Last updated: 11/04/2018 05:12:54
Rosiglitazone (extended release tablets) As Adjunctive Therapy For Subjects With Mild To Moderate Alzheimer’s DiseaseREFLECT-2
EudraCT ID
EU CT Number
Not applicable
Trial status
Study complete
Study complete
Trial overview
Official title: 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 ε4-stratified subjects with mild to moderate Alzheimer’s disease.
Trial description: 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.
Primary purpose:
Treatment
Trial design:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Allocation:
Randomized
Primary outcomes:
Change from baseline in Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-Cog) total score at Week 48
Timeframe: Baseline (Week 0) and Week 48
Change from baseline in Clinical Dementia Rating scale - Sum of Boxes (CDR-SB) at Week 48 for APOE E4
Timeframe: Baseline (Week 0) and Week 48
Secondary outcomes:
Change from baseline in Disability Assessment for Dementia Scale (DAD) total score
Timeframe: Baseline (Week 0), Week 8, 16, 24 and 48
Change from baseline in Neuropsychiatric Inventory (NPI) total score
Timeframe: Baseline (Week 0), Week 8, 16, 24 and 48
Change from screening in Mini Mental State Examination (MMSE) total score
Timeframe: Screening (Week -4) and Week 48
Change from baseline in the domains of the resource utilization in dementia scale (RUD)
Timeframe: Baseline (Week 0), Week 12, 24, 36 and 48
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
Timeframe: Baseline (Week 0), Week 12, 36 and 48
Change from baseline in ADAS-Cog total score for observed cases at weeks 8, 16, 24, 36 and 48
Timeframe: Baseline (Week 0), Week 8, 16, 24, 36 and 48
Change from baseline in CDR-SB score for observed cases at weeks 12, 24, 36 and 48
Timeframe: Baseline (Week 0), Week 12, 24, 36 and 48
Change in ADAS-Cog total score for observed cases at Week 54 compared to Week 48
Timeframe: Week 48 and 54
Change in CDR-SB total score at Week 54 compared to Week 48
Timeframe: Week 48 and 54
Change from baseline in Glycosylated hemoglobin (HbA1c) at Week 48
Timeframe: Baseline (Week 0) and Week 48
Number of Participants with Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Timeframe: Up to Week 54
Mean Change From Baseline in Systolic and Diastolic Blood Pressure (BP)
Timeframe: Baseline (Week 0), Week 4, 8, 12, 16, 24, 36, 48 and 56
Mean Change From Baseline in Heart rate
Timeframe: Baseline (Week 0), Week 4, 8, 12, 16, 24, 36, 48 and 56
Mean Change From Baseline in Weight
Timeframe: Baseline (Week 0), Week 4, 8, 12, 16, 24, 36, 48 and 56
Change from baseline in Hemoglobin values
Timeframe: Baseline (Week 0), Week 4, 16, 36 and 48
Change from baseline in Hematocrit values
Timeframe: Baseline (Week 0), Week 4, 8, 12, 16, 36 and 48
Mean change from Baseline in Short Term Memory Assessment score
Timeframe: Baseline (Week 0), Week 8, 16, 24, 36, 48 and 56
Change from baseline in HbA1c at Week 12, Week 24 and Week 36
Timeframe: Baseline (Week 0) and Week 12, 24 and 36
Number of participants with laboratory Potential Clinical Concern (PCC) values
Timeframe: Baseline (Week 0), Week 4, 8, 12, 16, 24, 36, 48 and 56
Change from baseline in Alzheimer’s Carer Quality of Life Instrument (ACQLI) total score
Timeframe: Baseline (Week 0), Week 12, 36 and 48
Interventions:
Enrollment:
1496
Primary completion date:
2009-28-01
Observational study model:
Not applicable
Time perspective:
Not applicable
Clinical publications:
Conn Harrington, Sharon Sawchak, Carl Chiang, John Davies, Carly Donovan, Ann Saunders, Michael Irrizary, Barbara Jeter, Marina Zvartau-Hind, Christopher van Dyke, Michael Gold. Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer's disease: Two phase 3 studies. [Curr Alzheimer Res]. 2011;8(5):592-584.
Conn Harrington, Sharon Sawchak, Carl Chiang, John Davies, Carly Donovan, Ann Saunders, Michael Irrizary, Barbara Jeter, Marina Zvartau-Hind, Christopher van Dyke, Michael Gold. Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer's disease: Two phase 3 studies. Curr Alzheimer Res. 2011;8(5):592-584.
Medical condition
Alzheimer's Disease
Product
rosiglitazone
Collaborators
Not applicable
Study date(s)
July 2006 to January 2009
Type
Interventional
Phase
Not applicable
Participation criteria
Sex
Female & Male
Age
50 - 90 years
Accepts healthy volunteers
No
- 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.
- 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.
Inclusion and exclusion criteria
Inclusion criteria:
- 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. (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.
- Age ≥50 and ≤90 years.
- At least 6 months of ongoing donepezil 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,).
- Female subjects must be post-menopausal (i.e. >1 year without menstrual period), surgically sterile, or agree to use adequate method of contraception 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]).)
Exclusion criteria:
- 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. (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 6.3.7.4 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;).
- 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) 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 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.
Trial location(s)
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Study documents
Clinical study report
Available language(s): English
Scientific result summary
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Results posted on ClinicalTrials.gov
Recruitment status
Study complete
Actual primary completion date
2009-28-01
Actual study completion date
2009-28-01
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.
Additional information about the trial
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