Trial Outcomes & Findings for Rosiglitazone (Extended Release Tablets) As Adjunctive Therapy In Subjects With Mild To Moderate Alzheimer's Disease (NCT NCT00348140)

A total of 1485 participants with Alzheimer's disease (AD) who were being treated with an approved Acetylcholinesterase inhibitor (AChEI) were randomized in the study and stratified by Apolipoprotein E gene (APOE) ε4 allele status. Total of 1468 were included in safety population and 1429 in the intent-to-treat population (ITT).

Rosiglitazone (Extended Release Tablets) As Adjunctive Therapy In Subjects With Mild To Moderate Alzheimer's Disease

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.