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

NCT ID: NCT00348140

Last Updated: 2017-09-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 1468 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-07-12
• Study Completion Date: 2009-03-20

Brief 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.

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 acetylcholinesterase inhibitors on cognition and overall clinical response in APOE e4-stratified subjects with mild to moderate Alzheimer's disease (REFLECT-3)

Conditions

Alzheimer's Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Arm 1

Rosiglitazone Extended Release 2mg OD

Group Type: EXPERIMENTAL

Rosiglitazone Extended Release 2mg

Intervention Type: DRUG

Rosiglitazone Extended Release 2mg OD

Arm 2

Rosiglitazone Extended Release 8mg OD

Group Type: EXPERIMENTAL

Rosiglitazone Extended Release 8mg

Intervention Type: DRUG

Rosiglitazone Extended Release 8mg OD

Arm 3

Placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Placebo

Interventions

Rosiglitazone Extended Release 2mg

Rosiglitazone Extended Release 2mg OD

Intervention Type: DRUG

Rosiglitazone Extended Release 8mg

Rosiglitazone Extended Release 8mg OD

Intervention Type: DRUG

Placebo

Placebo

Intervention Type: OTHER

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.

• Minimum Eligible Age: 50 Years
• Maximum Eligible Age: 90 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Sun City, Arizona, United States

GSK Investigational Site

Tucson, Arizona, United States

GSK Investigational Site

Little Rock, Arkansas, United States

GSK Investigational Site

Laguna Hills, California, United States

GSK Investigational Site

Redlands, California, United States

GSK Investigational Site

San Diego, California, United States

GSK Investigational Site

San Francisco, California, United States

GSK Investigational Site

Norwalk, Connecticut, United States

GSK Investigational Site

Deerfield Beach, Florida, United States

GSK Investigational Site

Delray Beach, Florida, United States

GSK Investigational Site

Fort Lauderdale, Florida, United States

GSK Investigational Site

Hialeah, Florida, United States

GSK Investigational Site

Ocala, Florida, United States

GSK Investigational Site

St. Petersburg, Florida, United States

GSK Investigational Site

Tampa, Florida, United States

GSK Investigational Site

Decatur, Georgia, United States

GSK Investigational Site

Chicago, Illinois, United States

GSK Investigational Site

Springfield, Massachusetts, United States

GSK Investigational Site

West Yarmouth, Massachusetts, United States

GSK Investigational Site

Eatontown, New Jersey, United States

GSK Investigational Site

Toms River, New Jersey, United States

GSK Investigational Site

Whiting, New Jersey, United States

GSK Investigational Site

Amherst, New York, United States

GSK Investigational Site

New York, New York, United States

GSK Investigational Site

New York, New York, United States

GSK Investigational Site

Rochester, New York, United States

GSK Investigational Site

Syracuse, New York, United States

GSK Investigational Site

Raleigh, North Carolina, United States

GSK Investigational Site

Winston-Salem, North Carolina, United States

GSK Investigational Site

Centerville, Ohio, United States

GSK Investigational Site

Columbus, Ohio, United States

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Toledo, Ohio, United States

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Oklahoma City, Oklahoma, United States

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Tulsa, Oklahoma, United States

GSK Investigational Site

Jenkintown, Pennsylvania, United States

GSK Investigational Site

Norristown, Pennsylvania, United States

GSK Investigational Site

Philadelphia, Pennsylvania, United States

GSK Investigational Site

Philadelphia, Pennsylvania, United States

GSK Investigational Site

Pittsburgh, Pennsylvania, United States

GSK Investigational Site

East Providence, Rhode Island, United States

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Providence, Rhode Island, United States

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Greer, South Carolina, United States

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San Antonio, Texas, United States

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Wichita Falls, Texas, United States

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Salt Lake City, Utah, United States

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Charlottesville, Virginia, United States

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Seattle, Washington, United States

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Middleton, Wisconsin, United States

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Milwaukee, Wisconsin, United States

GSK Investigational Site

Hornsby, New South Wales, Australia

GSK Investigational Site

Randwick, New South Wales, Australia

GSK Investigational Site

Auchenflower, Queensland, Australia

GSK Investigational Site

Chermside, Queensland, Australia

GSK Investigational Site

Kippa-Ring, Queensland, Australia

GSK Investigational Site

Adelaide, South Australia, Australia

GSK Investigational Site

Woodville, South Australia, Australia

GSK Investigational Site

Cheltenham, Victoria, Australia

GSK Investigational Site

Heidelberg West, Victoria, Australia

GSK Investigational Site

Kew, Victoria, Australia

GSK Investigational Site

Nedlands, Western Australia, Australia

GSK Investigational Site

Brussels, , Belgium

GSK Investigational Site

Kortrijk, , Belgium

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Leuven, , Belgium

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Woluwe-Saint-Lambert, , Belgium

GSK Investigational Site

Sofia, , Bulgaria

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Sofia, , Bulgaria

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Sofia, , Bulgaria

GSK Investigational Site

Varna, , Bulgaria

GSK Investigational Site

Kelowna, British Columbia, Canada

GSK Investigational Site

Saint John, New Brunswick, Canada

GSK Investigational Site

Kentville, Nova Scotia, Canada

GSK Investigational Site

Kingston, Ontario, Canada

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Ottawa, Ontario, Canada

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Ottawa, Ontario, Canada

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Peterborough, Ontario, Canada

GSK Investigational Site

Toronto, Ontario, Canada

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Toronto, Ontario, Canada

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Greenfield Park, Quebec, Canada

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Mirabel, Quebec, Canada

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Montreal, Quebec, Canada

GSK Investigational Site

Sherbrooke, Quebec, Canada

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Québec, , Canada

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Olomouc, , Czechia

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Prague, , Czechia

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Prague, , Czechia

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Trutnov, , Czechia

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Helsinki, , Finland

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Joensuu, , Finland

GSK Investigational Site

Kuopio, , Finland

GSK Investigational Site

Bordeaux, , France

GSK Investigational Site

La Chapelle-sur-Erdre, , France

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La Seyne-sur-Mer, , France

GSK Investigational Site

Lille, , France

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Limoges, , France

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Metz, , France

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Nantes, , France

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Nantes, , France

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Paris, , France

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Sautron, , France

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Toulon, , France

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Toulouse, , France

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Valence, , France

GSK Investigational Site

Aalen, Baden-Wurttemberg, Germany

GSK Investigational Site

Calw, Baden-Wurttemberg, Germany

GSK Investigational Site

Ellwangen, Baden-Wurttemberg, Germany

GSK Investigational Site

Ludwigsburg, Baden-Wurttemberg, Germany

GSK Investigational Site

Stuttgart, Baden-Wurttemberg, Germany

GSK Investigational Site

Tübingen, Baden-Wurttemberg, Germany

GSK Investigational Site

Ulm, Baden-Wurttemberg, Germany

GSK Investigational Site

Ulm, Baden-Wurttemberg, Germany

GSK Investigational Site

Wiesloch, Baden-Wurttemberg, Germany

GSK Investigational Site

Alzenau in Unterfranken, Bavaria, Germany

GSK Investigational Site

Munich, Bavaria, Germany

GSK Investigational Site

Unterhaching, Bavaria, Germany

GSK Investigational Site

Bad Saarow, Brandenburg, Germany

GSK Investigational Site

Bad Homburg, Hesse, Germany

GSK Investigational Site

Erbach im Odenwald, Hesse, Germany

GSK Investigational Site

Chemnitz, Saxony, Germany

GSK Investigational Site

Dresden, Saxony, Germany

GSK Investigational Site

Dresden, Saxony, Germany

GSK Investigational Site

Leipzig, Saxony, Germany

GSK Investigational Site

Leipzig, Saxony, Germany

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Leipzig, Saxony, Germany

GSK Investigational Site

Gera, Thuringia, Germany

GSK Investigational Site

Jena, Thuringia, Germany

GSK Investigational Site

Berlin, , Germany

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Berlin, , Germany

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Berlin, , Germany

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Berlin, , Germany

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Berlin, , Germany

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Berlin, , Germany

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Berlin, , Germany

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Berlin, , Germany

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Berlin, , Germany

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Berlin, , Germany

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Berlin, , Germany

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Berlin, , Germany

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Hong Kong, , Hong Kong

GSK Investigational Site

Shatin, , Hong Kong

GSK Investigational Site

Bandar Tun Razak, Cheras, , Malaysia

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Bandar Tun Razak, Cheras, , Malaysia

GSK Investigational Site

Ipoh, , Malaysia

GSK Investigational Site

Kelantan, , Malaysia

GSK Investigational Site

's-Hertogenbosch, , Netherlands

GSK Investigational Site

Alkmaar, , Netherlands

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Blaricum, , Netherlands

GSK Investigational Site

Hengelo, , Netherlands

GSK Investigational Site

Hilversum, , Netherlands

GSK Investigational Site

The Hague, , Netherlands

GSK Investigational Site

Manila, , Philippines

GSK Investigational Site

Pasig, , Philippines

GSK Investigational Site

Bydgoszcz, , Poland

GSK Investigational Site

Krakow, , Poland

GSK Investigational Site

Torun, , Poland

GSK Investigational Site

Warsaw, , Poland

GSK Investigational Site

Singapore, , Singapore

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Singapore, , Singapore

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Singapore, , Singapore

GSK Investigational Site

Bratislava, , Slovakia

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Bratislava, , Slovakia

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Bratislava, , Slovakia

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Košice, , Slovakia

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Ljubljana, , Slovenia

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Šempeter v Savinj. Dolini, , Slovenia

GSK Investigational Site

Loeventstein, , South Africa

GSK Investigational Site

Oakdale, , South Africa

GSK Investigational Site

Richards Bay, , South Africa

GSK Investigational Site

Rosebank, , South Africa

GSK Investigational Site

Somerset West, , South Africa

GSK Investigational Site

Waverley, Bloemfontein, , South Africa

GSK Investigational Site

Willows, X14, Pretoria, , South Africa

GSK Investigational Site

Seongnam-si, , South Korea

GSK Investigational Site

Seoul, , South Korea

GSK Investigational Site

Seoul, , South Korea

GSK Investigational Site

Baracaldo/Vizcaya, , Spain

GSK Investigational Site

Barcelona, , Spain

GSK Investigational Site

Barcelona, , Spain

GSK Investigational Site

Barcelona, , Spain

GSK Investigational Site

Barcelona, , Spain

GSK Investigational Site

Barcelona, , Spain

GSK Investigational Site

Palma de Mallorca, , Spain

GSK Investigational Site

Tarrasa, Barcelona, , Spain

GSK Investigational Site

Falköping, , Sweden

GSK Investigational Site

Jönköping, , Sweden

GSK Investigational Site

Kalix, , Sweden

GSK Investigational Site

Mölndal, , Sweden

GSK Investigational Site

Sundsvall, , Sweden

GSK Investigational Site

Umeå, , Sweden

GSK Investigational Site

Blackpool, Lancashire, United Kingdom

GSK Investigational Site

Bradford, , United Kingdom

GSK Investigational Site

Liverpool, , United Kingdom

GSK Investigational Site

Stirling, , United Kingdom

GSK Investigational Site

West End, Southampton, , United Kingdom

GSK Investigational Site

West of Scotland Science Park, Glasgow, , United Kingdom

Countries

United States; Australia; Belgium; Bulgaria; Canada; Czechia; Finland; France; Germany; Hong Kong; Malaysia; Netherlands; Philippines; Poland; Singapore; Slovakia; Slovenia; South Africa; South Korea; Spain; Sweden; United Kingdom

References

Harrington C, Sawchak S, Chiang C, Davies J, Donovan C, Saunders AM, Irizarry M, Jeter B, Zvartau-Hind M, van Dyck CH, Gold M. Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer's disease: two phase 3 studies. Curr Alzheimer Res. 2011 Aug;8(5):592-606. doi: 10.2174/156720511796391935.

Reference Type: BACKGROUND

PMID: 21592048 (View on PubMed)

Study Documents

Document Type: Dataset Specification

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Statistical Analysis Plan

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Individual Participant Data Set

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Informed Consent Form

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Study Protocol

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Clinical Study Report

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Annotated Case Report Form

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Related Links

https://www.clinicalstudydatarequest.com

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Other Identifiers

AVA102670

Identifier Type: -

Identifier Source: org_study_id