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Rosiglitazone (Extended Release Tablets) As Adjunctive Therapy For Subjects With Mild To Moderate Alzheimer's Disease (REFLECT-2)

This study has been completed.
Information provided by (Responsible Party):
GlaxoSmithKline Identifier:
First received: June 30, 2006
Last updated: August 8, 2013
Last verified: July 2013

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.

Condition Intervention Phase
Alzheimer's Disease
Drug: Rosiglitazone Extended Release 2mg
Drug: Rosiglitazone Extended Release 8mg
Other: Placebo
Other: Donepezil
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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.

Resource links provided by NLM:

Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Change from baseline in ADAS-Cog total score and CDR-Sum of Boxes score at Week 48, as a function of APOE e4 status. [ Time Frame: 48 Weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Assessments of changes in behaviorActivities of daily livingHealthcare resource utilizationSubject and caregiver quality of lifeExploratory pharmacogeneticsProteomicsTranscriptomics [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • Secondary endpoints include measures of:Cognition and function: MMSE, Neuropsychiatric Inventory (NPI), DAD. [ Time Frame: 48 Weeks ] [ Designated as safety issue: No ]
  • Health Outcomes: Resource Utilization in Dementia (RUD), European Quality of Life -5 Dimensions (EQ-5D), Alzheimer's Carer's Quality of Life Instrument (ACQLI). [ Time Frame: 48 Weeks ] [ Designated as safety issue: No ]

Enrollment: 1496
Study Start Date: July 2006
Study Completion Date: January 2009
Primary Completion Date: January 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1
Rosiglitazone Extended Release 2mg OD
Drug: Rosiglitazone Extended Release 2mg
Rosiglitazone Extended Release 2mg OD
Other: Donepezil
Donepezil (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).
Other Name: Aricept
Experimental: Arm 2
Rosiglitazone Extended Release 8mg OD
Drug: Rosiglitazone Extended Release 8mg
Rosiglitazone Extended Release 8mg OD
Other: Donepezil
Donepezil (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).
Other Name: Aricept
Placebo Comparator: Arm 3
Other: Placebo
Other: Donepezil
Donepezil (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).
Other Name: Aricept

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)

Ages Eligible for Study:   50 Years to 90 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

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 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00348309

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Sponsors and Collaborators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Responsible Party: GlaxoSmithKline Identifier: NCT00348309     History of Changes
Other Study ID Numbers: AVA102672 
Study First Received: June 30, 2006
Last Updated: August 8, 2013
Health Authority: Japan: Ministry of Health, Labor and Welfare
United States: Food and Drug Administration
Europe: European Medicines Agency

Keywords provided by GlaxoSmithKline:
apolipoprotein E
Alzheimer's disease
adjunctive therapy

Additional relevant MeSH terms:
Alzheimer Disease
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Hypoglycemic Agents
Physiological Effects of Drugs
Cholinesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Nootropic Agents processed this record on October 26, 2016