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

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

Population: 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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Population: 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.

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

Population: 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.

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])

Population: All subjects population.

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

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

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

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

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

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

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

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

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

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

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

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

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

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