Rosiglitazone (Extended Release Tablets) As Adjunctive Therapy For Subjects With Mild To Moderate Alzheimer's Disease
- Conditions
- Alzheimer's Disease
- Interventions
- Drug: Rosiglitazone Extended Release 2mgDrug: Rosiglitazone Extended Release 8mgOther: PlaceboOther: Donepezil
- Registration Number
- NCT00348309
- Lead Sponsor
- GlaxoSmithKline
- 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 the currently approved AD medication, Aricept (donepezil). 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 their 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.
- Detailed Description
A 54-week, double-blind, randomized, placebo-controlled, parallel-group study to investigate the effects of rosiglitazone (extended release tablets) as adjunctive therapy to donepezil on cognition and overall clinical response in APOE e4-stratified subjects with mild to moderate Alzheimer's disease (REFLECT-2)
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 1496
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm 1 Rosiglitazone Extended Release 2mg Rosiglitazone Extended Release 2mg OD Arm 1 Donepezil Rosiglitazone Extended Release 2mg OD Arm 2 Rosiglitazone Extended Release 8mg Rosiglitazone Extended Release 8mg OD Arm 2 Donepezil Rosiglitazone Extended Release 8mg OD Arm 3 Placebo Placebo Arm 3 Donepezil Placebo
- Primary Outcome Measures
Name Time Method Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score at Week 48 Baseline (Week 0) and Week 48 ADAS is a performance-based test that measures specific cognitive and behavioral dysfunctions in participants with Alzheimer's Disease. The cognitive subscale of the ADAS (ADAS-Cog) comprises 11 items that are summed to a total score ranging from 0 to 70, with lower scores indicating less severe impairment. Change from baseline is calculated as Week 48 value minus the baseline value. APOE4 negative, All except E4/E4's: comprised of APOE4 negative and E4 heterozygote and full population was analyzed for this outcome measure. A hierarchical testing procedure was used to control for the two rosiglitazone dose groups and the genetic subgroups. Least square mean is entered for adjusted mean.
Change From Baseline in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) at Week 48 for APOE E4 Baseline (Week 0) and Week 48 CDR-SB is a semi-structured interview of participants and their caregivers. Participant's cognitive status is rated across 6 domains of functioning, including memory, orientation, judgment/problem solving, community affairs, home/hobbies, and personal care. Severity score assigned for each of 6 domains; Total score (SB) ranges from 0 to 18. Higher scores indicate greater disease severity. Change from baseline is calculated as Week 48 value minus the baseline value. APOE4 negative, All except E4/E4's: comprised of APOE4 negative and E4 heterozygote and full population was analyzed for this outcome measure. A hierarchical testing procedure was used to control for the two rosiglitazone dose groups and the genetic subgroups.
- Secondary Outcome Measures
Name Time Method Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 48 Baseline (Week 0) and Week 48 Blood samples of participants were collected for HbA1c assessment. HbA1c is a form of hemoglobin that is measured primarily to identify the average plasma glucose concentration over a 2- to 3-month period. Change from Baseline in HbA1c was calculated as the value at Week 48 minus the value at Baseline.
Change From Baseline in Disability Assessment for Dementia Scale (DAD) Total Score Baseline (Week 0), Week 8, 16, 24 and 48 The DAD measures instrumental and basic activities of daily living in participants with Alzheimer's Disease (AD). This scale assesses 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. The scale includes 23 items relating to instrumental activities of daily living and 17 items relating to basic self-care. Each item can be scored as 1 = yes, 0 = no, non applicable = NA. Total score was obtained by adding the rating for each question and converting this total score out of 100. The total score ranged from 0 to 100, where higher score indicated better function and lower score indicated greater severity of symptoms; a positive change from baseline indicated an improvement. Change from baseline is calculated as endpoint value minus the baseline value.
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score Baseline (Week 0), Week 8, 16, 24 and 48 The NPI is a questionnaire that quantifies behavioral changes in dementia. For each of 12 behavioral domains there are 4 scores: Frequency (scale:1=occasionally to 4=very frequently), Severity (scale:1=Mild to 3=Severe), Total (frequency x severity), Caregiver distress (scale: 0=not at all distressing to 5=extremely distressing).The NPI Psychosis Subscale consists of the two domains of Delusions and Hallucinations, calculated by adding the Individual Item Scores, to yield a possible total score of 0 to 24. Lower score=less severity. Change from baseline is calculated as endpoint value minus the baseline value.
Change From Screening in Mini Mental State Examination (MMSE) Total Score Screening (Week -4) and Week 48 The MMSE consists of 11 tests of orientation, memory (recent and immediate), concentration, language and praxis. The scale was completed by the investigator, based on the performance of the participant, and took approximately 5 to 10 minutes to administer. The scores from 11 tests were combined to obtain the total score. The total scores range from 0 to 30, with lower scores indicating greater cognitive impairment and higher score indicating better outcome; a positive change from screening indicated an improvement. The total MMSE score for participants at screening was between 10 and 26, inclusive, in order to be eligible to participate in the trial. Change from screening is calculated as endpoint value minus the screening value.
Change From Baseline in the Domains of the Resource Utilization in Dementia Scale (RUD) Baseline (Week 0), Week 12, 24, 36 and 48 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.
Change From Baseline in European Quality of Life-5 Dimensions Proxy Version (EQ-5D Proxy) Scale Total Score Assessed by Thermometer (Visual Analog Scale [VAS]) and Utility Baseline (Week 0), Week 12, 36 and 48 The EQ-5D Proxy is a two part scale that evaluated the participant's health status via Thermometer and Utility scores. The Thermometer score was the caregiver's rating of the participant's overall health status on a VAS (0 \["worst possible status"\] to 100 \["best imaginable status"\]). The Utility score was a caregiver rating of health status on dimensions of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression\] where '1' indicated better health state (no problems); '3' indicated worst health state ("confined to bed"). Total possible score was the sum of individual items, ranged from 5 to 15; lower score indicated a better health state and higher score indicated greater severity of symptoms. A positive change from baseline indicated improvement in the Thermometer score and a negative change from baseline indicated improvement in the Utility score. Change from baseline is calculated as endpoint value minus the baseline value.
Change From Baseline in ADAS-Cog Total Score for Observed Cases at Weeks 8, 16, 24, 36 and 48 Baseline (Week 0), Week 8, 16, 24, 36 and 48 ADAS is a performance-based test that measures specific cognitive and behavioral dysfunctions in patients with Alzheimer's Disease. The cognitive subscale of the ADAS (ADAS-Cog) comprises 11 items that are summed to a total score ranging from 0 to 70, with lower scores indicating less severe impairment. Change from baseline is calculated as endpoint value minus the baseline value.
Change From Baseline in CDR-SB Score for Observed Cases at Weeks 12, 24, 36 and 48 Baseline (Week 0), Week 12, 24, 36 and 48 CDR-SB is a semi-structured interview of participants and their caregivers. Participant's cognitive status is rated across 6 domains of functioning, including memory, orientation, judgment/problem solving, community affairs, home/hobbies, and personal care. Severity score assigned for each of 6 domains; Total score (SB) ranges from 0 to 18. Higher scores indicate greater disease severity. Change from baseline is calculated as endpoint value minus the baseline value.
Change in ADAS-Cog Total Score for Observed Cases at Week 54 Compared to Week 48 Week 48 and 54 ADAS is a performance-based test that measures specific cognitive and behavioral dysfunctions in patients with Alzheimer's Disease. The cognitive subscale of the ADAS (ADAS-Cog) comprises 11 items that are summed to a total score ranging from 0 to 70, with lower scores indicating less severe impairment. Change was calculated as endpoint value (Week 54) minus Week 48 value.
Change in CDR-SB Total Score at Week 54 Compared to Week 48 Week 48 and 54 CDR-SB is a semi-structured interview of participants and their caregivers. Participant's cognitive status is rated across 6 domains of functioning, including memory, orientation, judgment/problem solving, community affairs, home/hobbies, and personal care. Severity score assigned for each of 6 domains; Total score (SB) ranges from 0 to 18. Higher scores indicate greater disease severity. Change was calculated as endpoint value (Week 54) minus Week 48 value.
Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Up to Week 54 An adverse event (AE) was defined as any untoward medical occurrence that occurred during the course of the trial after study treatment had started. An adverse event was therefore any unfavourable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose results in death, are life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, and congenital anomaly/birth defect. The data was reported for prospective period.
Mean Change From Baseline in Systolic and Diastolic Blood Pressure (BP) Baseline (Week 0), Week 4, 8, 12, 16, 24, 36, 48 and 56 The plethysmographic method was used to measure BP throughout the study. Change in Systolic and Diastolic BP was calculated as endpoint value minus the baseline value.
Mean Change From Baseline in Heart Rate Baseline (Week 0), Week 4, 8, 12, 16, 24, 36, 48 and 56 Mean Change From Baseline in heart rate was calculated as endpoint value minus the baseline value.
Change From Baseline in Hemoglobin Values Baseline (Week 0), Week 4, 16, 36 and 48 Blood samples of participants were collected for Hemoglobin. Change from baseline in Hemoglobin was calculated as endpoint value minus the baseline value.
Mean Change From Baseline in Weight Baseline (Week 0), Week 4, 8, 12, 16, 24, 36, 48 and 56 Body weight was measured at all visits, without shoes and wearing light clothing. Mean Change From Baseline in Weight was calculated as endpoint value minus the baseline value.
Change From Baseline in Hematocrit Values Baseline (Week 0), Week 4, 8, 12, 16, 36 and 48 Blood samples of participants were collected for Hematocrit . Change from baseline in Hematocrit was calculated as endpoint value minus the baseline value.
Mean Change From Baseline in Short Term Memory Assessment Score Baseline (Week 0), Week 8, 16, 24, 36, 48 and 56 Short term memory assessment score was based on ADAS-Cog questionnaire (Question 1 and 7). ADAS is a performance-based test that measures specific cognitive and behavioral dysfunctions in participants with AD. Question 1 (Word Recall) and Question 7 (Word Recognition) of the ADAS-Cog questionnaire were summed to get a short term memory assessment score. Word recall task consist of the participants score was the mean number of words not recalled on three trials (maximum score 10) and word recognition task, to score this item the number of incorrect responses was counted (maximum error score was 12). The total score ranged from 0 to 22 with 0 indicating absence of symptoms and higher scores indicating greater dysfunction; a negative change from baseline indicated improvement. Change from Baseline in short term memory assessment was calculated as endpoint value minus the baseline value.
Change From Baseline in HbA1c at Week 12, Week 24 and Week 36 Baseline (Week 0) and Week 12, 24 and 36 Blood samples of participants were collected for HbA1c assessment. HbA1c is a form of hemoglobin that is measured primarily to identify the average plasma glucose concentration over a 2- to 3-month period. Change from Baseline in HbA1c was calculated as the value at time point minus the value at Baseline.
Number of Participants With Laboratory Potential Clinical Concern (PCC) Values Baseline (Week 0), Week 4, 8, 12, 16, 24, 36, 48 and 56 Only those parameters for which at least one value of clinical concern (CC) was reported are summarized. Pre-defined limits of potential clinical concern (CC Low \[relative to the lower limit of normal\], CC High \[relative to the upper limit of normal\]) are: Hematocrit 0.8, 1.2; hemoglobin 10-11, 16.5-18; Red blood corpuscles(RBC) 0.8, 1.2; mean corpuscular volume (MCV) 0.8, 1.2; mean corpuscular hemoglobin (MCH) 0.8, 1.2; White blood corpuscles (WBC) 3- absolute value, 15-absolute value, Red Cell Distribution Width (RDW) 0.8, 1.2; Lymphocytes 0.75, 1.5; Monocytes NA, 2; Eosinophil NA, 2; platelet count 100-absolute, 500-absoulte; segmented neutrophil (SN) 0.75, 1.5 and Total Neutrophil (TN) 0.75, 1.5.
Change From Baseline in Alzheimer's Carer Quality of Life Instrument (ACQLI) Total Score Baseline (Week 0), Week 12, 36 and 48 The ACQLI was an assessment of caregiver quality of life. This instrument consists of 30 questions exploring various aspects of carer's quality of life. Each of the questions had a two point response and the 30 questions were summed to provide a total score. Items are assumed to be unidimensional (i.e., represent a single variable) and are scored 0/1 (false/true) before summation into a total score with a 0-30 range. The total score ranged from 0 to 30, where 0 indicated absence of symptoms and higher score indicated worse outcomes; a negative change from baseline indicated improvement. Change from baseline was calculated as endpoint value minus the baseline value.
Trial Locations
- Locations (1)
GSK Investigational Site
🇨🇭Zuerich, Switzerland