Clinical trial NCT00550420: Study Of Rosiglitazone XR In Subjects With Mild-to-Moderate Alzheimers
Official title: 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.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Alzheimer's Disease
Keywords: open-label extension
tolerability
Alzheimer's disease
Rosiglitazone extended-release (XR)
safety
cognition
BRL-049653
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2007-10-29
Enrollment: 331
Sex: ALL
Minimum age (years): 51
Maximum age (years): 91
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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


Eligibility criteria: 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)

Primary outcomes:
measure: Number of Participants With Any Adverse Events (AEs) and Severity of AEs
timeFrame: Up to Week 82
Secondary outcomes:
measure: Number of Participants With Serious AEs and Deaths
timeFrame: Up to Week 82
measure: Percentage of Participants With AEs of Edema
timeFrame: Up to 82 Weeks
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline (Visit 1, W0), W4, W8, W12, W16, W24, W36, W52, W64 and Follow-up (W82)
measure: Change From Baseline in Heart Rate (HR)
timeFrame: Baseline (Visit 1, W0), W4, W8, W12, W16, W24, W36, W52, W64 and Follow-up (W82)
measure: Number of Participants With Abnormal SBP and DBP at Any Time During Treatment Period
timeFrame: Up to 82 weeks
measure: Number of Participants With Abnormal HR at Any Time During Treatment Period
timeFrame: Up to 82 weeks
measure: Change From Baseline in Body Weight (BW)
timeFrame: Baseline (Visit 1, W0), W4, W8, W12, W16, W24, W36, W52, W64 and Follow-up (W82)
measure: Number of Participants With Abnormal BW at Any Time During Treatment Period
timeFrame: Baseline (Visit 1, W0) to W 52
measure: Change From Baseline in Non-fasting Measures of Lipid Metabolism Including Total Cholesterol, High Density Lipoprotein, Low Density Lipoprotein and Triglycerides at Indicated Timepoints.
timeFrame: Baseline (Visit 1, W0), W4, W16, W36, W52, W76, and W82
measure: Number of Participants With Hematological Parameters of Potential Clinical Concern
timeFrame: Up to 82 weeks
measure: Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern
timeFrame: Up to 82 weeks
measure: 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
timeFrame: Baseline (Visit 1, W0), W24 and W52
measure: Mean Clinician Interview-Based Impression of Change Plus Caregiver Input (CIBIC+) Score as a Function of APOE 4 Status
timeFrame: Baseline (Visit 1, W0), W 24 and W 52
measure: Change From Baseline in Mini Mental State Examination (MMSE) Total Score as a Function of APOE 4 Status at W24 and W52
timeFrame: Baseline (Visit 1, W0), W 24 and W52
measure: Change From Baseline in Disability Assessment for Dementia Scale (DAD) Total Score as a Function of APOEe 4 Status
timeFrame: Baseline (Visit 1, W0), W24 and W52
measure: Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score as a Function of APOE 4 Status at W24 and W52
timeFrame: Baseline (Visit 1, W0), W24 and W52
measure: Change From Baseline in Glycosylated Haemoglobin (HbA1c)
timeFrame: Baseline (Vsit 1 W0), W12, W24, W36, W52, W76 and Follow-up (W82)
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: GSK Investigational Site
state: California
city: Deerfield Beach
country: United States
facility: GSK Investigational Site
state: Florida
city: Hialeah
country: United States
facility: GSK Investigational Site
state: Florida
city: Melbourne
country: United States
facility: GSK Investigational Site
state: Florida
city: Plantation
country: United States
facility: GSK Investigational Site
state: Florida
city: Tampa
country: United States
facility: GSK Investigational Site
state: Florida
city: Centerville
country: United States
facility: GSK Investigational Site
state: Ohio
city: Tulsa
country: United States
facility: GSK Investigational Site
state: Oklahoma
city: Nashville
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Graz-Eggenberg
country: Austria
facility: GSK Investigational Site
city: Hall in Tirol
country: Austria
facility: GSK Investigational Site
city: Plovdiv
country: Bulgaria
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Santiago
country: Chile
facility: GSK Investigational Site
state: Región Metro De Santiago
city: Santiago
country: Chile
facility: GSK Investigational Site
state: Región Metro De Santiago
city: Viña del Mar
country: Chile
facility: GSK Investigational Site
state: Valparaíso
city: Guangzhou
country: China
facility: GSK Investigational Site
state: Guangdong
city: Beijing
country: China
facility: GSK Investigational Site
city: Beijing
country: China
facility: GSK Investigational Site
city: Shanghai
country: China
facility: GSK Investigational Site
city: Shanghai
country: China
facility: GSK Investigational Site
city: Shanghai
country: China
facility: GSK Investigational Site
city: Tianjin
country: China
facility: GSK Investigational Site
city: Zagreb
country: Croatia
facility: GSK Investigational Site
city: Tallinn
country: Estonia
facility: GSK Investigational Site
city: Tallinn
country: Estonia
facility: GSK Investigational Site
city: Tallinn
country: Estonia
facility: GSK Investigational Site
city: Tartu
country: Estonia
facility: GSK Investigational Site
city: Ellwangen
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Tuebingen
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Guenzburg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Muenchen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Nuernberg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Unterhaching
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Bad Homburg
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Schwerin
country: Germany
facility: GSK Investigational Site
state: Mecklenburg-Vorpommern
city: Schwerin
country: Germany
facility: GSK Investigational Site
state: Mecklenburg-Vorpommern
city: Achim
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Baesweiler
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Bochum
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Duisburg
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Juelich
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Koeln
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Dresden
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Dresden
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Athens
country: Greece
facility: GSK Investigational Site
city: Thessaloniki
country: Greece
facility: GSK Investigational Site
city: Pécs
country: Hungary
facility: GSK Investigational Site
city: Szeged
country: Hungary
facility: GSK Investigational Site
city: Seongnam-si,
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Saltillo
country: Mexico
facility: GSK Investigational Site
state: Coahuila
city: Monterrey
country: Mexico
facility: GSK Investigational Site
state: Nuevo León
city: Mexico
country: Mexico
facility: GSK Investigational Site
city: Auckland
country: New Zealand
facility: GSK Investigational Site
city: Lima
country: Peru
facility: GSK Investigational Site
city: Pasig City
country: Philippines
facility: GSK Investigational Site
city: San Juan
country: Puerto Rico
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: St.-Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: West of Scotland Science Park, Glasgow
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Gold M, Alderton C, Zvartau-Hind M, Egginton S, Saunders AM, Irizarry M, Craft S, Landreth G, Linnamagi U, Sawchak S. Rosiglitazone monotherapy in mild-to-moderate Alzheimer's disease: results from a randomized, double-blind, placebo-controlled phase III study. Dement Geriatr Cogn Disord. 2010;30(2):131-46. doi: 10.1159/000318845. Epub 2010 Aug 21.