Rosiglitazone (Extended Release Tablets) As Adjunctive Therapy In Subjects With Mild To Moderate Alzheimer's Disease
Condition: Alzheimer's Disease
MeSH terms: Alzheimer Disease
Intervention: Rosiglitazone Extended Release 2mg; Rosiglitazone Extended Release 8mg; Placebo
Intervention description: Rosiglitazone Extended Release 2mg OD; Rosiglitazone Extended Release 8mg OD; Placebo
Intervention MeSH terms: Rosiglitazone
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 1468.0
Sex: All
Minimum age: 50 Years
Maximum age: 90 Years
Healthy volunteers: No
Keywords: adjunctive therapy; moderate; Alzheimer's disease; apolipoprotein E; mild; rosiglitazone; cognition

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 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.
    

Eligibility 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 (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]).)

        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 (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.