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Study of SB-742457 or Donepezil Versus Placebo in Subjects With Mild-to-moderate Alzheimer's Disease

Primary Purpose

Alzheimer's Disease

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

SB-742457

Donepezil

Placebo

About this trial

This is an interventional treatment trial for Alzheimer's Disease focused on measuring Alzheimer's disease, Cognition, SB-742457

Eligibility Criteria

50 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria:

Subjects and their caregivers must provide informed consent prior to study entry.
Subjects must have a clinical diagnosis of probable mild-to-moderate Alzheimer's disease with a documented 6-month history of AD symptoms
Subjects must have a regular caregiver who is willing to attend visits, oversee the subject's compliance with the study and report on the subject's status.
Female subjects of child-bearing potential must agree to pregnancy testing and approved form of birth control.

Exclusion criteria:

Diagnosis of possible, probable or definite vascular dementia.
History/evidence of any other CNS disorder that could be interpreted as a cause of dementia
History of known or suspected seizures, loss of consciousness or significant head trauma
Subjects with ECG, blood pressure and laboratory values outside of protocol criteria are excluded.
Subjects with known photosensitivity
Subjects with a history of previous exposure to SB-742457, taking agents for which there is a theoretical risk of interaction with SB-742457, or taking medication for Alzheimer's disease or centrally acting agents which might impact study outcomes may not participate.

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Experimental

Active Comparator

Arm Label

SB-742457 - 15mg

Placebo

SB-742457 - 35mg

Donepezil

Arm Description

SB-742457 - 15mg

SB-742457 - 35mg

Outcomes

Primary Outcome Measures

Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score at Week 24

ADAS-Cog assesses a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Most items are evaluated by tests, but some are dependent on clinician ratings on a five point scale. The ADAS-Cog total score is the sum of the calculated scores for Questions 1 (Word recall task), 2 (Naming objects and fingers), and 7 (Word recognition task) and the scores recorded on the CRF for Questions 3 to 6 (Commands, Constructional praxis, Ideational praxis, Orientation) and 8 to 11 (Remembering test instructions, Spoken language ability, Word finding difficulty in spontaneous speech, Comprehension). The total score ranges from 0-70 with higher scores indicating greater dysfunction while lower indicates better cognitive function. Baseline was defined as the value at Week 0. Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Clinician's Interview-Based Impression of Change - Plus (CIBIC+) Score at Week 24

Secondary Outcome Measures

Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score at Week 24

RBANS is an individually administered neurocognitive battery comprising 12 subtests across five domains (Attention, Language, Visuospatial/Constructional Abilities, and Immediate and Delayed memory). The scale is completed by a trained and experienced neurologist, psychiatrist or neuropsychologist, or another trained and experienced person. It is preferred that this individual is the same person who administers the ADAS-Cog, but he/she must be a separate individual from the person who completes the CIBIC+. The scale is based on the performance of the participant and takes approximately 25-30 minutes to administer. Raw total scores are calculated by adding up the scores for each of the 12 individual subtests and ranges between 0 and 311, where low score= (greater impairment) and high score=(better cognitive function). Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline Mini Mental State Examination [MMSE] Scores 16-26) on the Change From Baseline in ADAS-Cog Total Score, the Change From Baseline in RBANS Total Score at Week 24

The MMSE was used to measure cognitive impairment. The MMSE consists of 11 tests namely orientation to time, orientation to place, registration, attention and calculation, recall, naming, repetition, comprehension, reading, writing and drawing corresponding to 5 domains orientation, memory, attention, and construction. All items were scored as 0 (incorrect response) or 1 (correct response). Total scores ranges from 0 to 30, with lower scores indicating greater cognitive impairment and higher scores indicating better function. Stratification by Baseline severity, using MMSE score at Baseline, with the strata being MMSE score of 10-15, 16-20 and 21-26. Two subgroups using MMSE score at Baseline were also examined, moderate 10-20 and mild 16-26. Data has been presented for participants with Baseline MMSE 16-26. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline [MMSE Scores 10-20) on the Change From Baseline in ADAS-Cog Total Score, the Change From Baseline in RBANS Total Score at Week 24

The MMSE was used to measure cognitive impairment. The MMSE consists of 11 tests namely orientation to time, orientation to place, registration, attention and calculation, recall, naming, repetition, comprehension, reading, writing and drawing corresponding to 5 domains orientation, memory, attention, and construction. All items were scored as 0 (incorrect response) or 1 (correct response). Total scores ranges from 0 to 30, with lower scores indicating greater cognitive impairment and higher scores indicating better function. Stratification by Baseline severity, using MMSE score at Baseline, with the strata being MMSE score of 10-15, 16-20 and 21-26. Two subgroups using MMSE score at Baseline were also examined, moderate 10-20 and mild 16-26. Data has been presented for participants with Baseline MMSE 10-20. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 16-26) on the CIBIC+ Score at Week 24

The CIBIC+ is a rating scale derived from an interview with the participant and caregiver with an independent rater designed to measure several domains of participant function, such as mental/cognitive state, behavior, and functioning. The scores are rated on a scale of 1 to 7 as follows: 1 (marked improvement), 2 (moderately improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (moderately worse) and 7 (markedly worse). Stratification by Baseline severity, using MMSE score at Baseline, with the strata being MMSE score of 10-15, 16-20 and 21-26. Two subgroups using MMSE score at Baseline were also examined, moderate 10-20 and mild 16-26. Data has been presented for participants with Baseline MMSE 16-26. Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 10-20) on the CIBIC+ Score at Week 24

The CIBIC+ is a rating scale derived from an interview with the participant and caregiver with an independent rater designed to measure several domains of participant function, such as mental/cognitive state, behavior, and functioning. The scores are rated on a scale of 1 to 7 as follows: 1 (marked improvement), 2 (moderately improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (moderately worse) and 7 (markedly worse). Higher scores indicate worst outcome. Stratification by Baseline severity, using MMSE score at Baseline, with the strata being MMSE score of 10-15, 16-20 and 21-26. Two subgroups using MMSE score at Baseline were also examined, moderate 10-20 and mild 16-26. Data has been presented for participants with baseline MMSE 10-20. Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Change From Baseline in ADAS-Cog Total Score at Week 12

ADAS-Cog assesses a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Most items are evaluated by tests, but some are dependent on clinician ratings on a five point scale. The ADAS-Cog total score is the sum of the calculated scores for Questions 1 (Word recall task), 2 (Naming objects and fingers), and 7 (Word recognition task) and the scores recorded on the CRF for Questions 3 to 6 (Commands, Constructional praxis, Ideational praxis, Orientation) and 8 to 11 (Remembering test instructions, Spoken language ability, Word finding difficulty in spontaneous speech, Comprehension). The total score ranges from 0-70 with higher scores indicating greater dysfunction while lower indicates better cognitive function. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 12.

CIBIC+ Score at Week 12

Change From Baseline in RBANS Total Score at Week 12

Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 16-26) on the Change From Baseline in ADAS-Cog Total Score, the Change From Baseline in RBANS Total Score at Week 12

The MMSE was used to measure cognitive impairment. The MMSE consists of 11 tests namely orientation to time, orientation to place, registration, attention and calculation, recall, naming, repetition, comprehension, reading, writing and drawing corresponding to 5 domains orientation, memory, attention, and construction. All items were scored as 0 (incorrect response) or 1 (correct response). Total scores ranges from 0 to 30, with lower scores indicating greater cognitive impairment and higher scores indicating better function. Stratification by Baseline severity, using MMSE score at Baseline, with the strata being MMSE score of 10-15, 16-20 and 21-26. Two subgroups using MMSE score at Baseline were also examined, moderate 10-20 and mild 16-26. Data has been presented for Participants with Baseline MMSE score 16-26. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 12.

Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 10-20) on the Change From Baseline in ADAS-Cog Total Score, the Change From Baseline in RBANS Total Score at Week 12

The MMSE was used to measure cognitive impairment. The MMSE consists of 11 tests namely orientation to time, orientation to place, registration, attention and calculation, recall, naming, repetition, comprehension, reading, writing and drawing corresponding to 5 domains orientation, memory, attention, and construction. All items were scored as 0 (incorrect response) or 1 (correct response). Total scores ranges from 0 to 30, with lower scores indicating greater cognitive impairment and higher scores indicating better function. Stratification by Baseline severity, using MMSE score at Baseline, with the strata being MMSE score of 10-15, 16-20 and 21-26. Two subgroups using MMSE score at Baseline were also examined, moderate 10-20 and mild 16-26. Data has been presented for participants with Baseline MMSE score 10-20. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 12.

Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 16-26) on the CIBIC+ Score at Week 12

Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 10-20) on the CIBIC+ Score at Week 12

Change From Baseline in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Total Score at Weeks 12 and 24

The ADCS-ADL measures functional impairment in terms of activities of daily living. The ADCS-ADL is an interviewer-administered informant-based scale where the informant (caregiver) responds to 23 activities of daily living questions (i.e. those necessary for personal care, communicating and interacting with other people, maintaining a household, conducting hobbies and interests, making judgments and decisions) about the participant. The questions range from basic to instrumental activities of daily living and take approximately 20 minutes to complete. The Total score ranges from 0-78 and a higher score signifies greater functional ability and lower scores indicating greater impairment. The total score is the sum of all items and sub-questions. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Weeks 12 and 24.

Change From Baseline in Cornell Scale for Depression in Dementia (CSDD) Total Score at Week 24

The CSDD is used to assess signs and symptoms of major depression in demented participants. The CSDD scale contains 19 items on mood-related signs of depression, behavioral disturbance, physical signs of depression, cyclic functions and ideational disturbances, where each item is rated for severity on a scale of 0-2 (0=absent, 1=mild/intermittent, 2=severe). Scores above 10 (probable major depression),scores above 18 (definite major depression), scores below 6 (absence of significant depressive symptoms). The total score was calculated as a weighted average of the scores provided for the remaining 18 questions as follows: Imputed Total= Observed Total Score x 1+ Maximum Score of the missing value/ Sum of the Maximum Score of the non -missing values) and ranges from 0-38. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Change From Baseline in MMSE Total Score at Week 24

The MMSE is used to test for cognitive dysfunction. The scale is completed by a trained and experienced neurologist/psychiatrist/neuropsychologist based on the performance of the participants, and takes approximately 5 to 10 minutes to administer. It consists of 11 tests namely orientation to time, orientation to place, registration, attention and calculation, recall, naming, repetition, comprehension, reading, writing, drawing across 5 sections (orientation, registration, attention-calculation, recall, and language). Scoring was done by circling 0 if the response was incorrect, or 1 if the response was correct. Scores range from 0 to 30, with lower scores indicating greater cognitive impairment and higher scores indicating better cognitive function. The total MMSE score was a sum of all item scores. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Change From Baseline in ADCS-ADL-Basic Score; ADCS-ADL: Instrumental Score and ADCS-ADL: Total Independence Score at Weeks 12 and 24

Basic score was calculated as the sum of questions 1-6b and ranges from 0-22 (activities included are: eating, walking, using the toilet, bathing, grooming and dressing) and Instrumental score, sum of questions 7-23, ranges from 0-56 (activities included are: using the telephone, watching television, conversations, clearing dishes, personal belongings, making drinks, making snacks, taking rubbish out, getting out and about, shopping, keeping appointments, being left alone, current events, reading, writing, pastimes/hobbies, household chores). Total independence score is calculated by re-scoring the individual questions for each activity. The total independence score therefore ranges between 0 to 23, where 23 indicates that a participant is independent (based on these 23 ADL). Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Weeks 12 and 24.

Number of Participants With Any Adverse Event (Serious and Non-serious) and Serious Adverse Events (SAEs)

An Adverse Event (AE) is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, may jeopardize the participant or require medical or surgical intervention to prevent one of the other outcomes listed in the definition above, or is an event of possible drug-induced liver injury. Number of participants with any adverse event (serious and non-serious) and SAEs were reported.

Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT)

Vital sign measurements included systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Heart Rate (HR), Body weight (BW). SBP and DBP and HR were measured once after the participant sat quietly for at least 5 minutes and in addition, upon standing to assess participants for postural hypotension. DBP was measured at the disappearance of Korotkoff sounds (Phase V). The plethysmographic method (preferably with a column sphygmomanometer where available) was used to measure blood pressure throughout the study. Body weight was measured, without shoes and wearing light clothing. The PCC range were as follows: SBP (Reference Range [RR] <90-140> Increase from Baseline [IFB]>=40 and decrease from baseline [DFB] >=30), DBP (RR < 50-90> IFB>=30 and DFB >=20), HR (RR <50-100> IFB >=30 and DFB >=30, BW (IFB >= 7% and DFB >=7%).

Number of Participants With Hematology Data of PCC ATOT

Hematology parameters included hematocrit ratio (reference range males 0.410-0.500, females 0.350-0.460 [18-64 years] and males 0.360-0.490, females 0.330-0.460 [65+ years]), hemoglobin grams per liter (13.8-17.2), lymphocytes giga per liter (0.85-4.10), monocytes giga per liter (0.20-1.10), platelet count giga per liter (130-400), segmented neutrophils giga per liter (1.80-8.00), total neutrophils (1.80-8.00). Data has been presented in a consolidated format for hematology parameters high and low from the reference range of PCC ATOT.

Number of Participants With Chemistry Data of PCC ATOT

Clinical chemistry parameters included alanine amino transferase international units per liter (IU/L) RR [0-48], alkaline phosphatase IU/L (20-125), aspartate amino transferase international units per liter (0-55), blood urea nitrogen/creatinine ratio (24-101), calcium millimoles per liter (mmol/L) [2.12-2.56], carbon dioxide content/bicarbonate mmol/L (20-32), cholesterol mmol/L (0.00-5.15), creatine kinase IU/L (males 0-235 and females 0-190), creatinine micromoles per liter (umol/L) [44-124], direct bilirubin umol/L (0-6), gamma glutamyl transferase IU/L (males 0-65 and females 0-45), glucose mmol/L (3.9-6.9), low density lipoprotein cholesterol mmol/L (0.00-3.35), lactate dehydrogenase IU/L (0-270), potassium mmol/L (3.5-5.3), sodium mmol/L (135-146), total bilirubin umol/L (0-22), triglycerides mmol/L (0.00-2.24), urea/blood urea nitrogen mmol/L (2.5-10.5). Data has been presented in a consolidated format for clinical chemistry parameters high and low from the RR of PCC ATOT.

Change From Baseline in Clinical Chemistry Parameters Alanine Amino Transferase, Alkaline Phosphatase, Aspartate Amino Transferase, Creatine Kinase, Gamma Glutamyl Transferase and Lactate Dehydrogenase at Week 24

Clinical chemistry parameters included alanine amino transferase, alkaline phosphatase, aspartate amino transferase, creatine kinase, gamma glutamyl transferase and lactate dehydrogenase. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Weeks 24.

Change From Baseline in Clinical Chemistry Parameters Albumin and Total Protein at Week 24

Clinical chemistry parameters included albumin and total protein. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Change From Baseline in Clinical Chemistry Parameter Blood Urea Nitrogen /Creatinine Ratio at Week 24

Clinical chemistry parameter included blood urea nitrogen /creatinine ratio. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Change From Baseline in Clinical Chemistry Parameters Calcium, CO2 Content/Bicarbonate, Chloride, Glucose, HDL Cholesterol, LDL Cholesterol, Magnesium, Phosphorus, Potassium, Sodium, Triglycerides, Urea/Blood Urea Nitrogen at Week 24

Clinical chemistry parameters included calcium, CO2 content/bicarbonate, chloride, glucose, HDL cholesterol, LDL cholesterol, magnesium, phosphorus, potassium, sodium, triglycerides, urea/blood urea nitrogen. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Change From Baseline in Clinical Chemistry Parameters Creatinine, Direct Bilirubin and Total Bilirubin at Week 24

Clinical chemistry parameters included creatinine, direct bilirubin and total bilirubin. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24

Hematology parameters included basophils, eosinophils, lymphocytes, monocytes, platelet count, segmented neutrophils, total neutrophils, white blood cell count. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Change From Baseline in Hematology Parameter Hematocrit

Hematology parameter included hematocrit. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Change From Baseline in Hematology Parameters Hemoglobin and Mean Corpuscle Hemoglobin Concentration at Week 24

Hematology parameter included hemoglobin and mean corpuscle hemoglobin concentration. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Change From Baseline in Hematology Parameter Mean Corpuscle Hemoglobin at Week 24

Hematology parameter included mean corpuscle hemoglobin. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Change From Baseline in Hematology Parameter Mean Corpuscle Volume and Mean Platelet Volume at Week 24

Hematology parameter included mean corpuscle volume and mean platelet volume. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Change From Baseline in Hematology Parameter Red Blood Cell Count at Week 24

Hematology parameter included red blood cell count. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Number of Participants With Electrocardiogram (ECG) Findings as Assessed by Investigator and Central Cardiologist

The clinical interpretation of the ECG by the investigator was recorded as Normal, Abnormal but not clinically significant (ANCS) and Abnormal clinically significant (ACS). ECG interpretation by the central cardiologist included the most extreme result of the available ECGs where the central cardiologist's interpretation of the ECG was recorded as Normal, Unable to Evaluate and Abnormal. Data has been presented for number of participants with most severe on-treatment abnormal ECG findings.

Exposure Estimates for SB-742457 Area Under Curve Over the Dosing Interval at Steady State (AUCτss)

A total of five pharmacokinetic samples per participant were collected for the purpose of assessing plasma concentrations of SB-742457 and donepezil. At each visit (Day 28±5, 56±5, 84±5, 126±5 and 168±5) one sample was collected post 24 hours of last dose.

Exposure Estimates for SB-742457 Minimum Concentration at Steady State (Cmin-ss)

Blood sample for pharmacokinetic analysis, were obtained within 24 hours of last dose. A total of five pharmacokinetic samples per participants were taken at Weeks 4, 8,12,18 and Week 24. The SB-742457 exposures at steady state Cmin-ss for each participant were estimated via nonlinear mixed effect analysis. Data has been presented in a consolidated format for SB-742457 exposures at steady state Cmin-ss.

Exposure Estimates for Donepezil Average Concentration at Steady State (Cavgss)

Blood sample for pharmacokinetic analysis, were obtained within 24 hours of last dose. A total of five pharmacokinetic samples per participants were taken at Weeks 4, 8,12,18 and Week 24. The Donepezil exposures at steady state Cavgss for each participant were estimated via nonlinear mixed effect analysis. Data has been presented in a consolidated format for SB-742457 exposures at steady state Cavgss.

Full Information

NCT ID

NCT00708552

First Posted

June 30, 2008

Last Updated

May 31, 2018

Sponsor

GlaxoSmithKline

1. Study Identification

Unique Protocol Identification Number

NCT00708552

Brief Title

Study of SB-742457 or Donepezil Versus Placebo in Subjects With Mild-to-moderate Alzheimer's Disease

Official Title

Study AZ3110865, a Study Comparing SB-742457 or Donepezil Versus Placebo in Subjects With Mild-to-moderate Alzheimer's Disease

Study Type

Interventional

2. Study Status

Record Verification Date

May 2018

Overall Recruitment Status

Completed

Study Start Date

July 4, 2008 (undefined)

Primary Completion Date

March 1, 2010 (Actual)

Study Completion Date

March 9, 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

GlaxoSmithKline

4. Oversight

5. Study Description

Brief Summary

The study is designed to investigate the efficacy, safety and tolerability of SB-742457 versus placebo in subjects with mild-to-moderate Alzheimer's disease. SB-742457 is an experimental treatment which increases the levels of certain chemicals in the brain that are often decreased in patients with Alzheimer's disease.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Alzheimer's Disease

Keywords

Alzheimer's disease, Cognition, SB-742457

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

576 (Actual)

8. Arms, Groups, and Interventions

Arm Title

SB-742457 - 15mg

Arm Type

Experimental

Arm Description

SB-742457 - 15mg

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Title

SB-742457 - 35mg

Arm Type

Experimental

Arm Description

SB-742457 - 35mg

Arm Title

Donepezil

Arm Type

Active Comparator

Intervention Type

Drug

Intervention Name(s)

SB-742457

Intervention Description

investigational drug

Intervention Type

Drug

Intervention Name(s)

Donepezil

Intervention Description

comparator

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

comparator

Primary Outcome Measure Information:

Title

Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score at Week 24

Description

Time Frame

Baseline (Week 0) and Week 24

Title

Clinician's Interview-Based Impression of Change - Plus (CIBIC+) Score at Week 24

Description

Time Frame

Week 24

Secondary Outcome Measure Information:

Title

Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score at Week 24

Description

Time Frame

Baseline (Week 0) and Week 24

Title

Description

Time Frame

Baseline (Week 0) and Week 24

Title

Description

The MMSE was used to measure cognitive impairment. The MMSE consists of 11 tests namely orientation to time, orientation to place, registration, attention and calculation, recall, naming, repetition, comprehension, reading, writing and drawing corresponding to 5 domains orientation, memory, attention, and construction. All items were scored as 0 (incorrect response) or 1 (correct response). Total scores ranges from 0 to 30, with lower scores indicating greater cognitive impairment and higher scores indicating better function. Stratification by Baseline severity, using MMSE score at Baseline, with the strata being MMSE score of 10-15, 16-20 and 21-26. Two subgroups using MMSE score at Baseline were also examined, moderate 10-20 and mild 16-26. Data has been presented for participants with Baseline MMSE 10-20. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Time Frame

Baseline (Week 0) and Week 24

Title

Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 16-26) on the CIBIC+ Score at Week 24

Description

Time Frame

Baseline (Week 0) and Week 24

Title

Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 10-20) on the CIBIC+ Score at Week 24

Description

The CIBIC+ is a rating scale derived from an interview with the participant and caregiver with an independent rater designed to measure several domains of participant function, such as mental/cognitive state, behavior, and functioning. The scores are rated on a scale of 1 to 7 as follows: 1 (marked improvement), 2 (moderately improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (moderately worse) and 7 (markedly worse). Higher scores indicate worst outcome. Stratification by Baseline severity, using MMSE score at Baseline, with the strata being MMSE score of 10-15, 16-20 and 21-26. Two subgroups using MMSE score at Baseline were also examined, moderate 10-20 and mild 16-26. Data has been presented for participants with baseline MMSE 10-20. Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Time Frame

Baseline (Week 0) and Week 24

Title

Change From Baseline in ADAS-Cog Total Score at Week 12

Description

ADAS-Cog assesses a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Most items are evaluated by tests, but some are dependent on clinician ratings on a five point scale. The ADAS-Cog total score is the sum of the calculated scores for Questions 1 (Word recall task), 2 (Naming objects and fingers), and 7 (Word recognition task) and the scores recorded on the CRF for Questions 3 to 6 (Commands, Constructional praxis, Ideational praxis, Orientation) and 8 to 11 (Remembering test instructions, Spoken language ability, Word finding difficulty in spontaneous speech, Comprehension). The total score ranges from 0-70 with higher scores indicating greater dysfunction while lower indicates better cognitive function. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 12.

Time Frame

Baseline (Week 0) and Week 12

Title

CIBIC+ Score at Week 12

Description

Time Frame

Week 12

Title

Change From Baseline in RBANS Total Score at Week 12

Description

Time Frame

Baseline (Week 0) and Week 12

Title

Description

The MMSE was used to measure cognitive impairment. The MMSE consists of 11 tests namely orientation to time, orientation to place, registration, attention and calculation, recall, naming, repetition, comprehension, reading, writing and drawing corresponding to 5 domains orientation, memory, attention, and construction. All items were scored as 0 (incorrect response) or 1 (correct response). Total scores ranges from 0 to 30, with lower scores indicating greater cognitive impairment and higher scores indicating better function. Stratification by Baseline severity, using MMSE score at Baseline, with the strata being MMSE score of 10-15, 16-20 and 21-26. Two subgroups using MMSE score at Baseline were also examined, moderate 10-20 and mild 16-26. Data has been presented for Participants with Baseline MMSE score 16-26. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 12.

Time Frame

Baseline (Week 0) and Week 12

Title

Description

The MMSE was used to measure cognitive impairment. The MMSE consists of 11 tests namely orientation to time, orientation to place, registration, attention and calculation, recall, naming, repetition, comprehension, reading, writing and drawing corresponding to 5 domains orientation, memory, attention, and construction. All items were scored as 0 (incorrect response) or 1 (correct response). Total scores ranges from 0 to 30, with lower scores indicating greater cognitive impairment and higher scores indicating better function. Stratification by Baseline severity, using MMSE score at Baseline, with the strata being MMSE score of 10-15, 16-20 and 21-26. Two subgroups using MMSE score at Baseline were also examined, moderate 10-20 and mild 16-26. Data has been presented for participants with Baseline MMSE score 10-20. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 12.

Time Frame

Baseline (Week 0) and Week 12

Title

Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 16-26) on the CIBIC+ Score at Week 12

Description

Time Frame

Week 12

Title

Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 10-20) on the CIBIC+ Score at Week 12

Description

Time Frame

Week 12

Title

Change From Baseline in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Total Score at Weeks 12 and 24

Description

Time Frame

Baseline (Week 0) and Weeks 12 and 24

Title

Change From Baseline in Cornell Scale for Depression in Dementia (CSDD) Total Score at Week 24

Description

Time Frame

Baseline (Week 0) and Week 24

Title

Change From Baseline in MMSE Total Score at Week 24

Description

Time Frame

Baseline (Week 0) and Week 24

Title

Change From Baseline in ADCS-ADL-Basic Score; ADCS-ADL: Instrumental Score and ADCS-ADL: Total Independence Score at Weeks 12 and 24

Description

Time Frame

Baseline (Week 0) and Weeks 12 and 24

Title

Number of Participants With Any Adverse Event (Serious and Non-serious) and Serious Adverse Events (SAEs)

Description

Time Frame

Upto Week 24

Title

Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT)

Description

Time Frame

Upto Week 24

Title

Number of Participants With Hematology Data of PCC ATOT

Description

Time Frame

Upto Week 24

Title

Number of Participants With Chemistry Data of PCC ATOT

Description

Time Frame

Upto Week 24

Title

Description

Time Frame

Baseline (Week 0) and Week 24

Title

Change From Baseline in Clinical Chemistry Parameters Albumin and Total Protein at Week 24

Description

Time Frame

Baseline (Week 0) and Week 24

Title

Change From Baseline in Clinical Chemistry Parameter Blood Urea Nitrogen /Creatinine Ratio at Week 24

Description

Time Frame

Baseline (Week 0) and Week 24

Title

Description

Time Frame

Baseline (Week 0) and Week 24

Title

Change From Baseline in Clinical Chemistry Parameters Creatinine, Direct Bilirubin and Total Bilirubin at Week 24

Description

Time Frame

Baseline (Week 0) and Week 24

Title

Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24

Description

Time Frame

Baseline (Week 0) and Week 24

Title

Change From Baseline in Hematology Parameter Hematocrit

Description

Time Frame

Baseline (Week 0) and Week 24

Title

Change From Baseline in Hematology Parameters Hemoglobin and Mean Corpuscle Hemoglobin Concentration at Week 24

Description

Time Frame

Baseline (Week 0) and Week 24

Title

Change From Baseline in Hematology Parameter Mean Corpuscle Hemoglobin at Week 24

Description

Time Frame

Baseline (Week 0) and Week 24

Title

Change From Baseline in Hematology Parameter Mean Corpuscle Volume and Mean Platelet Volume at Week 24

Description

Time Frame

Baseline (Week 0) and Week 24

Title

Change From Baseline in Hematology Parameter Red Blood Cell Count at Week 24

Description

Time Frame

Baseline (Week 0) and Week 24

Title

Number of Participants With Electrocardiogram (ECG) Findings as Assessed by Investigator and Central Cardiologist

Description

Time Frame

Upto Week 24

Title

Exposure Estimates for SB-742457 Area Under Curve Over the Dosing Interval at Steady State (AUCτss)

Description

Time Frame

One sample at Day 28±5, 56±5, 84±5, 126±5 and 168±5 post 24 hours of last dose

Title

Exposure Estimates for SB-742457 Minimum Concentration at Steady State (Cmin-ss)

Description

Time Frame

One sample at Day 28±5, 56±5, 84±5, 126±5 and 168±5 post 24 hours of last dose

Title

Exposure Estimates for Donepezil Average Concentration at Steady State (Cavgss)

Description

Blood sample for pharmacokinetic analysis, were obtained within 24 hours of last dose. A total of five pharmacokinetic samples per participants were taken at Weeks 4, 8,12,18 and Week 24. The Donepezil exposures at steady state Cavgss for each participant were estimated via nonlinear mixed effect analysis. Data has been presented in a consolidated format for SB-742457 exposures at steady state Cavgss.

Time Frame

Weeks 4, 8,12,18 and Week 24

10. Eligibility

Sex

All

Minimum Age & Unit of Time

50 Years

Maximum Age & Unit of Time

85 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion criteria: Subjects and their caregivers must provide informed consent prior to study entry. Subjects must have a clinical diagnosis of probable mild-to-moderate Alzheimer's disease with a documented 6-month history of AD symptoms Subjects must have a regular caregiver who is willing to attend visits, oversee the subject's compliance with the study and report on the subject's status. Female subjects of child-bearing potential must agree to pregnancy testing and approved form of birth control. Exclusion criteria: Diagnosis of possible, probable or definite vascular dementia. History/evidence of any other CNS disorder that could be interpreted as a cause of dementia History of known or suspected seizures, loss of consciousness or significant head trauma Subjects with ECG, blood pressure and laboratory values outside of protocol criteria are excluded. Subjects with known photosensitivity Subjects with a history of previous exposure to SB-742457, taking agents for which there is a theoretical risk of interaction with SB-742457, or taking medication for Alzheimer's disease or centrally acting agents which might impact study outcomes may not participate.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

GSK Clinical Trials

Organizational Affiliation

GlaxoSmithKline

Official's Role

Study Director

Facility Information:

Facility Name

GSK Investigational Site

City

Shumen

ZIP/Postal Code

9700

Country

Bulgaria

Facility Name

GSK Investigational Site

City

Sofia

ZIP/Postal Code

1113

Country

Bulgaria

Facility Name

GSK Investigational Site

City

Sofia

ZIP/Postal Code

1431

Country

Bulgaria

Facility Name

GSK Investigational Site

City

Varna

ZIP/Postal Code

9010

Country

Bulgaria

Facility Name

GSK Investigational Site

City

Santiago

State/Province

Región Metro De Santiago

ZIP/Postal Code

7510186

Country

Chile

Facility Name

GSK Investigational Site

City

Santiago

State/Province

Región Metro De Santiago

ZIP/Postal Code

7560356

Country

Chile

Facility Name

GSK Investigational Site

City

Viña del Mar

State/Province

Valparaíso

ZIP/Postal Code

252-0997

Country

Chile

Facility Name

GSK Investigational Site

City

Santiago

Country

Chile

Facility Name

GSK Investigational Site

City

Brno

ZIP/Postal Code

656 91

Country

Czechia

Facility Name

GSK Investigational Site

City

Olomouc

ZIP/Postal Code

775 20

Country

Czechia

Facility Name

GSK Investigational Site

City

Praha 10

ZIP/Postal Code

100 00

Country

Czechia

Facility Name

GSK Investigational Site

City

Praha 10

ZIP/Postal Code

10000

Country

Czechia

Facility Name

GSK Investigational Site

City

Praha 1

ZIP/Postal Code

110 00

Country

Czechia

Facility Name

GSK Investigational Site

City

Praha 2

ZIP/Postal Code

120 00

Country

Czechia

Facility Name

GSK Investigational Site

City

Tallinn

ZIP/Postal Code

10138

Country

Estonia

Facility Name

GSK Investigational Site

City

Tallinn

ZIP/Postal Code

10617

Country

Estonia

Facility Name

GSK Investigational Site

City

Tartu

ZIP/Postal Code

51014

Country

Estonia

Facility Name

GSK Investigational Site

City

Stuttgart

State/Province

Baden-Wuerttemberg

ZIP/Postal Code

70178

Country

Germany

Facility Name

GSK Investigational Site

City

Tuebingen

State/Province

Baden-Wuerttemberg

ZIP/Postal Code

72076

Country

Germany

Facility Name

GSK Investigational Site

City

Muenchen

State/Province

Bayern

ZIP/Postal Code

80331

Country

Germany

Facility Name

GSK Investigational Site

City

Muenchen

State/Province

Bayern

ZIP/Postal Code

81675

Country

Germany

Facility Name

GSK Investigational Site

City

Neuburg / Donau

State/Province

Bayern

ZIP/Postal Code

86633

Country

Germany

Facility Name

GSK Investigational Site

City

Nuernberg

State/Province

Bayern

ZIP/Postal Code

90402

Country

Germany

Facility Name

GSK Investigational Site

City

Unterhaching

State/Province

Bayern

ZIP/Postal Code

82008

Country

Germany

Facility Name

GSK Investigational Site

City

Bad Homburg

State/Province

Hessen

ZIP/Postal Code

61348

Country

Germany

Facility Name

GSK Investigational Site

City

Erbach

State/Province

Hessen

ZIP/Postal Code

64711

Country

Germany

Facility Name

GSK Investigational Site

City

Huettenberg

State/Province

Hessen

ZIP/Postal Code

35625

Country

Germany

Facility Name

GSK Investigational Site

City

Achim

State/Province

Niedersachsen

ZIP/Postal Code

28832

Country

Germany

Facility Name

GSK Investigational Site

City

Hannover

State/Province

Niedersachsen

ZIP/Postal Code

30559

Country

Germany

Facility Name

GSK Investigational Site

City

Bochum

State/Province

Nordrhein-Westfalen

ZIP/Postal Code

44805

Country

Germany

Facility Name

GSK Investigational Site

City

Bochum

State/Province

Nordrhein-Westfalen

ZIP/Postal Code

44892

Country

Germany

Facility Name

GSK Investigational Site

City

Dueren

State/Province

Nordrhein-Westfalen

ZIP/Postal Code

52349

Country

Germany

Facility Name

GSK Investigational Site

City

Duisburg

State/Province

Nordrhein-Westfalen

ZIP/Postal Code

47051

Country

Germany

Facility Name

GSK Investigational Site

City

Hattingen

State/Province

Nordrhein-Westfalen

ZIP/Postal Code

45525

Country

Germany

Facility Name

GSK Investigational Site

City

Koeln

State/Province

Nordrhein-Westfalen

ZIP/Postal Code

50935

Country

Germany

Facility Name

GSK Investigational Site

City

Siegen

State/Province

Nordrhein-Westfalen

ZIP/Postal Code

57072

Country

Germany

Facility Name

GSK Investigational Site

City

Dresden

State/Province

Sachsen

ZIP/Postal Code

01097

Country

Germany

Facility Name

GSK Investigational Site

City

Leipzig

State/Province

Sachsen

ZIP/Postal Code

04107

Country

Germany

Facility Name

GSK Investigational Site

City

Leipzig

State/Province

Sachsen

ZIP/Postal Code

04157

Country

Germany

Facility Name

GSK Investigational Site

City

Hamburg

ZIP/Postal Code

20249

Country

Germany

Facility Name

GSK Investigational Site

City

Athens

ZIP/Postal Code

115 21

Country

Greece

Facility Name

GSK Investigational Site

City

Athens

ZIP/Postal Code

11528

Country

Greece

Facility Name

GSK Investigational Site

City

Athens

Country

Greece

Facility Name

GSK Investigational Site

City

Melissia

ZIP/Postal Code

151 27

Country

Greece

Facility Name

GSK Investigational Site

City

Thessaloniki

ZIP/Postal Code

57010

Country

Greece

Facility Name

GSK Investigational Site

City

Busan

ZIP/Postal Code

602-715

Country

Korea, Republic of

Facility Name

GSK Investigational Site

City

Seoul

ZIP/Postal Code

133-792

Country

Korea, Republic of

Facility Name

GSK Investigational Site

City

Seoul

ZIP/Postal Code

135-710

Country

Korea, Republic of

Facility Name

GSK Investigational Site

City

Seoul

ZIP/Postal Code

138-736

Country

Korea, Republic of

Facility Name

GSK Investigational Site

City

Seoul

ZIP/Postal Code

158-710

Country

Korea, Republic of

Facility Name

GSK Investigational Site

City

Aguascalientes, Ags

State/Province

Aguascalientes

ZIP/Postal Code

20127

Country

Mexico

Facility Name

GSK Investigational Site

City

Tijuana

State/Province

Baja California Norte

ZIP/Postal Code

22320

Country

Mexico

Facility Name

GSK Investigational Site

City

Saltillo

State/Province

Coahuila

ZIP/Postal Code

25000

Country

Mexico

Facility Name

GSK Investigational Site

City

Monterrey

State/Province

Nuevo León

ZIP/Postal Code

64660

Country

Mexico

Facility Name

GSK Investigational Site

City

Mexico City

ZIP/Postal Code

06700

Country

Mexico

Facility Name

GSK Investigational Site

City

Mexico, D.F.

ZIP/Postal Code

14050

Country

Mexico

Facility Name

GSK Investigational Site

City

Bydgoszcz

ZIP/Postal Code

85-094

Country

Poland

Facility Name

GSK Investigational Site

City

Bydgoszcz

ZIP/Postal Code

85-796

Country

Poland

Facility Name

GSK Investigational Site

City

Mosina

ZIP/Postal Code

62-050

Country

Poland

Facility Name

GSK Investigational Site

City

Poznan

ZIP/Postal Code

61-298

Country

Poland

Facility Name

GSK Investigational Site

City

Sopot

ZIP/Postal Code

81-824

Country

Poland

Facility Name

GSK Investigational Site

City

Warsaw

ZIP/Postal Code

02-097

Country

Poland

Facility Name

GSK Investigational Site

City

Moscow

ZIP/Postal Code

115522

Country

Russian Federation

Facility Name

GSK Investigational Site

City

Moscow

ZIP/Postal Code

115552

Country

Russian Federation

Facility Name

GSK Investigational Site

City

Moscow

ZIP/Postal Code

117049

Country

Russian Federation

Facility Name

GSK Investigational Site

City

St.-Petersburg

ZIP/Postal Code

198103

Country

Russian Federation

Facility Name

GSK Investigational Site

City

Durban

ZIP/Postal Code

4001

Country

South Africa

Facility Name

GSK Investigational Site

City

Loeventstein

ZIP/Postal Code

7530

Country

South Africa

Facility Name

GSK Investigational Site

City

Oakdale

ZIP/Postal Code

7530

Country

South Africa

Facility Name

GSK Investigational Site

City

Pretoria

ZIP/Postal Code

0181

Country

South Africa

Facility Name

GSK Investigational Site

City

Rosebank

ZIP/Postal Code

2196

Country

South Africa

Facility Name

GSK Investigational Site

City

Sunninghill

ZIP/Postal Code

2157

Country

South Africa

12. IPD Sharing Statement

Citations:

PubMed Identifier

29854923

Citation

Maher-Edwards G, Watson C, Ascher J, Barnett C, Boswell D, Davies J, Fernandez M, Kurz A, Zanetti O, Safirstein B, Schronen JP, Zvartau-Hind M, Gold M. Two randomized controlled trials of SB742457 in mild-to-moderate Alzheimer's disease. Alzheimers Dement (N Y). 2015 May 7;1(1):23-36. doi: 10.1016/j.trci.2015.04.001. eCollection 2015 Jun.

Results Reference

derived

Learn more about this trial

Study of SB-742457 or Donepezil Versus Placebo in Subjects With Mild-to-moderate Alzheimer's Disease

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Study of SB-742457 or Donepezil Versus Placebo in Subjects With Mild-to-moderate Alzheimer's Disease

Alzheimer's Disease

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial