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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 1,468
- 试验地点
- 1
- 主要终点
- Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score at Week 48, as a Function of APOE ε4 Status in APOE4 Negatives Cohort
研究概览
简要总结
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.
详细描述
A 54-week, double-blind, randomized, 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 APOE e4-stratified subjects with mild to moderate Alzheimer's disease (REFLECT-3)
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 50 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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]).)
排除标准
- •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 PPARγ 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.
研究组 & 干预措施
Arm 1
Rosiglitazone Extended Release 2mg OD
干预措施: Rosiglitazone Extended Release 2mg (Drug)
Arm 2
Rosiglitazone Extended Release 8mg OD
干预措施: Rosiglitazone Extended Release 8mg (Drug)
Arm 3
Placebo
干预措施: Placebo (Other)
结局指标
主要结局
Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score at Week 48, as a Function of APOE ε4 Status in APOE4 Negatives Cohort
时间窗: Baseline (Week 0) and 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. 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.
Change From Baseline in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) Score at Week 48, as a Function of APOE ε4 Status in APOE4 Negatives Cohort
时间窗: Baseline (Week 0) and Week 48
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.
Change From Baseline in CDR-SB Score at Week 48, as a Function of APOE ε4 Status in All Except E4/E4s Cohort
时间窗: Baseline (Week 0) and Week 48
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.
Change From Baseline in CDR-SB Score at Week 48, as a Function of APOE ε4 Status in Full Population Cohort
时间窗: Baseline (Week 0) and Week 48
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.
Change From Baseline in ADAS-Cog Total Score at Week 48, as a Function of APOE ε4 Status in Full Population Cohort
时间窗: Baseline (Week 0) and 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. 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.
Change From Baseline in ADAS-Cog Total Score at Week 48, as a Function of APOE ε4 Status in All Except E4/E4s Cohort
时间窗: Baseline (Week 0) and 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. 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.
次要结局
- Change From Baseline in ADAS-Cog Total Score at Weeks 8, 16, 24 and 36(Baseline (Week 0) and Week 8, 16, 24, 36)
- Change From Baseline in Alzheimer's Carer's Quality of Life Instrument (ACQLI) Score(Baseline (Week 0) and Week 12, 36, 48)
- Change in ADAS-Cog Total Score for Observed Cases at Week 54 Compared to Week 48(Week 48 and Week 54)
- Change From Baseline in Disability Assessment for Dementia (DAD) Total Score(Baseline (Week 0) and Week 8, 16, 24, 48)
- Change in CDR-SB Total Score for Observed Cases at Week 54 Compared to Week 48(Week 48 and Week 54)
- Change From Baseline in Hematocrit(Baseline (Week 0) and Weeks 4, 16, 36, 48)
- Changes From Baseline in ECG Parameters- RR Interval, QT Interval, QTcB, QTcF, PR Interval and QRS Duration(Baseline (Week 0) and Weeks 4, 8, 16, 24, 36, 48, 54)
- Change From Baseline in CDR-SB Score at Weeks 12, 24 and 36(Baseline (Week 0) and Week 12, 24, 36)
- Change From Screening in Mini Mental State Examination (MMSE) Total Score(Screening (Week -4) and Week 48)
- Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score(Baseline (Week 0) and Week 8, 16, 24, 48)
- Change From Baseline in Domains of the Resource Utilization in Dementia Scale (RUD)- Q1 and Q2 Caregiver Hours(Baseline (Week 0) and Week 12, 24, 36, 48)
- Change From Baseline in EQ-5D Scale Total Score- Utility Score(Baseline (Week 0) and Week 12, 36, 48)
- Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 48(Baseline (Week 0) and Week 48)
- Number of Participants With Change From Baseline in Vital Signs of Clinical Concern at Any Time on Treatment- Weight(Upto Week 54)
- 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)(Upto Week 54)
- Change From Baseline in European Quality of Life -5 Dimensions (EQ-5D) Scale Total Score- Thermometer Score(Baseline (Week 0) and Week 12, 36, 48)
- Number of Participants With On-treatment Adverse Events (AEs), Serious Adverse Events (SAEs) and Severity of AEs(Upto Week 48)
- Number of Participants With Change From Baseline in Vital Signs of Clinical Concern at Any Time on Treatment- Heart Rate (HR)(Upto Week 54)
- Change From Baseline in Weight(Baseline (Week 0) and Weeks 4, 8, 12, 16, 24, 36, 48, 54)
- Any Time on Treatment Differences in Frequencies of Hematology Data Outside the Reference Range(Up to Week 48)
- Change From Baseline in Hemoglobin(Baseline (Week 0) and Weeks 4, 16, 36, 48)
- Any Time on Treatment Differences in Frequencies of Clinical Chemistry Data Outside the Reference Range(Upto Week 48)
- Changes From Baseline in Electrocardiogram (ECG) Parameters- HR(Baseline (Week 0) and Weeks 4, 8, 16, 24, 36, 48, 54)
- Change From Baseline in HbA1c up to Week 54(Baseline (Week 0) and Weeks 12, 24, 36, 48, 54)
- Change From Baseline in Short Term Memory Assessment(Baseline (Week 0) and upto Week 48)