msec]) /
(cube root of RR interval [seconds]).)
Minimum age
50 Years
Maximum age
90 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
A subject will not be eligible for inclusion in this study if any of the following criteria
apply:

- Diagnosis of possible, probable, or definite vascular dementia in accordance with
NINDS-AIREN criteria (Appendix 5).

(Note: National Institute of Neurological Disorders and Stroke (NINDS) and Association
Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN).)

- History or evidence of any other CNS disorder that could be interpreted as a cause of
dementia: e.g. cerebrovascular disease (stroke, hemorrhage), structural abnormality,
epilepsy, infectious or inflammatory/demyelinating CNS conditions, Parkinson's
disease.

- Evidence of the following disorders: current vitamin B12 deficiency, positive syphilis
serology, or active thyroid dysfunction (particularly that suggestive of
hypothyroidism), including abnormally high or low serum levels of thyroid stimulating
hormone (TSH), that are clinically significant in the opinion of the investigator.

(Note: Testing is required for each parameter only when no result is available from
previous 12 months.)

- History of Type 1 diabetes mellitus or secondary diabetes mellitus.

- Type 2 diabetes mellitus where the subject is being treated with insulin, a PPAR?
agonist, or an insulin secretagogue (e.g. a sulfonylurea or glitinide).

- Any patient with an HbA1c =8.5%. (See Section 6.3.8.4 for Safety Measures for Enrolled
Subjects with Type 2 Diabetes Mellitus.)

- History or clinical/investigational evidence of congestive heart failure defined by
the New York Heart Association criteria (Class I to IV cardiac status; Appendix 6).

- History of 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 of significant psychiatric illness such as schizophrenia or bipolar affective
disorder that in the opinion of the Investigator would interfere with participation in
the study, major depressive disorder (according to DSM-IV) in the past year, or
current active depression requiring initiation of treatment.

(Note: If not currently treated, but active depression is suspected, the Cornell Scale for
Depression in Dementia (CSDD, Appendix 7) can be used by the Investigator as a guide for
deciding whether a prospective subject requires treatment. If the subject has a CSDD score
>7, the Investigator should decide if the subject has depression in need of prescribed
medication, and a CSDD >12 is considered a strong indicator that treatment is needed.
Subjects will be allowed to re-screen after their depression has been adequately managed
for >3 months.)

- History or presence of gastro-intestinal, hepatic, or renal disease or other condition
known to interfere with the absorption, distribution, metabolism, or excretion of
drugs, or any other clinically relevant abnormality, medical or psychiatric condition,
which, in the opinion of the Investigator, makes the subject unsuitable for inclusion
in the study.

- Clinically significant peripheral edema at the time of screening.

- Current or recent drug or alcohol abuse or dependence (defined by DSM-IV criteria for
substance-related disorders), or recent or remote history of the same if that could be
a contributing factor to the dementia.

- Systolic blood pressure >165 or <90 mmHg or diastolic blood pressure >95 or <60 mmHg
at the time of screening.

- Clinically significant anemia (i.e. hemoglobin <11 g/dL for males or <10 g/dL for
females) or presence of hemoglobinopathies which would prevent accurate assessment of
HbA1c.

- Abnormal kidney function tests (>1.5 times the upper limit of normal (ULN)).

- ALT, AST, or alkaline phosphatase values >2.5 times the ULN, total bilirubin values
>1.5 times the ULN, or history of severe hepatobiliary disease (e.g. hepatitis B or C,
or cirrhosis, Child-Pugh Class B/C).

(Note: For subjects with a diagnosis of Gilberts Syndrome and an isolated increase in total
bilirubin >1.5 ULN, fractionation should be performed. If all of the following conditions
are met, the patient may enter or remain in the study, even if total bilirubin >1.5 ULN:

- an elevated unconjugated (indirect) bilirubin;

- the percentage of direct bilirubin <35%;

- ALT, AST, and alkaline phosphatase <2.5 ULN if subject is in screening (<2.0 ULN for
Canadian subjects only), or =3 ULN if subject is already randomized into the study)

- History of a bone marrow transplant.

- Subject is unable (with assistance, if appropriate) to take study medication as
prescribed throughout the study or is at risk of non-compliance with study medication
or procedures.

- Subject is an immediate family member or employee of the participating Investigator,
of any of the participating site staff, or of GSK.

- In France, a subject is neither affiliated with nor a beneficiary of a social security
category.

- The French subject has participated in any study using an investigational drug during
the previous 30 days or 5 half-lives (whichever is longer).

- Cognitive tasks prescribed for cognitive rehabilitation and performed under medical
supervision are prohibited for 6 months prior to Screening, as well as for the
duration of the study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC,WA
Recruitment hospital [1] 0 0
GSK Investigational Site - Hornsby
Recruitment hospital [2] 0 0
GSK Investigational Site - Randwick
Recruitment hospital [3] 0 0
GSK Investigational Site - Auchenflower
Recruitment hospital [4] 0 0
GSK Investigational Site - Chermside
Recruitment hospital [5] 0 0
GSK Investigational Site - Kippa Ring
Recruitment hospital [6] 0 0
GSK Investigational Site - Adelaide
Recruitment hospital [7] 0 0
GSK Investigational Site - Woodville
Recruitment hospital [8] 0 0
GSK Investigational Site - Cheltenham
Recruitment hospital [9] 0 0
GSK Investigational Site - Heidelberg West
Recruitment hospital [10] 0 0
GSK Investigational Site - Kew
Recruitment hospital [11] 0 0
GSK Investigational Site - Nedlands
Recruitment postcode(s) [1] 0 0
2077 - Hornsby
Recruitment postcode(s) [2] 0 0
2031 - Randwick
Recruitment postcode(s) [3] 0 0
4066 - Auchenflower
Recruitment postcode(s) [4] 0 0
4032 - Chermside
Recruitment postcode(s) [5] 0 0
4021 - Kippa Ring
Recruitment postcode(s) [6] 0 0
5000 - Adelaide
Recruitment postcode(s) [7] 0 0
5011 - Woodville
Recruitment postcode(s) [8] 0 0
3192 - Cheltenham
Recruitment postcode(s) [9] 0 0
3084 - Heidelberg West
Recruitment postcode(s) [10] 0 0
3101 - Kew
Recruitment postcode(s) [11] 0 0
6009 - Nedlands
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
Arkansas
Country [3] 0 0
United States of America
State/province [3] 0 0
California
Country [4] 0 0
United States of America
State/province [4] 0 0
Connecticut
Country [5] 0 0
United States of America
State/province [5] 0 0
Florida
Country [6] 0 0
United States of America
State/province [6] 0 0
Georgia
Country [7] 0 0
United States of America
State/province [7] 0 0
Illinois
Country [8] 0 0
United States of America
State/province [8] 0 0
Massachusetts
Country [9] 0 0
United States of America
State/province [9] 0 0
New Jersey
Country [10] 0 0
United States of America
State/province [10] 0 0
New York
Country [11] 0 0
United States of America
State/province [11] 0 0
North Carolina
Country [12] 0 0
United States of America
State/province [12] 0 0
Ohio
Country [13] 0 0
United States of America
State/province [13] 0 0
Oklahoma
Country [14] 0 0
United States of America
State/province [14] 0 0
Pennsylvania
Country [15] 0 0
United States of America
State/province [15] 0 0
Rhode Island
Country [16] 0 0
United States of America
State/province [16] 0 0
South Carolina
Country [17] 0 0
United States of America
State/province [17] 0 0
Texas
Country [18] 0 0
United States of America
State/province [18] 0 0
Utah
Country [19] 0 0
United States of America
State/province [19] 0 0
Virginia
Country [20] 0 0
United States of America
State/province [20] 0 0
Washington
Country [21] 0 0
United States of America
State/province [21] 0 0
Wisconsin
Country [22] 0 0
Belgium
State/province [22] 0 0
Bruxelles
Country [23] 0 0
Belgium
State/province [23] 0 0
Kortrijk
Country [24] 0 0
Belgium
State/province [24] 0 0
Leuven
Country [25] 0 0
Belgium
State/province [25] 0 0
Woluwe-Saint-Lambert
Country [26] 0 0
Bulgaria
State/province [26] 0 0
Sofia
Country [27] 0 0
Bulgaria
State/province [27] 0 0
Varna
Country [28] 0 0
Canada
State/province [28] 0 0
British Columbia
Country [29] 0 0
Canada
State/province [29] 0 0
New Brunswick
Country [30] 0 0
Canada
State/province [30] 0 0
Nova Scotia
Country [31] 0 0
Canada
State/province [31] 0 0
Ontario
Country [32] 0 0
Canada
State/province [32] 0 0
Quebec
Country [33] 0 0
Canada
State/province [33] 0 0
Québec
Country [34] 0 0
Czechia
State/province [34] 0 0
Olomouc
Country [35] 0 0
Czechia
State/province [35] 0 0
Praha 10
Country [36] 0 0
Czechia
State/province [36] 0 0
Praha 8
Country [37] 0 0
Czechia
State/province [37] 0 0
Trutnov
Country [38] 0 0
Finland
State/province [38] 0 0
Helsinki
Country [39] 0 0
Finland
State/province [39] 0 0
Joensuu
Country [40] 0 0
Finland
State/province [40] 0 0
Kuopio
Country [41] 0 0
France
State/province [41] 0 0
Bordeaux
Country [42] 0 0
France
State/province [42] 0 0
La Chapelle sur Erdre
Country [43] 0 0
France
State/province [43] 0 0
La Seyne sur Mer
Country [44] 0 0
France
State/province [44] 0 0
Lille
Country [45] 0 0
France
State/province [45] 0 0
Limoges
Country [46] 0 0
France
State/province [46] 0 0
Metz
Country [47] 0 0
France
State/province [47] 0 0
Nantes
Country [48] 0 0
France
State/province [48] 0 0
Paris
Country [49] 0 0
France
State/province [49] 0 0
Sautron
Country [50] 0 0
France
State/province [50] 0 0
Toulon
Country [51] 0 0
France
State/province [51] 0 0
Toulouse
Country [52] 0 0
France
State/province [52] 0 0
Valence
Country [53] 0 0
Germany
State/province [53] 0 0
Baden-Wuerttemberg
Country [54] 0 0
Germany
State/province [54] 0 0
Bayern
Country [55] 0 0
Germany
State/province [55] 0 0
Brandenburg
Country [56] 0 0
Germany
State/province [56] 0 0
Hessen
Country [57] 0 0
Germany
State/province [57] 0 0
Sachsen
Country [58] 0 0
Germany
State/province [58] 0 0
Thueringen
Country [59] 0 0
Germany
State/province [59] 0 0
Berlin
Country [60] 0 0
Hong Kong
State/province [60] 0 0
Hong Kong
Country [61] 0 0
Hong Kong
State/province [61] 0 0
Shatin
Country [62] 0 0
Korea, Republic of
State/province [62] 0 0
Seongnam-si,
Country [63] 0 0
Korea, Republic of
State/province [63] 0 0
Seoul
Country [64] 0 0
Malaysia
State/province [64] 0 0
Bandar Tun Razak, Cheras
Country [65] 0 0
Malaysia
State/province [65] 0 0
Ipoh
Country [66] 0 0
Malaysia
State/province [66] 0 0
Kelantan
Country [67] 0 0
Netherlands
State/province [67] 0 0
Alkmaar
Country [68] 0 0
Netherlands
State/province [68] 0 0
Blaricum
Country [69] 0 0
Netherlands
State/province [69] 0 0
Den Bosch
Country [70] 0 0
Netherlands
State/province [70] 0 0
Den Haag
Country [71] 0 0
Netherlands
State/province [71] 0 0
Hengelo
Country [72] 0 0
Netherlands
State/province [72] 0 0
Hilversum
Country [73] 0 0
Philippines
State/province [73] 0 0
Manila
Country [74] 0 0
Philippines
State/province [74] 0 0
Pasig City
Country [75] 0 0
Poland
State/province [75] 0 0
Bydgoszcz
Country [76] 0 0
Poland
State/province [76] 0 0
Krakow
Country [77] 0 0
Poland
State/province [77] 0 0
Torun
Country [78] 0 0
Poland
State/province [78] 0 0
Warsaw
Country [79] 0 0
Singapore
State/province [79] 0 0
Singapore
Country [80] 0 0
Slovakia
State/province [80] 0 0
Bratislava
Country [81] 0 0
Slovakia
State/province [81] 0 0
Kosice
Country [82] 0 0
Slovenia
State/province [82] 0 0
Ljubljana
Country [83] 0 0
Slovenia
State/province [83] 0 0
Ĺ empeter
Country [84] 0 0
South Africa
State/province [84] 0 0
Loeventstein
Country [85] 0 0
South Africa
State/province [85] 0 0
Oakdale
Country [86] 0 0
South Africa
State/province [86] 0 0
Richards Bay
Country [87] 0 0
South Africa
State/province [87] 0 0
Rosebank
Country [88] 0 0
South Africa
State/province [88] 0 0
Somerset West
Country [89] 0 0
South Africa
State/province [89] 0 0
Waverley, Bloemfontein
Country [90] 0 0
South Africa
State/province [90] 0 0
Willows, X14, Pretoria
Country [91] 0 0
Spain
State/province [91] 0 0
Baracaldo/Vizcaya
Country [92] 0 0
Spain
State/province [92] 0 0
Barcelona
Country [93] 0 0
Spain
State/province [93] 0 0
Palma de Mallorca
Country [94] 0 0
Spain
State/province [94] 0 0
Tarrasa, Barcelona
Country [95] 0 0
Sweden
State/province [95] 0 0
Falköping
Country [96] 0 0
Sweden
State/province [96] 0 0
Jönköping
Country [97] 0 0
Sweden
State/province [97] 0 0
Kalix
Country [98] 0 0
Sweden
State/province [98] 0 0
Mölndal
Country [99] 0 0
Sweden
State/province [99] 0 0
Sundsvall
Country [100] 0 0
Sweden
State/province [100] 0 0
Umeå
Country [101] 0 0
United Kingdom
State/province [101] 0 0
Lancashire
Country [102] 0 0
United Kingdom
State/province [102] 0 0
Bradford
Country [103] 0 0
United Kingdom
State/province [103] 0 0
Liverpool
Country [104] 0 0
United Kingdom
State/province [104] 0 0
Stirling
Country [105] 0 0
United Kingdom
State/province [105] 0 0
West End, Southampton
Country [106] 0 0
United Kingdom
State/province [106] 0 0
West of Scotland Science Park, Glasgow

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
GlaxoSmithKline
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Rosiglitazone (RSG) has been tested in clinical studies and is approved by the FDA as a
treatment for type II diabetes mellitus, a disease that occurs when the body is unable to
effectively use glucose. RSG XR, the investigational drug used in this study, is an
extended-release form of RSG.

This study tests whether RSG XR safely provides clinical benefit to people with mild to
moderate Alzheimer's disease (AD) when combined with one of the currently approved AD
medications, Aricept®, Razadyne® or Exelon®. RSG XR is a new approach to AD therapy and this
study tests a new way to treat AD by testing whether one's genetic makeup affects the
response to the study drug. Clinical data suggesting that RSG may benefit AD patients was
first seen in a small study performed at the University of Washington and then from a larger
GSK study conducted in Europe and New Zealand. In the first study, subjects receiving RSG
once daily for 6 months scored significantly better on 3 tests of memory and thought than
those who did not receive RSG. In the GSK study, those that appeared to benefit most from
treatment with RSG XR had a specific genetic pattern. They did not have the gene that caused
them to produce the protein apolipoprotein E e4 (APOE e4). Subjects who have the APOE e4 gene
may have two copies, one from each parent, or they may have only one APOE e4 gene meaning
that they inherited either the APOE e2 or APOE e3 version of the gene, instead of APOE e4,
from one of their parents. Subjects with one copy of the APOE e4 gene remained at their same
level of thinking ability while those with two copies of the APOE e4 gene, continued to
worsen during the 6-month treatment. The current study will more directly test the
effectiveness or RSG XR on people who either have or lack the APOE e4 gene.
Trial website
https://clinicaltrials.gov/show/NCT00348140
Trial related presentations / publications
Harrington C, Sawchak S, Chiang C, Davies J, Donovan C, Saunders AM, Irizarry M, Jeter B, Zvartau-Hind M, van Dyck CH, Gold M. Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer's disease: two phase 3 studies. Curr Alzheimer Res. 2011 Aug;8(5):592-606.
Public notes

Contacts
Principal investigator
Name 0 0
GSK Clinical Trials
Address 0 0
GlaxoSmithKline
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries