Study Of Rosiglitazone XR In Subjects With Mild-to-Moderate Alzheimers

Study Overview
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Brief Summary
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This is a Phase III, multicenter, open-label extension, single-group study in male and female outpatients with mild-to-moderate Alzheimer's disease (AD) who have completed AVA105640. All subjects will receive rosiglitazone extended-release (RSG XR) 4mg once daily for the first 4 weeks of the study followed by 8mg RSG XR. Subject participation will last until one of 5 conditions applies. After a 52-week open-label treatment phase, subjects will attend a final Follow-Up Visit 6 weeks after the end of treatment. The primary objective of this study is to evaluate the long-term safety and tolerability of RSG XR in subjects with mild-to-moderate AD who have completed AVA105640. The secondary objective of this study is to explore further the long-term efficacy of RSG XR in terms of cognitive function and overall clinical response as a function of apolipoprotein E (APOE) e4 allele status

Official Title
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An Open-label Extension to Study AVA105640, to Assess the Long-term Safety and Efficacy of Rosiglitazone (Extended Release Tablets) on Cognition in Subjects With Mild to Moderate Alzheimer's Disease.

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: Rosiglitazone XR


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male or female subject who has successfully completed Visit 8 of AVA105640 without safety/tolerability issues, where in the opinion of the subject /carer and of the investigator, it would be beneficial to receive RSG XR Female subjects able to bear children must agree to use an adequate method of contraception for the duration of the study for details of highly effective methods to avoid pregnancy). Female subjects who are pre-menopausal or who have been post-menopausal for <1 year must undertake pregnancy testing (urine test) £7 days before Visit 1, which must be negative Subject is willing to participate in the extension study and 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 (where this is in accordance with local laws, regulations and ethics committee policy) 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 Subject has the ability to comply with procedures for cognitive and other testing Caregiver has provided full written informed consent on his or her own behalf prior to the performance of any protocol-specified procedure Subjects considered for enrollment 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) In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category Post-menopause [Becker, 2001]: Menopause is the age associated with complete cessation of menstrual cycles, menses, and implies the loss of reproductive potential by ovarian failure. This typically occurs around age 50, although it may occur earlier. A practical definition accepts menopause after one year without menses with an appropriate clinical profile, e.g., age appropriate, >45 years, in the absence of hormone replacement therapy. In questionable cases, a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<140 pmol/L) is confirmatory (these levels are suggested guidelines and may need to be adjusted for specific laboratories/assays Females, who are on hormone replacement therapy (HRT), and whose menopausal status is in doubt, will be required to use a highly effective method to avoid pregnancy, as outlined in the protocol, if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw as detailed in the preceding paragraph; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a highly effective method to avoid pregnancy 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 behaviour, 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 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: Subject had a serious adverse experience or clinically significant laboratory abnormality during AVA105640, which in the opinion of the investigator could have been attributable to study medication, and which is ongoing at Visit 1 The subject is felt by the investigator to be unsuitable (on the basis of health, compliance, caregiver availability, or for any other reason) for inclusion in the study The subject experienced a significant cardiovascular event during AVA105640 (e.g. intervention, percutaneous coronary intervention, vascular surgery, acute coronary syndrome [non Q-wave myocardial infarction, Q-wave myocardial infarction, unstable angina] or significant arrhythmia), unless a thorough cardiovascular evaluation has been performed which confirms that the subject does not have congestive heart failure, and is clinically stable Clinical/investigational evidence of congestive heart failure defined by the New York Heart Association (NYHA) criteria (Class I to IV cardiac status) at the time of Visit 1 Clinically significant peripheral oedema at the time of Visit 1 Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase values >2.5 times the upper limit of normal (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) 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 In France, a subject has participated in any study using an investigational drug during the previous 30 days (except for participation in AVA105640)

Ages Eligible for Study
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Minimum Age: 51 Years
Maximum Age: 91 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>Rosiglitazone XR | Drug: Rosiglitazone XR<br>* experimental drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Any Adverse Events (AEs) and Severity of AEs | AE was defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The drug related-AEs of special interest (AESI) was reported. The severity of the AESI was categorized as mild, moderate and severe. Number of participants with AEs were reported for treatment duration of the study. | Up to Week 82 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serious AEs and Deaths | A serious adverse event is defined as any untoward medical occurrence that, at any dose results in death, life-threatening condition, requires hospitalization or prolongation of existing hospitalization, results in disability or incapacity, or a congenital anomaly or birth defect. The SAEs and deaths are reported from Visit 1 (W0) till end of the follow-up period (W110) | Up to Week 82 | 
| Percentage of Participants With AEs of Edema | Edema was considered as adverse event of special interest (AESI). The process for AESI selection was based on RSG's pharmacologic class and relevant AEs potentially associated with RSG. Percentage of participants reported with edema as AESI were reported. | Up to 82 Weeks | 
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP and DBP of participant were recorded in sitting posture as vital sign at each visit. The blood pressure (BP) values were identified as of potential clinical concern if the vales were out of the reference range (for SBP, 90 to 140 mmHg and DBP, 50 to 90 mmHg) or meet a change from Baseline criterion. The change from Baseline criterion for SBP, was increase from Baseline (high) if increased by more than or equal to (>=) 40 mmHg from Baseline; decrease from Baseline (low) if decreased by >= 30 mmHg from Baseline. For DBP, increase form Baseline (high) if increased by >= 30 mmHg from Baseline; decrease from Baseline (low) if decreased by >= 20 mmHg from Baseline. The Baseline assessments were referred to assessments at Visit 1 (W 0). Change from Baseline was measured as the blood pressure value recorded at specified visit minus the Baseline value. | Baseline (Visit 1, W0), W4, W8, W12, W16, W24, W36, W52, W64 and Follow-up (W82) | 
| Change From Baseline in Heart Rate (HR) | HR of participants was recorded as vital sign at each visit. The HR values were identified as of potential clinical concern if the vales were out of the reference range 50 to 100 beats per minute (BPM) or meet a change from Baseline criterion. The change from Baseline criterion was as, increase in HR (high) from Baseline if HR was increased by >= 30 bpm or decrease in HR (Low) from Baseline if HR was decreased by >= 30 bpm from Baseline. The Baseline assessments were referred to assessments at Visit 1 (W 0). Change from Baseline was measured as the HR at specified visit minus the Baseline value. | Baseline (Visit 1, W0), W4, W8, W12, W16, W24, W36, W52, W64 and Follow-up (W82) | 
| Number of Participants With Abnormal SBP and DBP at Any Time During Treatment Period | SBP and DBP of participant were recorded in sitting posture as vital sign at each visit. The blood pressure (BP) values were identified as of potential clinical concern if the vales were out of the reference range (for SBP, 90 to 140 mmHg and DBP, 50 to 90 mmHg) or meet a change from Baseline criterion. The change from Baseline criterion for SBP, was increase from Baseline (high) if increased by more than or equal to (>=) 40 mmHg from Baseline; decrease from Baseline (low) if decreased by >= 30 mmHg from Baseline. For DBP, increase form Baseline (high) if increased by >= 30 mmHg from Baseline; decrease from Baseline (low) if decreased by >= 20 mmHg from Baseline. The Baseline assessments were referred to assessments at Visit 1 (W 0). Change from Baseline was measured as the blood pressure value recorded at specified visit minus the Baseline value. | Up to 82 weeks | 
| Number of Participants With Abnormal HR at Any Time During Treatment Period | HR of participants was recorded as vital sign at each visit. The HR values were identified as of potential clinical concern if the vales were out of the reference range 50 to 100 beats per minute (BPM) or meet a change from Baseline criterion. The change from Baseline criterion was as, increase in HR (high) from Baseline if HR was increased by >= 30 bpm or decrease in HR (Low) from Baseline if HR was decreased by >= 30 bpm from Baseline. The Baseline assessments were referred to assessments at Visit 1 (W 0). Change from Baseline was measured as the HR at specified visit minus the Baseline value. Number of participants with abnormal HR at any time during treatment period were reported. | Up to 82 weeks | 
| Change From Baseline in Body Weight (BW) | BW of participants were recorded as vital sign at each visit. The BW were identified as of potential clinical concern if the vales were increased or decreased from Baseline by >=7%. The Baseline assessments were referred to assessments at Visit 1 (W0). Change from Baseline was measured as the BW at specified visit minus the Baseline value. | Baseline (Visit 1, W0), W4, W8, W12, W16, W24, W36, W52, W64 and Follow-up (W82) | 
| Number of Participants With Abnormal BW at Any Time During Treatment Period | BW of participants were recorded as vital sign at each visit. The BW were identified as of potential clinical concern if the vales were increased or decreased from Baseline by >=7%. The Baseline assessments were referred to assessments at Visit 1 (W0). Change from Baseline in BW was measured as the BW value at specified visit minus the Baseline BW value. Number of participants with abnormal BW at any time during treatment period were reported. | Baseline (Visit 1, W0) to W 52 | 
| Change From Baseline in Non-fasting Measures of Lipid Metabolism Including Total Cholesterol, High Density Lipoprotein, Low Density Lipoprotein and Triglycerides at Indicated Timepoints. | Non-fasting measures of lipid metabolism including cholesterol (TC), high density lipoprotein (HDL), low density lipoprotein (LDL), triglycerides (TG) were measured at Baseline (W0), W4, W16, W36, W52, Year 2 W24 and Follow-up. The Baseline assessments were referred to assessments at Visit 1 (W0). Change from Baseline was calculated as the value at the indicated visit minus the Baseline value. | Baseline (Visit 1, W0), W4, W16, W36, W52, W76, and W82 | 
| Number of Participants With Hematological Parameters of Potential Clinical Concern | The hematological parameters including eosinophils, lymphocytes, monocytes, platelet count, Segmented Neutrophils, total neutrophils, white blood cell (WBC), red blood cell (RBC) counts, hemoglobin, hematocrit count, mean corpuscle hemoglobin (MCH) and mean corpuscle volume (MCV) were analyzed as safety parameters. The number of participants with values outside the reference range (potential clinical concern ) at any time on treatment (ATOT) and follow-up period were reported. The treatment period was till W104 followed by 6 weeks of follow-up period till W110 of study. | Up to 82 weeks | 
| Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern | The clinical chemistry parameters including alanine amino transferase (ALT), aldolase, aspartate amino transferase (AST), blood urea nitrogen /creatinine (BUN/Creat) ratio, cholesterol (Chol), creatine kinase, creatinine, direct bilirubin, gamma glutamyl transferase (GGT), glucose, high density lipid (HDL), low density lipid (LDL), potassium, troponin 1, and urea were assessed as safety parameters. The number of participants with values outside the reference range (potential clinical concern ) at any time on treatment (ATOT) and follow-up period were reported. The treatment period was till W104 followed by 6 weeks of follow-up period till W110 of study. | Up to 82 weeks | 
| Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog) Total Score as a Function of Apolipoprotein E (APOE) 4 Status at W24 and W52 | The 11-item ADAS-cog was used to 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 ranged from 0 to 70 with higher scores indicating greater dysfunction. Baseline was referred to Visit 1 (W0)assessments. Change from Baseline was calculated as value at scheduled time point minus Baseline value. | Baseline (Visit 1, W0), W24 and W52 | 
| Mean Clinician Interview-Based Impression of Change Plus Caregiver Input (CIBIC+) Score as a Function of APOE 4 Status | The CIBIC+ score used for global functioning assessment. The CIBIC+ assessment comprised of a 7-point rating of severity. It was rated on a scale of 1 to 7 as 1: markedly improved, 2.: moderately improved, 3: minimally improved, 4: no change, 5: minimally worse, 6: moderately worse and 7: markedly worse; The lower score indicated betterment in functioning and higher score means greater dysfunction. The scale was based on interviews with the participant and the caregiver and was completed by an independent rater. | Baseline (Visit 1, W0), W 24 and W 52 | 
| Change From Baseline in Mini Mental State Examination (MMSE) Total Score as a Function of APOE 4 Status at W24 and W52 | The MMSE consisted of 11 tests of orientation, memory (recent and immediate), concentration, language and praxis. Scores range from 0 to 30, with lower scores indicating greater cognitive impairment. The scale was completed by the investigator, based on the performance of the participant, and took approximately 5 to 10 minutes to administer. Change from parent Baseline in MMSE was analyzed using a mixed model for repeated measures (MMRM). Baseline was referred to Visit 1 (W0)assessments. Change from Baseline was calculated as value at scheduled time point minus Baseline value. | Baseline (Visit 1, W0), W 24 and W52 | 
| Change From Baseline in Disability Assessment for Dementia Scale (DAD) Total Score as a Function of APOEe 4 Status | The DAD, assessed the ability of a participant to execute basic and instrumental activities of daily living (ADL) and leisure activities. The scale consists of 40 questions assessing basic and instrumental ADLs. This scale assesses a participant's ability to initiate, plan, and perform activities related to hygiene, dressing, continence, eating, meal preparation, telephoning, going on an outing, finance and correspondence, medications, leisure, and housework. Each item was scored as yes: 1, no: 0 and N/A: not applicable. Higher scores indicate less disability with a score of 100 indicating no disability and 0 indicating no functional ability. The percentage score was calculated as (DAD total score/total number of applicable items) multiplied by 100. The DAD was conducted as an interview with the caregiver and took approximately 20 minutes. Baseline was referred to Visit 1 (W0) assessments. Change from Baseline was calculated as value at scheduled time point minus Baseline value. | Baseline (Visit 1, W0), W24 and W52 | 
| Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score as a Function of APOE 4 Status at W24 and W52 | The NPI assessed behavioural disturbances comprises 10 dimensions: delusions, hallucinations, dysphoria, apathy, euphoria, disinhibition, aggressiveness and agitation, irritability, anxiety and aberrant motor activity. The participant caregiver asked about behaviour in the participant. If Yes, the informant then rates both the severity on a 3-point scale, 1: mild to 3: severe (total range: 0-36) and the frequency using a 4-point scale, 1: occasionally to 4: very frequently. The total domain score was frequency × severity. The distress was scored on 5-point scale, 0: no distress to 5 - very severe or extreme. A total NPI score was calculated by adding all domain scores together: NPI total score (from 0-144) and NPI distress score (from 0-60), with higher scores indicating more severe behavioral disturbance. Baseline was referred to Visit 1 (W0) assessments. Change from Baseline was calculated as value at scheduled time point minus Baseline value. | Baseline (Visit 1, W0), W24 and W52 | 
| Change From Baseline in Glycosylated Haemoglobin (HbA1c) | HbA1c was evaluated as safety parameter in this study. The values of change from Baseline was presented. The Baseline assessments were referred to assessments at Visit 1 (W0). Change from Baseline was measured as the BW at specified visit minus the Baseline value. | Baseline (Vsit 1 W0), W12, W24, W36, W52, W76 and Follow-up (W82) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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safety, open-label extension, tolerability, Alzheimer's disease, Rosiglitazone extended-release (XR), cognition, BRL-049653