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

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ClinicalTrials.gov Identifier: NCT00708552
Recruitment Status : Completed
First Posted : July 2, 2008
Results First Posted : February 12, 2018
Last Update Posted : February 12, 2018
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition: Alzheimer's Disease
Interventions: Drug: SB-742457
Drug: Donepezil
Drug: Placebo

  Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
This study was conducted at 68 centers in the following 11 countries: Bulgaria, Chile, Czech Republic, Estonia, Germany, Greece, Korea, Mexico, Poland, Russia, and South Africa from 04 July 2008 to 09 Mar 2010 and a total of 967 participants were screened over the recruitment period of 55 weeks.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Of 967 participants screened, 618 (349 screen failures) entered into the placebo run-in period and a total of 576 (42 placebo run-in failures) were randomized of which 2 participants did not take study medication, formed Safety population (574) comprising of randomized participants who took atleast one dose of study medication.

Reporting Groups
  Description
Placebo Participants received one tablet of matching placebo to SB-742457 (Week 1 to 4) and one capsule of matching placebo orally each evening just prior to going to bed (Week 4 to 24).
SB-742457-15mg Participants received one tablet of SB-742457-15 milligrams (mg) and one capsule of matching placebo to Donepezil orally each evening just prior to going to bed in the two treatment period (Week 1 to 4 and Week 4 to 24).
SB-742457-35mg Participants received one tablet of SB-742457-35 mg and one capsule of matching placebo to Donepezil orally each evening just prior to going to bed in the two treatment period (Week 1 to 4 and Week 4 to 24).
Donepezil Participants received Donepezil capsule by one-step titration 5mg Donepezil once daily (Week 1 to Week 4) before up-titrating at Visit 4 (Week 4) to 10 mg once daily dose for the remaining 20 weeks of the treatment period (Week 4 to 24) along with matching placebo to SB-747457.

Participant Flow:   Overall Study
    Placebo   SB-742457-15mg   SB-742457-35mg   Donepezil
STARTED   145   145   133   151 
COMPLETED   118   127   118   130 
NOT COMPLETED   27   18   15   21 
Adverse Event                10                3                4                6 
Lack of Efficacy                0                4                1                0 
Protocol Violation                0                0                2                4 
Lost to Follow-up                4                2                0                1 
Physician Decision                1                2                0                0 
Withdrawal by Subject                12                7                8                10 



  Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The population used to define the Baseline Characteristics was the Intent-to-Treat (ITT Population) which comprised of all participants randomized to treatment, and who received at least one dose of study medication and who had at least one post baseline assessment.

Reporting Groups
  Description
Placebo Participants received one tablet of matching placebo to SB-742457 (Week 1 to 4) and one capsule of matching placebo orally each evening just prior to going to bed (Week 4 to 24).
SB-742457-15mg Participants received one tablet of SB-742457-15 mg and one capsule of matching placebo to Donepezil orally each evening just prior to going to bed in the two treatment period (Week 1 to 4 and Week 4 to 24).
SB-742457-35mg Participants received one tablet of SB-742457-35 mg and one capsule of matching placebo to Donepezil orally each evening just prior to going to bed in the two treatment period (Week 1 to 4 and Week 4 to 24).
Donepezil Participants received Donepezil capsule by one-step titration 5mg Donepezil once daily (Week 1 to Week 4) before up-titrating at Visit 4 (Week 4) to 10 mg once daily dose for the remaining 20 weeks of the treatment period (Week 4 to 24) along with matching placebo to SB-747457.
Total Total of all reporting groups

Baseline Measures
   Placebo   SB-742457-15mg   SB-742457-35mg   Donepezil   Total 
Overall Participants Analyzed 
[Units: Participants]
 135   142   130   147   554 
Age 
[Units: Years]
Mean (Standard Deviation)
 73.3  (6.80)   72.4  (8.12)   72.5  (7.38)   71.1  (7.49)   72.3  (7.49) 
Sex: Female, Male 
[Units: Participants]
Count of Participants
         
Female      87  64.4%      96  67.6%      75  57.7%      95  64.6%      353  63.7% 
Male      48  35.6%      46  32.4%      55  42.3%      52  35.4%      201  36.3% 
Race (NIH/OMB) 
[Units: Participants]
Count of Participants
         
American Indian or Alaska Native      3   2.2%      9   6.3%      5   3.8%      9   6.1%      26   4.7% 
Asian      4   3.0%      7   4.9%      6   4.6%      6   4.1%      23   4.2% 
Native Hawaiian or Other Pacific Islander      0   0.0%      0   0.0%      0   0.0%      0   0.0%      0   0.0% 
Black or African American      0   0.0%      0   0.0%      1   0.8%      2   1.4%      3   0.5% 
White      128  94.8%      126  88.7%      118  90.8%      130  88.4%      502  90.6% 
More than one race      0   0.0%      0   0.0%      0   0.0%      0   0.0%      0   0.0% 
Unknown or Not Reported      0   0.0%      0   0.0%      0   0.0%      0   0.0%      0   0.0% 


  Outcome Measures

1.  Primary:   Change From Baseline in Alzheimer's Disease Assessment Scale – Cognitive Subscale (ADAS-Cog) Total Score at Week 24   [ Time Frame: Baseline (Week 0) and Week 24 ]

2.  Primary:   Clinician’s Interview-Based Impression of Change – Plus (CIBIC+) Score at Week 24   [ Time Frame: Week 24 ]

3.  Secondary:   Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score at Week 24   [ Time Frame: Baseline (Week 0) and Week 24 ]

4.  Secondary:   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   [ Time Frame: Baseline (Week 0) and Week 24 ]

5.  Secondary:   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   [ Time Frame: Baseline (Week 0) and Week 24 ]

6.  Secondary:   Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 16-26) on the CIBIC+ Score at Week 24   [ Time Frame: Baseline (Week 0) and Week 24 ]

7.  Secondary:   Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 10-20) on the CIBIC+ Score at Week 24   [ Time Frame: Baseline (Week 0) and Week 24 ]

8.  Secondary:   Change From Baseline in ADAS-Cog Total Score at Week 12   [ Time Frame: Baseline (Week 0) and Week 12 ]

9.  Secondary:   CIBIC+ Score at Week 12   [ Time Frame: Week 12 ]

10.  Secondary:   Change From Baseline in RBANS Total Score at Week 12   [ Time Frame: Baseline (Week 0) and Week 12 ]

11.  Secondary:   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   [ Time Frame: Baseline (Week 0) and Week 12 ]

12.  Secondary:   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   [ Time Frame: Baseline (Week 0) and Week 12 ]

13.  Secondary:   Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 16-26) on the CIBIC+ Score at Week 12   [ Time Frame: Week 12 ]

14.  Secondary:   Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 10-20) on the CIBIC+ Score at Week 12   [ Time Frame: Week 12 ]

15.  Secondary:   Change From Baseline in Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) Total Score at Weeks 12 and 24   [ Time Frame: Baseline (Week 0) and Weeks 12 and 24 ]

16.  Secondary:   Change From Baseline in Cornell Scale for Depression in Dementia (CSDD) Total Score at Week 24   [ Time Frame: Baseline (Week 0) and Week 24 ]

17.  Secondary:   Change From Baseline in MMSE Total Score at Week 24   [ Time Frame: Baseline (Week 0) and Week 24 ]

18.  Secondary:   Change From Baseline in ADCS-ADL-Basic Score; ADCS-ADL: Instrumental Score and ADCS-ADL: Total Independence Score at Weeks 12 and 24   [ Time Frame: Baseline (Week 0) and Weeks 12 and 24 ]

19.  Secondary:   Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)   [ Time Frame: Upto Week 24 ]

20.  Secondary:   Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT)   [ Time Frame: Upto Week 24 ]

21.  Secondary:   Number of Participants With Hematology Data of PCC ATOT   [ Time Frame: Upto Week 24 ]

22.  Secondary:   Number of Participants With Chemistry Data of PCC ATOT   [ Time Frame: Upto Week 24 ]

23.  Secondary:   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   [ Time Frame: Baseline (Week 0) and Week 24 ]

24.  Secondary:   Change From Baseline in Clinical Chemistry Parameters Albumin and Total Protein at Week 24   [ Time Frame: Baseline (Week 0) and Week 24 ]

25.  Secondary:   Change From Baseline in Clinical Chemistry Parameter Blood Urea Nitrogen /Creatinine Ratio at Week 24   [ Time Frame: Baseline (Week 0) and Week 24 ]

26.  Secondary:   Change From Baseline in Clinical Chemistry Parameters Calcium, CO2 Content/Bicarbonate, Chloride, Cholesterol, Glucose, HDL Cholesterol, LDL Cholesterol, Magnesium, Phosphorus, Potassium, Sodium, Triglycerides, Urea/Blood Urea Nitrogen at Week 24   [ Time Frame: Baseline (Week 0) and Week 24 ]

27.  Secondary:   Change From Baseline in Clinical Chemistry Parameters Creatinine, Direct Bilirubin and Total Bilirubin at Week 24   [ Time Frame: Baseline (Week 0) and Week 24 ]

28.  Secondary:   Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24   [ Time Frame: Baseline (Week 0) and Week 24 ]

29.  Secondary:   Change From Baseline in Hematology Parameter Hematocrit   [ Time Frame: Baseline (Week 0) and Week 24 ]

30.  Secondary:   Change From Baseline in Hematology Parameters Hemoglobin and Mean Corpuscle Hemoglobin Concentration at Week 24   [ Time Frame: Baseline (Week 0) and Week 24 ]

31.  Secondary:   Change From Baseline in Hematology Parameter Mean Corpuscle Hemoglobin at Week 24   [ Time Frame: Baseline (Week 0) and Week 24 ]

32.  Secondary:   Change From Baseline in Hematology Parameter Mean Corpuscle Volume and Mean Platelet Volume at Week 24   [ Time Frame: Baseline (Week 0) and Week 24 ]

33.  Secondary:   Change From Baseline in Hematology Parameter Red Blood Cell Count at Week 24   [ Time Frame: Baseline (Week 0) and Week 24 ]

34.  Secondary:   Number of Participants With Electrocardiogram (ECG) Findings as Assessed by Investigator and Central Cardiologist   [ Time Frame: Upto Week 24 ]

35.  Secondary:   Exposure Estimates for SB-742457 Area Under Curve Over the Dosing Interval at Steady State (AUCτss)   [ Time Frame: Weeks 4, 8,12,18 and Week 24 ]

36.  Secondary:   Exposure Estimates for SB-742457 Minimum Concentration at Steady State (Cmin-ss)   [ Time Frame: Weeks 4, 8,12,18 and Week 24 ]

37.  Secondary:   Exposure Estimates for Donepezil Average Concentration at Steady State (Cavgss)   [ Time Frame: Weeks 4, 8,12,18 and Week 24 ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


  More Information

Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: GSK Response Center
Organization: GlaxoSmithKline
phone: 866-435-7343



Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00708552     History of Changes
Other Study ID Numbers: AZ3110865
First Submitted: June 30, 2008
First Posted: July 2, 2008
Results First Submitted: July 24, 2017
Results First Posted: February 12, 2018
Last Update Posted: February 12, 2018