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

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)

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.