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NCT00348140: REFLECT-3

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

Completed Phase 3 Results posted Last updated 5 September 2017
What this trial tests

Phase 3 trial testing Rosiglitazone Extended Release 2mg in Alzheimer's Disease in 1,468 participants. Completed in 20 March 2009.

Timeline
12 July 2006
Primary endpoint
20 March 2009
20 March 2009

Quick facts

Lead sponsorGlaxoSmithKline
PhasePhase 3
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingquadruple
Primary purposetreatment
Enrollment1,468
Start date12 July 2006
Primary completion20 March 2009
Estimated completion20 March 2009
Sites194 locations across Hong Kong, Finland, Malaysia, Poland, South Korea, Philippines, Netherlands, Belgium

Drugs / interventions tested

Conditions studied

Sponsor

GlaxoSmithKline — full company profile →

Who can join

Adults 50 to 90, any sex, with Alzheimer's Disease. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score at Week 48, as a Function of APOE ε4 Status in APOE4 Negatives Cohort Primary · Baseline (Week 0) and Week 48

The 11-item ADAS-Cog 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 range from 0 to 70 with higher scores indicating greater dysfunction. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at Week 0. Estimated value was calculated by Active treatment minus Placebo. The adjusted means were presented. A hierarchical testing procedure was u

GroupValue95% CI
Placebo3.2± 0.54
RSG XR 2mg3.5± 0.53
RSG XR 8mg4.0± 0.63
Change From Baseline in ADAS-Cog Total Score at Week 48, as a Function of APOE ε4 Status in All Except E4/E4s Cohort Primary · Baseline (Week 0) and Week 48

The 11-item ADAS-Cog 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 range from 0 to 70 with higher scores indicating greater dysfunction. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value a t Week 0. Estimated value was calculated by Active treatment minus Placebo. The adjusted means were presented. A hierarchical testing procedure was

GroupValue95% CI
Placebo3.8± 0.38
RSG XR 2mg3.6± 0.35
RSG XR 8mg3.8± 0.41
Change From Baseline in ADAS-Cog Total Score at Week 48, as a Function of APOE ε4 Status in Full Population Cohort Primary · Baseline (Week 0) and Week 48

The 11-item ADAS-Cog 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 range from 0 to 70 with higher scores indicating greater dysfunction. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value a t Week 0. Estimated value was calculated by Active treatment minus Placebo. The adjusted means were presented. A hierarchical testing procedure was

GroupValue95% CI
Placebo3.9± 0.35
RSG XR 2mg3.8± 0.33
RSG XR 8mg3.8± 0.36
Change From Baseline in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) Score at Week 48, as a Function of APOE ε4 Status in APOE4 Negatives Cohort Primary · Baseline (Week 0) and Week 48

The CDR-SB was a validated clinical assessment of global function in patients with AD. Impairment was scored in each of 6 cognitive categories on a scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2, and severe = 3. The 6 individual category ratings, or "box scores", can be added together to give the CDR-Sum of Boxes which ranges from 0 to 18 (severe impairment). Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value a t Week 0. Estimated value was calculated by Active treatment minus Placebo. The adjusted means

GroupValue95% CI
Placebo1.8± 0.20
RSG XR 2mg1.7± 0.20
RSG XR 8mg1.7± 0.17
Change From Baseline in CDR-SB Score at Week 48, as a Function of APOE ε4 Status in All Except E4/E4s Cohort Primary · Baseline (Week 0) and Week 48

The CDR-SB was a validated clinical assessment of global function in patients with AD. Impairment was scored in each of 6 cognitive categories on a scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2, and severe = 3. The 6 individual category ratings, or "box scores", can be added together to give the CDR-Sum of Boxes which ranges from 0 to 18 (severe impairment). Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value a t Week 0. Estimated value was calculated by Active treatment minus Placebo. The adjusted means

GroupValue95% CI
Placebo1.8± 0.13
RSG XR 2mg1.8± 0.13
RSG XR 8mg1.7± 0.13
Change From Baseline in CDR-SB Score at Week 48, as a Function of APOE ε4 Status in Full Population Cohort Primary · Baseline (Week 0) and Week 48

The CDR-SB was a validated clinical assessment of global function in patients with AD. Impairment was scored in each of 6 cognitive categories on a scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2, and severe = 3. The 6 individual category ratings, or "box scores", can be added together to give the CDR-Sum of Boxes which ranges from 0 to 18 (severe impairment). Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value a t Week 0. Estimated value was calculated by Active treatment minus Placebo. The adjusted means

GroupValue95% CI
Placebo1.9± 0.12
RSG XR 2mg1.8± 0.13
RSG XR 8mg1.8± 0.12
Change From Baseline in ADAS-Cog Total Score at Weeks 8, 16, 24 and 36 Secondary · Baseline (Week 0) and Week 8, 16, 24, 36

The 11-item ADAS-Cog 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 range from 0 to 70 with higher scores indicating greater dysfunction. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value a t Week 0. It was calculated at Weeks 8, 16, 24 and 36. Full population data was presented.

Week 8
GroupValue95% CI
Placebo0.1± 0.23
RSG XR 2mg0.2± 0.23
RSG XR 8mg0.3± 0.23
Week 16
GroupValue95% CI
Placebo0.2± 0.24
RSG XR 2mg0.3± 0.23
RSG XR 8mg0.2± 0.24
Week 24
GroupValue95% CI
Placebo1.1± 0.26
RSG XR 2mg1.5± 0.28
RSG XR 8mg1.1± 0.27
Week 36
GroupValue95% CI
Placebo2.6± 0.31
RSG XR 2mg2.8± 0.29
RSG XR 8mg2.6± 0.31
Change From Baseline in CDR-SB Score at Weeks 12, 24 and 36 Secondary · Baseline (Week 0) and Week 12, 24, 36

The CDR-SB was a validated clinical assessment of global function in patients with AD. Impairment was scored in each of 6 cognitive categories on a scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2, and severe = 3. The 6 individual category ratings, or "box scores", can be added together to give the CDR-Sum of Boxes which ranges from 0 to 18 (severe impairment). Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value a t Week 0. Estimated value was calculated by Active treatment minus Placebo. The adjusted means

Week 12
GroupValue95% CI
Placebo0.3± 0.07
RSG XR 2mg0.4± 0.08
RSG XR 8mg0.3± 0.07
Week 24
GroupValue95% CI
Placebo0.9± 0.10
RSG XR 2mg0.8± 0.10
RSG XR 8mg0.9± 0.09
Week 36
GroupValue95% CI
Placebo1.4± 0.11
RSG XR 2mg1.3± 0.11
RSG XR 8mg1.3± 0.10
Change From Screening in Mini Mental State Examination (MMSE) Total Score Secondary · Screening (Week -4) and Week 48

The MMSE consists 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 is completed by the investigator, based on the performance of the participant. Change from screening was calculated as value at scheduled time point minus screening value. Baseline was defined as value a t Week 0. Estimated value was calculated by Active treatment minus Placebo. The adjusted means were presented. Full population data was presented.

GroupValue95% CI
Placebo-2.0± 0.21
RSG XR 2mg-2.3± 0.22
RSG XR 8mg-2.0± 0.22
Change From Baseline in Disability Assessment for Dementia (DAD) Total Score Secondary · Baseline (Week 0) and Week 8, 16, 24, 48

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 assessed a participants' 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 d

Week 8
GroupValue95% CI
Placebo-2.3± 0.50
RSG XR 2mg-1.2± 0.50
RSG XR 8mg-2.3± 0.46
Week 16
GroupValue95% CI
Placebo-3.0± 0.57
RSG XR 2mg-2.3± 0.55
RSG XR 8mg-3.9± 0.59
Week 24
GroupValue95% CI
Placebo-4.6± 0.60
RSG XR 2mg-2.8± 0.62
RSG XR 8mg-4.7± 0.63
Week 48
GroupValue95% CI
Placebo-9.5± 0.81
RSG XR 2mg-9.4± 0.81
RSG XR 8mg-10.4± 0.82
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score Secondary · Baseline (Week 0) and Week 8, 16, 24, 48

NPI is an assessment of frequency and severity of behavioral disturbances in dementia that comprised of 10 dimensions: delusions, hallucinations, dysphoria, apathy, euphoria, disinhibition, aggressiveness and agitation, irritability, anxiety, aberrant motor activity. Participant's caregiver asked about behavior in participant. If "Yes", informant then rated both severity on a 3-point scale, 1-mild to 3-severe (total range: 0-36) and frequency using a 4-point scale, 1-occasionally to 4-very frequently. Total score was frequency × severity. Distress was scored on 5-point scale, 0-no distress to

Week 8
GroupValue95% CI
Placebo-0.0± 0.32
RSG XR 2mg-0.3± 0.33
RSG XR 8mg-0.2± 0.31
Week 16
GroupValue95% CI
Placebo0.1± 0.34
RSG XR 2mg0.2± 0.37
RSG XR 8mg0.1± 0.37
Week 24
GroupValue95% CI
Placebo1.3± 0.43
RSG XR 2mg0.3± 0.41
RSG XR 8mg0.2± 0.39
Week 48
GroupValue95% CI
Placebo2.6± 0.52
RSG XR 2mg1.5± 0.49
RSG XR 8mg1.9± 0.50
Change From Baseline in Domains of the Resource Utilization in Dementia Scale (RUD)- Q1 and Q2 Caregiver Hours Secondary · Baseline (Week 0) and Week 12, 24, 36, 48

The RUD instrument was developed as a comprehensive tool to assess the amount of resource use among demented patients. RUD assessd both formal and informal resource use of the patient and the primary caregiver, making it possible to calculate costs from a societal perspective. Q1 corresponds to the number of hours during the last month the caregiver spent assisting the patient with toilet visits, eating, dressing, grooming, walking and bathing and Q2 corresponds to the number of hours during the last month the caregiver spent assisting the patient with shopping, food preparation, housekeeping,

Q1 Week 12
GroupValue95% CI
Placebo-2.4± 2.72
RSG XR 2mg1.8± 2.56
RSG XR 8mg3.5± 2.68
Q1 Week 24
GroupValue95% CI
Placebo7.4± 3.43
RSG XR 2mg9.0± 2.92
RSG XR 8mg10.9± 3.69
Q1 Week 36
GroupValue95% CI
Placebo11.2± 4.36
RSG XR 2mg12.7± 3.70
RSG XR 8mg13.4± 4.09
Q1 Week 48
GroupValue95% CI
Placebo15.7± 4.14
RSG XR 2mg19.7± 4.06
RSG XR 8mg19.2± 4.54
Q2 Week 12
GroupValue95% CI
Placebo-1.1± 4.06
RSG XR 2mg5.8± 3.70
RSG XR 8mg6.4± 4.04
Q2 Week 24
GroupValue95% CI
Placebo5.6± 4.41
RSG XR 2mg15.6± 4.90
RSG XR 8mg12.3± 4.79
Q2 Week 36
GroupValue95% CI
Placebo16.4± 5.52
RSG XR 2mg23.4± 6.10
RSG XR 8mg15.2± 4.53
Q2 Week 48
GroupValue95% CI
Placebo21.8± 5.62
RSG XR 2mg26.0± 5.69
RSG XR 8mg21.6± 4.92

Adverse events — posted to ClinicalTrials.gov

Time frame: Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of investigational product until Week 54 following early withdrawal of the study medication/follow up. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Placebo
Serious: 60/487 (12%)
Deaths: 9/487
RSG XR 2mg
Serious: 58/490 (12%)
Deaths: 11/490
RSG XR 8mg
Serious: 66/491 (13%)
Deaths: 11/491

Serious adverse events (148 terms)

ReactionSystemPlaceboRSG XR 2mgRSG XR 8mg
SyncopeNervous system disorders
Cerebrovascular accidentNervous system disorders
FallInjury, poisoning and procedural complications
Hip fractureInjury, poisoning and procedural complications
PneumoniaInfections and infestations
BronchitisInfections and infestations
Urinary tract infectionInfections and infestations
Cardiac failureCardiac disorders
Myocardial infarctionCardiac disorders
Nervous system disorderNervous system disorders
Femur fractureInjury, poisoning and procedural complications
Pelvic fractureInjury, poisoning and procedural complications
Humerus fractureInjury, poisoning and procedural complications
ArrhythmiaCardiac disorders
Prostate cancerNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Confusional statePsychiatric disorders
HypotensionVascular disorders
DehydrationMetabolism and nutrition disorders
Transient ischaemic attackNervous system disorders
ConvulsionNervous system disorders
Loss of consciousnessNervous system disorders
Cerebral haematomaNervous system disorders
Cerebral haemorrhageNervous system disorders
Cerebral hypoperfusionNervous system disorders
Cerebral infarctionNervous system disorders
Other adverse events (2 terms — click to expand)

ReactionSystemPlaceboRSG XR 2mgRSG XR 8mg
Oedema peripheralGeneral disorders
AnaemiaBlood and lymphatic system disorders

Most-reported serious reactions: Syncope, Cerebrovascular accident, Fall, Hip fracture, Pneumonia, Bronchitis, Urinary tract infection, Cardiac failure.

Data from ClinicalTrials.gov NCT00348140 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Alzheimer's disease and the amyloid cascade hypothesis: a critical review.
    Reitz C. · · 2012 · cited 194× · PMID 22506132 · DOI 10.1155/2012/369808
  2. PPARγ/PGC1α signaling as a potential therapeutic target for mitochondrial biogenesis in neurodegenerative disorders.
    Jamwal S, Blackburn JK, Elsworth JD. · · 2021 · cited 189× · PMID 33039420 · DOI 10.1016/j.pharmthera.2020.107705
  3. Current Research Therapeutic Strategies for Alzheimer's Disease Treatment.
    Folch J, Petrov D, Ettcheto M, Abad S, et al · · 2016 · cited 173× · PMID 26881137 · DOI 10.1155/2016/8501693
  4. Therapeutics of Neurotransmitters in Alzheimer's Disease.
    Kandimalla R, Reddy PH. · · 2017 · cited 161× · PMID 28211810 · DOI 10.3233/jad-161118
  5. Therapeutic approaches targeting Apolipoprotein E function in Alzheimer's disease.
    Williams T, Borchelt DR, Chakrabarty P. · · 2020 · cited 116× · PMID 32005122 · DOI 10.1186/s13024-020-0358-9
  6. Molecular Mechanisms of Neuroinflammation in Aging and Alzheimer's Disease Progression.
    Andronie-Cioara FL, Ardelean AI, Nistor-Cseppento CD, Jurcau A, et al · · 2023 · cited 109× · PMID 36768235 · DOI 10.3390/ijms24031869
  7. Current and future therapeutic strategies for Alzheimer's disease: an overview of drug development bottlenecks.
    Peng Y, Jin H, Xue YH, Chen Q, et al · · 2023 · cited 99× · PMID 37600514 · DOI 10.3389/fnagi.2023.1206572
  8. Reassessment of Pioglitazone for Alzheimer's Disease.
    Saunders AM, Burns DK, Gottschalk WK. · · 2021 · cited 48× · PMID 34220427 · DOI 10.3389/fnins.2021.666958

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Data sources for this page

Drug Landscape aggregates and links these public records for informational use only. Always verify against the primary source before clinical or regulatory decisions. Canonical URL: https://druglandscape.com/trial/NCT00348140.

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