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

Phase 2

Completed

Conditions: Alzheimer's Disease

Interventions: Drug: Rosiglitazone
Other: Placebo

Registration Number: NCT00265148

Lead Sponsor: GlaxoSmithKline

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).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 80

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Rosiglitazone	Rosiglitazone	4 mg once a day for 1 month increasing to 8 mg once a day (Extended Released Tablets)
Placebo	Placebo	Placebo dummy to match

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.