Trial Outcomes & Findings for Rosiglitazone (Extended Release Tablets) As Monotherapy In Subjects With Mild To Moderate Alzheimer's Disease (NCT NCT00428090)

Last Updated: 2017-05-19

Results Overview

The 11-item ADAS-Cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Items were evaluated by tests and clinician ratings on a 5-point scale. Scores ranged from 0-70 with higher scores indicates more dysfunction. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline is defined as value at W0. Estimated value was calculated by Active treatment minus Placebo. The adjusted means were presented. A hierarchical testing procedure was used to control for the two rosiglitazone dose groups and the three genetic subgroups. There was no adjustment for the donepezil versus placebo comparisons, which were included to assess the sensitivity of the trial to detect a treatment effect.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

862 participants

Primary outcome timeframe

Baseline (W0) and W24

Results posted on

2017-05-19

Participant Flow

Participants (par.) were enrolled across 134 centres Austria, Bulgaria, Chile, China, Crotia, Estonia, Germany, Greece, Hungry, Korea, Mexico, New Zealand, Pakistan, Peru, Philippines, Puerto Rico, Russia, the United Kingdom and the United States from February 2007 to September 2008. The total study duration was 30 weeks (W).

Total of 639 par. were screened out of which 581 were randomized and 58 were placebo run-in failures. Analysis population included 579 par. of 581 randomized participants as 2 par. did not take study drug: 1 from placebo and 1 from donepezil arm.

Participant milestones

Participant milestones
Measure	Placebo Par. in this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg Par. in this arm received rosiglitazone extended release (RSGXR) 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg Par. in this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4W of treatment. From Visit 4 (W4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg Par. in this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4W of treatment. From Visit 4 (W4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Overall Study STARTED	165	166	165	83
Overall Study COMPLETED	131	135	127	55
Overall Study NOT COMPLETED	34	31	38	28

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Par. in this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg Par. in this arm received rosiglitazone extended release (RSGXR) 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg Par. in this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4W of treatment. From Visit 4 (W4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg Par. in this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4W of treatment. From Visit 4 (W4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Overall Study Adverse Event	10	8	10	11
Overall Study Lost to Follow-up	3	6	1	4
Overall Study Protocol Violation	3	1	3	3
Overall Study Withdrawal by Subject	10	12	15	5
Overall Study Sponsor terminated study	0	1	0	0
Overall Study Non-compliance	4	0	1	3
Overall Study Par. did not returned to visit	1	0	0	1
Overall Study Follow-Up visit not possible	1	0	0	0
Overall Study Prohibited medication used for SAE	1	0	0	0
Overall Study Death of par.	1	0	1	0
Overall Study Visit 7 exceed the visit window	0	1	0	0
Overall Study Medical monitor terminated par.	0	1	0	0
Overall Study Mental status of par. was	0	1	0	0
Overall Study Worsening of AD	0	0	1	0
Overall Study Excluded for concerning QTc value	0	0	1	0
Overall Study Insufficient AD documentation	0	0	1	0
Overall Study High MMSE scores	0	0	1	0
Overall Study Deterioration of cognitive status	0	0	1	0
Overall Study Serious adverse event	0	0	1	0
Overall Study Excluded for heart insufficiency	0	0	1	0
Overall Study Raised Creatinine Value	0	0	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=159 Participants Par. in this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=162 Participants Par. in this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=156 Participants Par. in this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4W of treatment. From Visit 4 (W4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=76 Participants Par. in this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4W of treatment. From Visit 4 (W4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Total n=553 Participants Total of all reporting groups
Age, Continuous	72.5 Years STANDARD_DEVIATION 8.56 • n=5 Participants	71.7 Years STANDARD_DEVIATION 7.91 • n=7 Participants	72.6 Years STANDARD_DEVIATION 8.63 • n=5 Participants	72.9 Years STANDARD_DEVIATION 7.97 • n=4 Participants	72.4 Years STANDARD_DEVIATION 8.30 • n=21 Participants
Sex: Female, Male Female	95 Participants n=5 Participants	103 Participants n=7 Participants	101 Participants n=5 Participants	48 Participants n=4 Participants	347 Participants n=21 Participants
Sex: Female, Male Male	64 Participants n=5 Participants	59 Participants n=7 Participants	55 Participants n=5 Participants	28 Participants n=4 Participants	206 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants	0 Participants n=4 Participants	4 Participants n=21 Participants
Race (NIH/OMB) Asian	33 Participants n=5 Participants	50 Participants n=7 Participants	37 Participants n=5 Participants	14 Participants n=4 Participants	134 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants	3 Participants n=4 Participants	7 Participants n=21 Participants
Race (NIH/OMB) White	123 Participants n=5 Participants	109 Participants n=7 Participants	112 Participants n=5 Participants	57 Participants n=4 Participants	401 Participants n=21 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants	2 Participants n=4 Participants	7 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants

PRIMARY outcome

Timeframe: Baseline (W0) and W24

Population: ITT Population. Only those par. available at the indicated time points were analyzed. These comparisons were conducted for APOE e4 negative (neg) par. (e2/e2, e2/e3, and e3/e3) cohort

Outcome measures

Outcome measures
Measure	Placebo n=63 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=69 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=65 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=28 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Change From Baseline (W0) in Mean ADAS-Cog Total Score at W24 as a Function of APOE e4 Status in Apolipoprotein epsilon4 (APOE e4) Negative Cohort	1.6 Score on a scale Standard Error 0.78	-0.2 Score on a scale Standard Error 0.67	0.6 Score on a scale Standard Error 0.67	0.9 Score on a scale Standard Error 1.16

PRIMARY outcome

Timeframe: Baseline (W0) and W24

Population: ITT Population. Only those par. available at the indicated time points were analyzed. These comparisons were conducted in all except e4/e4's: comprised of APOE e4 neg par. (e2/e2, e2/e3, and e3/e3) and APOE e4 heterozygote par. (e2/e4, e3/e4)

The 11-item ADAS-Cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Items were evaluated by tests and clinician ratings on a 5-point scale. Scores ranged from 0-70 with higher scores indicates more dysfunction. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline is defined as value at W0. Estimated value was calculated by Active treatment minus Placebo. A hierarchical testing procedure was used to control for the two rosiglitazone dose groups and the three genetic subgroups. There was no adjustment for the donepezil versus placebo comparisons, which were included to assess the sensitivity of the trial to detect a treatment effect.

Outcome measures

Outcome measures
Measure	Placebo n=117 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=115 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=112 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=49 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Change From Baseline (W0) in Mean ADAS-Cog Total Score at W24 as a Function of APOE e4 Status in All Except e4/e4's Cohort	1.5 Score on a scale Standard Error 0.58	0.3 Score on a scale Standard Error 0.54	0.7 Score on a scale Standard Error 0.57	-0.1 Score on a scale Standard Error 0.79

PRIMARY outcome

Timeframe: Baseline (W0) and W24

Population: ITT Population

The 11-item ADAS-Cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Items were evaluated by tests and clinician ratings on a 5-point scale. Scores ranged from 0-70 with higher scores indicates more dysfunction. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline is defined as value at W0. Estimated value was calculated by Active treatment minus Placebo. A hierarchical testing procedure was used to control for the two rosiglitazone dose groups and the three genetic subgroups. There was no adjustment for the donepezil versus placebo comparisons, which were included to assess the sensitivity of the trial to detect a treatment effect.

Outcome measures

Outcome measures
Measure	Placebo n=131 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=130 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=125 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=56 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Change From Baseline (W0) in Mean ADAS-Cog Total Score at W24 as a Function of APOE e4 Status in Full Population Cohort	2.0 Score on a scale Standard Error 0.56	1.2 Score on a scale Standard Error 0.53	1.2 Score on a scale Standard Error 0.55	0.6 Score on a scale Standard Error 0.74

PRIMARY outcome

Timeframe: Baseline (W0) and W24

Population: ITT Population. Only those par. available at the indicated time points were analyzed. These comparisons were conducted in APOE e4 negative (neg) par. (e2/e2, e2/e3, and e3/e3).

The CIBIC+ assessment comprised of a 7-point rating of severity (at baseline) and change (at indicated time points). It was rated on a scale of 1 to 7 as 1: markedly improved, 2.: moderately improved, 3: minimally improved, 4: no change, 5: minimally worse, 6: moderately worse and 7: markedly worse; higher score means greater dysfunction. It was based on interviews with the par. and caregiver by an independent rater. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0. Endpoint treatment differences which were adjusted to take account of missing data are derived. Estimated value was calculated by Active treatment minus Placebo. A hierarchical testing procedure was used to control for the two rosiglitazone dose groups and the three genetic subgroups. There was no adjustment for the donepezil versus placebo comparisons, which were included to assess the sensitivity of the trial to detect a treatment effect.

Outcome measures

Outcome measures
Measure	Placebo n=63 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=71 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=66 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=28 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Change From Baseline (W0) in Mean CIBIC+ Global Functioning Total Score at W24 as a Function of APOE e4 Status in APOE4 Negative Cohort	4.2 Score on a scale Standard Error 0.14	4.2 Score on a scale Standard Error 0.12	4.1 Score on a scale Standard Error 0.11	3.9 Score on a scale Standard Error 0.22

PRIMARY outcome

Timeframe: Baseline (W0) and W24

Outcome measures

Outcome measures
Measure	Placebo n=117 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=117 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=114 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=49 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Change From Baseline (W0) in Mean CIBIC+ Global Functioning Total Score at W24 as a Function of APOE e4 Status in All Except e4/e4's Cohort	4.3 Score on a scale Standard Error 0.10	4.3 Score on a scale Standard Error 0.10	4.1 Score on a scale Standard Error 0.10	3.8 Score on a scale Standard Error 0.17

PRIMARY outcome

Timeframe: Baseline (W0) and W24

Population: ITT Population. Only those par. available at the indicated time points were analyzed. These comparisons were conducted in full population.

Outcome measures

Outcome measures
Measure	Placebo n=131 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=133 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=127 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=56 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Change From Baseline (W0) in Mean CIBIC+ Global Functioning Total Score at W24 as a Function of APOE e4 Status in Full Population Cohort	4.3 Score on a scale Standard Error 0.09	4.3 Score on a scale Standard Error 0.09	4.2 Score on a scale Standard Error 0.10	3.8 Score on a scale Standard Error 0.16

SECONDARY outcome

Timeframe: Baseline (W0) and up to W24

Population: ITT Population. Only those participants available at the specified time points were analyzed (represented as n=x,x,x,x in the category titles).

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 5-point scale. Scores ranged from 0-70 with higher scores indicating greater dysfunction. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline is defined as value at W0. Endpoint treatment differences were adjusted to take account of missing data. It was evaluated at Baseline, W8, W16 and W24.

Outcome measures

Outcome measures
Measure	Placebo n=159 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=162 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=156 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=76 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Change From Baseline (W0) in Mean ADAS-Cog Total Score at W8, W16, W24 ADAS-Cog, W24, n=131, 130,125,156	2.0 Score on a scale Standard Error 0.56	1.2 Score on a scale Standard Error 0.53	1.2 Score on a scale Standard Error 0.55	0.6 Score on a scale Standard Error 0.74
Change From Baseline (W0) in Mean ADAS-Cog Total Score at W8, W16, W24 ADAS-Cog, W8, n=153, 155,147,67	0.4 Score on a scale Standard Error 0.42	-0.5 Score on a scale Standard Error 0.45	0.5 Score on a scale Standard Error 0.43	-0.3 Score on a scale Standard Error 0.63
Change From Baseline (W0) in Mean ADAS-Cog Total Score at W8, W16, W24 ADAS-Cog, W16, n=143,145,132,62	0.5 Score on a scale Standard Error 0.46	0.6 Score on a scale Standard Error 0.49	1.3 Score on a scale Standard Error 0.45	-1.1 Score on a scale Standard Error 0.80

SECONDARY outcome

Timeframe: Baseline (W0) and up to W24

Population: ITT Population. Only those participants available at the specified time points were analyzed (represented as n=x,x,x,x in the category titles).

The CIBIC+ assessment comprised of a 7-point rating of severity (at baseline) and change (at indicated time points). It was rated on a scale of 1 to 7 as 1: markedly improved, 2.: moderately improved, 3: minimally improved, 4: no change, 5: minimally worse, 6: moderately worse and 7: markedly worse; higher score means more dysfunction. The scale was based on interviews with the par. and caregiver and was completed by an independent rater. It required separate structured 15-20 minute interviews with the par. and caregiver. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0. Endpoint treatment differences which were adjusted to take account of missing data are derived. It was evaluated at Baseline, W8, W16 and W24.

Outcome measures

Outcome measures
Measure	Placebo n=159 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=162 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=156 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=76 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Change From Baseline (W0) in Mean CIBIC+ Global Functioning Total Score at W8, W16, W24 CIBIC+, W8, n=150, 156,147,67	4.1 Score on a scale Standard Error 0.07	3.9 Score on a scale Standard Error 0.08	4.1 Score on a scale Standard Error 0.08	3.9 Score on a scale Standard Error 0.12
Change From Baseline (W0) in Mean CIBIC+ Global Functioning Total Score at W8, W16, W24 CIBIC+, W16, n=144,145,127,61	4.2 Score on a scale Standard Error 0.08	4.0 Score on a scale Standard Error 0.08	4.1 Score on a scale Standard Error 0.09	3.8 Score on a scale Standard Error 0.14
Change From Baseline (W0) in Mean CIBIC+ Global Functioning Total Score at W8, W16, W24 CIBIC+, W24, n=131,133, 127, 56	4.3 Score on a scale Standard Error 0.09	4.3 Score on a scale Standard Error 0.09	4.2 Score on a scale Standard Error 0.10	3.8 Score on a scale Standard Error 0.16

SECONDARY outcome

Timeframe: Baseline (W0) and up to W24

Population: ITT Population. Only those participants available at the specified time points were analyzed (represented as n=x,x,x,x in the category titles). Endpoint treatment differences which were adjusted to take account of missing data are derived.

The NPI assessed behavioral disturbances comprises 10 dimensions: delusions, hallucinations, dysphoria, apathy, euphoria, disinhibition, aggressiveness and agitation, irritability, anxiety and aberrant motor activity. The par. caregiver asked about behavior in the par. If "Yes", the informant then rates both the severity on a 3-point scale, 1: mild to 3: severe (total range: 0-36) and the frequency using a 4-point scale, 1: occasionally to 4: very frequently. The total domain score was frequency × severity. The distress was scored on 5-point scale, 0: no distress to 5 - very severe or extreme. A total NPI score can be calculated by adding all domain scores together; NPI total score: from 0-144 and NPI distress score: from 0-60, all with higher scores indicating more severe behavioral disturbance. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0.

Outcome measures

Outcome measures
Measure	Placebo n=159 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=162 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=156 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=76 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Change From Baseline (W0) in Mean Neuropsychiatric Inventory (NPI) Total Score at W8, W16, W24 NPI, W8, n=146,151,144,65	0.2 Score on a scale Standard Error 0.59	0.1 Score on a scale Standard Error 0.63	0.5 Score on a scale Standard Error 0.81	-0.1 Score on a scale Standard Error 0.87
Change From Baseline (W0) in Mean Neuropsychiatric Inventory (NPI) Total Score at W8, W16, W24 NPI, W16, n=139,142,131,59	-0.1 Score on a scale Standard Error 0.69	-0.0 Score on a scale Standard Error 0.69	-0.1 Score on a scale Standard Error 0.90	0.5 Score on a scale Standard Error 0.97
Change From Baseline (W0) in Mean Neuropsychiatric Inventory (NPI) Total Score at W8, W16, W24 NPI, W24, n=129,133,127,55	1.2 Score on a scale Standard Error 1.04	1.6 Score on a scale Standard Error 0.74	1.1 Score on a scale Standard Error 1.01	-0.6 Score on a scale Standard Error 1.12

SECONDARY outcome

Timeframe: Baseline (W0) and up to W24

Population: ITT Population. Only those par. available at the specified time points were analyzed (represented as n=x,x,x,x in the category titles).

The DAD, assessed the ability of a par. 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 assesses 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 disability and 0 indicating no functional ability. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0. The percentage score was calculated as (DAD total score/total number of applicable items) multiplied by 100. Endpoint treatment differences which were adjusted to take account of missing data are derived.

Outcome measures

Outcome measures
Measure	Placebo n=159 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=162 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=156 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=76 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Change From Baseline (W0) in Mean Disability Assessment for Dementia (DAD) Scale Total Score at W8, W16, W24 DAD, W8, n=147,152, 144, 65	-0.8 Score on a scale Standard Error 0.80	-0.6 Score on a scale Standard Error 0.94	-0.3 Score on a scale Standard Error 0.78	0.5 Score on a scale Standard Error 1.00
Change From Baseline (W0) in Mean Disability Assessment for Dementia (DAD) Scale Total Score at W8, W16, W24 DAD, W16, n=141,143,131,59	-2.6 Score on a scale Standard Error 0.98	-1.7 Score on a scale Standard Error 1.07	-1.7 Score on a scale Standard Error 1.05	1.1 Score on a scale Standard Error 1.40
Change From Baseline (W0) in Mean Disability Assessment for Dementia (DAD) Scale Total Score at W8, W16, W24 DAD, W24, n=129,133,127,55	-3.7 Score on a scale Standard Error 0.97	-2.4 Score on a scale Standard Error 1.21	-3.8 Score on a scale Standard Error 1.19	-0.2 Score on a scale Standard Error 1.81

SECONDARY outcome

Timeframe: Baseline (W0) and up to W24

Population: ITT Population. Only those par. available at the specified time points were analyzed (represented as n=x,x,x,x in the category titles).

Change from Baseline in short term memory assessment score was assessed from a combined analysis of items 1 (word recall task) and 7 (word recognition task) of ADAS-Cog scale. Word recall task consist of the participants score was the mean number of words not recalled on three trials (maximum score 10) and word recognition task, to score this item the number of incorrect responses was counted (maximum error score was 12). Higher score indicating greater dysfunction. Total score is sum of individual score. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0. Endpoint treatment differences which were adjusted to take account of missing data are derived.

Outcome measures

Outcome measures
Measure	Placebo n=159 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=162 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=156 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=76 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Change From Baseline (W0) in Mean Short Term Memory Assessment Total Score (ADAS-Cog Q1 Plus Q7) at W8, W16, W24 ADAS-Cog Q1 plus Q7, W16, n=143,143,130,62	0.1 Score on a scale Standard Error 0.27	0.6 Score on a scale Standard Error 0.26	0.8 Score on a scale Standard Error 0.24	-0.6 Score on a scale Standard Error 0.45
Change From Baseline (W0) in Mean Short Term Memory Assessment Total Score (ADAS-Cog Q1 Plus Q7) at W8, W16, W24 ADAS-Cog Q1 plus Q7, W24, n=131,128,123,56	0.7 Score on a scale Standard Error 0.27	0.3 Score on a scale Standard Error 0.30	0.6 Score on a scale Standard Error 0.29	0.2 Score on a scale Standard Error 0.43
Change From Baseline (W0) in Mean Short Term Memory Assessment Total Score (ADAS-Cog Q1 Plus Q7) at W8, W16, W24 ADAS-Cog Q1 plus Q7, W8, n=152,155,146,67	0.1 Score on a scale Standard Error 0.25	-0.1 Score on a scale Standard Error 0.27	0.5 Score on a scale Standard Error 0.25	-0.4 Score on a scale Standard Error 0.40

SECONDARY outcome

Timeframe: Baseline (W0) and up to W24

Population: ITT Population. Only those par. available at the specified time points were analyzed (represented as n=x,x,x,x in the category titles).

The EQ-5D Proxy was a 2 part scale used to assess the quality of life and utility benefit. The data for Part 1 is presented. It is a 5 dimensional Health State Classification. Caregivers were asked to respond as they feel the par. would on dimensions of mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Answers to each question were recorded on a 3-point scale which indicates the level of impairment (level 1= no problem; level 2=some or moderate problem(s) and level 3=unable, or extreme problem with higher scores indicating greater dysfunction. EQ-5D Proxy assessments was performed at Baseline, W12 and W24. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0. Endpoint treatment differences which were adjusted to take account of missing data are derived.

Outcome measures

Outcome measures
Measure	Placebo n=159 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=162 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=156 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=76 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Change From Baseline (W0) in Mean European Quality of Life -5 Dimensions Proxy Version (EQ-5D Proxy) Total Score at W12, W24 Assessed by Utility EQ-5D Proxy Utility, W12, n=141,146, 135, 62	-0.02 Score on a scale Standard Error 0.017	0.00 Score on a scale Standard Error 0.016	0.01 Score on a scale Standard Error 0.016	0.01 Score on a scale Standard Error 0.021
Change From Baseline (W0) in Mean European Quality of Life -5 Dimensions Proxy Version (EQ-5D Proxy) Total Score at W12, W24 Assessed by Utility EQ-5D Proxy Utility, W24, n=128, 130, 125, 55	-0.02 Score on a scale Standard Error 0.017	0.02 Score on a scale Standard Error 0.016	-0.02 Score on a scale Standard Error 0.019	0.00 Score on a scale Standard Error 0.018

SECONDARY outcome

Timeframe: Baseline (W0) and up to W24

Population: ITT Population. Only those par. available at the specified time points were analyzed (represented as n=x,x,x,x in the category titles).

The EQ-5D Proxy is a 2 part scale used to assess the quality of life and utility benefit. The data for Part 2 is presented. It is a the visual analogue scale Thermometer which assessed caregiver's impression of par. overall health. The Thermometer has endpoints of 100 (best imaginable health state) and 0 (worst imaginable health state). EQ-5D Proxy assessments was performed at Baseline, W12 and W24. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0. Endpoint treatment differences which were adjusted to take account of missing data are derived.

Outcome measures

Outcome measures
Measure	Placebo n=159 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=162 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=156 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=76 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Change From Baseline (W0) in Mean European Quality of Life -5 Dimensions Proxy Version (EQ-5D Proxy) Total Score at W12, W24 Assessed by Thermometer (Visual Analog Scale [VAS]) EQ-5D Proxy Thermometer, W12, n=141, 146, 135, 62	1.4 Score on a scale Standard Error 1.35	0.3 Score on a scale Standard Error 1.37	1.7 Score on a scale Standard Error 1.41	-2.6 Score on a scale Standard Error 2.41
Change From Baseline (W0) in Mean European Quality of Life -5 Dimensions Proxy Version (EQ-5D Proxy) Total Score at W12, W24 Assessed by Thermometer (Visual Analog Scale [VAS]) EQ-5D Proxy Thermometer, W24, n=128, 130, 126, 55	1.9 Score on a scale Standard Error 1.56	-0.7 Score on a scale Standard Error 1.52	0.2 Score on a scale Standard Error 1.71	1.5 Score on a scale Standard Error 2.40

SECONDARY outcome

Timeframe: Baseline (W0) and up to W24

Population: ITT Population. Only those par. available at the specified time points were analyzed (represented as n=x,x,x,x in the category titles).

The RUD instrument was developed as a comprehensive tool to assess the amount of resource use among demented par. RUD assess both formal and informal resource use of the par. and the primary caregiver, making it possible to calculate costs from a societal perspective. Q1 relates to assisting par. with basic activities of daily living and Q2 relates to instrumental activities of daily living. The assessments was performed at Baseline, W12 and W24. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0. Endpoint treatment differences which were adjusted to take account of missing data are derived.

Outcome measures

Outcome measures
Measure	Placebo n=159 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=162 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=156 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=76 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Time Spent Caring for Basic and Instrumental Activities Resource Utilization in Dementia (RUD) Scale at W12 and W24 RUD Q1, W12, n=141, 149, 137, 69	2.3 Hours Standard Deviation 43.31	4.5 Hours Standard Deviation 81.21	-9.8 Hours Standard Deviation 77.44	-5.7 Hours Standard Deviation 70.19
Time Spent Caring for Basic and Instrumental Activities Resource Utilization in Dementia (RUD) Scale at W12 and W24 RUD Q1, W24, n=128, 133, 127, 55	19.4 Hours Standard Deviation 109.41	-0.6 Hours Standard Deviation 58.72	-2.7 Hours Standard Deviation 86.26	3.7 Hours Standard Deviation 19.26
Time Spent Caring for Basic and Instrumental Activities Resource Utilization in Dementia (RUD) Scale at W12 and W24 RUD Q2, W12, n=141, 149, 137, 62	13.7 Hours Standard Deviation 73.94	9.0 Hours Standard Deviation 60.54	4.9 Hours Standard Deviation 80.97	-5.3 Hours Standard Deviation 56.50
Time Spent Caring for Basic and Instrumental Activities Resource Utilization in Dementia (RUD) Scale at W12 and W24 RUD Q2, W24, n=128, 133, 127, 55	17.1 Hours Standard Deviation 75.45	9.7 Hours Standard Deviation 47.96	11.6 Hours Standard Deviation 107.52	1.1 Hours Standard Deviation 61.49

SECONDARY outcome

Timeframe: Baseline (W0) and up to W24

Population: ITT Population. Only those par. available at the specified time points were analyzed (represented as n=x,x,x,x in the category titles).

The ACQLI was an assessment of caregiver quality of life. This instrument consists of 30 questions exploring various aspects of carer's quality of life. Each of the questions had a two point response and the 30 questions were summed to provide a total score. Items are assumed to be unidimensional (i.e., represent a single variable) and are scored 0/1 (false/true) before summation into a total score with a 0-30 range. To ease comparisons between scales, ACQLI scores were transformed to range between 0-100 (100: worse). The assessments was performed at Baseline, W12 and W24. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0. Endpoint treatment differences which were adjusted to take account of missing data are derived.

Outcome measures

Outcome measures
Measure	Placebo n=159 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=162 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=156 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=76 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Change From Baseline (W0) in Alzheimer's Carer's Quality of Life Instrument (ACQLI) Score at W12 and W24. ACQLI, W12, n=141, 148, 137, 60	0.5 Score on a scale Standard Error 0.38	-0.6 Score on a scale Standard Error 0.41	-0.1 Score on a scale Standard Error 0.46	0.5 Score on a scale Standard Error 0.50
Change From Baseline (W0) in Alzheimer's Carer's Quality of Life Instrument (ACQLI) Score at W12 and W24. ACQLI, W24, n=128, 132, 126, 54	0.6 Score on a scale Standard Error 0.45	-0.2 Score on a scale Standard Error 0.49	0.0 Score on a scale Standard Error 0.54	-0.0 Score on a scale Standard Error 0.69

SECONDARY outcome

Timeframe: Baseline (W0) and W24

Population: ITT Population. Only those par. available at the specified time points were analyzed (represented as n=x,x,x,x in the category titles).

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 par. and takes approximately 5 to 10 minutes to administer. The assessments was performed at Baseline and W24. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0. Endpoint treatment differences which were adjusted to take account of missing data are derived

Outcome measures

Outcome measures
Measure	Placebo n=131 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=133 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=127 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=56 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Change From Baseline (W0) in Mini Mental State Examination (MMSE) Total Score at W24.	-0.5 Score on a scale Standard Error 0.27	-0.6 Score on a scale Standard Error 0.27	-0.7 Score on a scale Standard Error 0.28	0.4 Score on a scale Standard Error 0.38

SECONDARY outcome

Timeframe: Baseline (W0) and W24

Population: ITT Population. Only those par. available at the specified time points were analyzed (represented as n=x,x,x,x in the category titles).

The blood sample was collected for assessments of HbA1c levels at Baseline and W24. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0. Endpoint treatment differences which were adjusted to take account of missing data are derived.

Outcome measures

Outcome measures
Measure	Placebo n=123 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=120 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=117 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=52 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Change From Baseline (W0) in Glycosylated Hemoglobin (HbA1c) at W24.	0.1 Percentage (%) Standard Error 0.05	0.2 Percentage (%) Standard Error 0.05	0.1 Percentage (%) Standard Error 0.05	0.1 Percentage (%) Standard Error 0.07

SECONDARY outcome

Timeframe: Up to W24

Population: Safety population: This included all par. randomized to treatment who have taken at least one dose of study medication.

An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE included significant or unexpected worsening or exacerbation of the condition/indication under study, exacerbation of a chronic or intermittent pre-existing condition, new conditions detected or diagnosed, signs, symptoms, or the clinical sequelae of a suspected overdose of either investigational product or a concurrent medication. Number of participants with any AE and as per severity were reported. Refer to the general AE/SAE module for a list of AEs and SAEs.

Outcome measures

Outcome measures
Measure	Placebo n=165 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=166 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=165 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=83 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Number of Participants With Adverse Events Defined by Severity Any AE	62 Participants	60 Participants	69 Participants	42 Participants
Number of Participants With Adverse Events Defined by Severity Mild AE	32 Participants	35 Participants	37 Participants	22 Participants
Number of Participants With Adverse Events Defined by Severity Moderate AE	25 Participants	22 Participants	30 Participants	15 Participants
Number of Participants With Adverse Events Defined by Severity Severe AE	5 Participants	3 Participants	2 Participants	5 Participants

SECONDARY outcome

Timeframe: Up to W24

Population: Safety Population. Only those par. available at the specified time points were analyzed (represented as n=x,x,x,x in the category titles).

SBP, DBP and HR of par. were recorded in sitting posture as vital signs, while body weight was measured without shoes and wearing light clothing at each visit. The blood pressure (BP) and HR values were identified as of PCC if the vales were out of the reference range (for SBP, 90 to 140 millimeters of mercury (mmHg), DBP, 50 to 90 mmHg, and HR \>100 or \<50 beats per minute \[bpm\]) or meet a change from Baseline criterion. For SBP it was increase from Baseline (high) if increased by more than or equal to (\>=) 40 mmHg; decrease from Baseline (low) if decreased by \>=30 mmHg. For DBP, increase from Baseline (high) if increased by \>=30 mmHg; decrease from Baseline (low) if decreased by \>=20 mmHg. For HR, increase from Baseline (high) if increased by \>=30 bpm; decrease from Baseline (low) if decreased by \>=30 bpm. For weight, increase from Baseline (high) if increased by \>=7%; decrease from Baseline (low) if decreased by \>=7%. Baseline was defined as value at W0.

Outcome measures

Outcome measures
Measure	Placebo n=160 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=162 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=154 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=79 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Number of Participants With Systolic and Diastolic Blood Pressure (SBP and DBP), Heart Rate (HR) and Weight Values of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT). SBP, >140 or <90	52 Participants	61 Participants	41 Participants	24 Participants
Number of Participants With Systolic and Diastolic Blood Pressure (SBP and DBP), Heart Rate (HR) and Weight Values of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT). SBP, Increase from Baseline >=40	1 Participants	3 Participants	3 Participants	3 Participants
Number of Participants With Systolic and Diastolic Blood Pressure (SBP and DBP), Heart Rate (HR) and Weight Values of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT). SBP, Decrease from Baseline >=30	7 Participants	9 Participants	15 Participants	6 Participants
Number of Participants With Systolic and Diastolic Blood Pressure (SBP and DBP), Heart Rate (HR) and Weight Values of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT). DBP, >90 or <50	17 Participants	16 Participants	13 Participants	8 Participants
Number of Participants With Systolic and Diastolic Blood Pressure (SBP and DBP), Heart Rate (HR) and Weight Values of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT). DBP, Increase from Baseline >=30	4 Participants	1 Participants	1 Participants	1 Participants
Number of Participants With Systolic and Diastolic Blood Pressure (SBP and DBP), Heart Rate (HR) and Weight Values of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT). DBP, Decrease from Baseline >=20	8 Participants	12 Participants	25 Participants	8 Participants
Number of Participants With Systolic and Diastolic Blood Pressure (SBP and DBP), Heart Rate (HR) and Weight Values of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT). HR, >100 or <50	2 Participants	4 Participants	4 Participants	2 Participants
Number of Participants With Systolic and Diastolic Blood Pressure (SBP and DBP), Heart Rate (HR) and Weight Values of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT). HR, Increase from Baseline >=30	1 Participants	3 Participants	3 Participants	1 Participants
Number of Participants With Systolic and Diastolic Blood Pressure (SBP and DBP), Heart Rate (HR) and Weight Values of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT). HR, Decrease from Baseline >=30	3 Participants	0 Participants	0 Participants	1 Participants
Number of Participants With Systolic and Diastolic Blood Pressure (SBP and DBP), Heart Rate (HR) and Weight Values of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT). Weight, Increase from Baseline >=7%	9 Participants	21 Participants	25 Participants	1 Participants
Number of Participants With Systolic and Diastolic Blood Pressure (SBP and DBP), Heart Rate (HR) and Weight Values of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT). Weight, Decrease from Baseline >=7%	7 Participants	4 Participants	3 Participants	5 Participants

SECONDARY outcome

Timeframe: Baseline (W0) and up to W24

Population: Safety Population. Only those par. available at the specified time points were analyzed (represented as n=x,x,x,x in the category titles).

Triplicate 12-lead ECG measures was obtained digitally, approximately one minute apart after the par. had rested in the supine position in a quiet room (no TV, minimal talking) for at least 10 minutes. Conduction intervals from the 12-lead ECGs were manually read and confirmed by an external cardiologist/vendor. The ECG parameters includes PR interval, QRS duration, QT - uncorrected interval, QTc Bazett (QTcB), QTc Fridericia (QTcF) and RR interval of Central Cardiologist are reported. The assessments was performed at Baseline and W24. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at Screening/Visit 1/W-6.

Outcome measures

Outcome measures
Measure	Placebo n=165 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=166 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=165 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=83 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Change From Baseline (W0) in 12-lead Electrocardiogram (ECG) PR Interval, n=16,11, 14, 4	2.2 milliseconds (MSEC) Standard Deviation 14.39	6.9 milliseconds (MSEC) Standard Deviation 30.44	6.0 milliseconds (MSEC) Standard Deviation 19.98	-5.5 milliseconds (MSEC) Standard Deviation 8.50
Change From Baseline (W0) in 12-lead Electrocardiogram (ECG) QRS Duration, n=17, 11, 14, 5	1.1 milliseconds (MSEC) Standard Deviation 8.28	0.7 milliseconds (MSEC) Standard Deviation 5.50	3.6 milliseconds (MSEC) Standard Deviation 6.14	0.9 milliseconds (MSEC) Standard Deviation 9.04
Change From Baseline (W0) in 12-lead Electrocardiogram (ECG) QT Interval, n=17, 11, 14, 5	5.3 milliseconds (MSEC) Standard Deviation 27.69	15.6 milliseconds (MSEC) Standard Deviation 25.06	19.8 milliseconds (MSEC) Standard Deviation 22.17	15.9 milliseconds (MSEC) Standard Deviation 22.57
Change From Baseline (W0) in 12-lead Electrocardiogram (ECG) QTcB, n=17, 11, 14, 5	10.2 milliseconds (MSEC) Standard Deviation 18.21	7.1 milliseconds (MSEC) Standard Deviation 22.69	20.0 milliseconds (MSEC) Standard Deviation 13.54	-0.2 milliseconds (MSEC) Standard Deviation 17.22
Change From Baseline (W0) in 12-lead Electrocardiogram (ECG) QTcF, n=17, 11, 14, 5	8.1 milliseconds (MSEC) Standard Deviation 17.12	10.0 milliseconds (MSEC) Standard Deviation 21.47	20.1 milliseconds (MSEC) Standard Deviation 12.71	4.9 milliseconds (MSEC) Standard Deviation 15.50
Change From Baseline (W0) in 12-lead Electrocardiogram (ECG) RR Interval	-12.3 milliseconds (MSEC) Standard Deviation 107.35	43.8 milliseconds (MSEC) Standard Deviation 89.52	-0.5 milliseconds (MSEC) Standard Deviation 107.49	76.5 milliseconds (MSEC) Standard Deviation 109.43

SECONDARY outcome

Timeframe: Baseline (W0) and up to W24

Population: Safety Population. Only those par. available at the specified time points were analyzed (represented as n=x,x,x,x in the category titles).

Triplicate 12-lead ECG measures was obtained digitally, approximately one minute apart after the par. had rested in the supine position in a quiet room (no TV, minimal talking) for at least 10 minutes. Conduction intervals from the 12-lead ECGs were manually read and confirmed by an external cardiologist/vendor. The ECG HR of Central Cardiologist reported. The assessments was performed at Baseline and W24. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at Screening/Visit 1/W-6.

Outcome measures

Outcome measures
Measure	Placebo n=17 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=11 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=14 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=5 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Change From Baseline (W0) in Heart Rate (HR) Measured From 12-lead Electrocardiogram (ECG)	2.1 Beats per minute Standard Deviation 12.08	-2.8 Beats per minute Standard Deviation 7.77	-0.3 Beats per minute Standard Deviation 8.39	-4.7 Beats per minute Standard Deviation 9.23

SECONDARY outcome

Timeframe: Baseline (W0) and up to W24

Population: Safety Population. Only those par. available at the specified time points were analyzed (represented as n=x,x,x,x in the category titles).

Body weight will be measured at all visits, without shoes and wearing light clothing. The assessments was performed at Baseline, W4, W8, W12, W16, and W24. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0.

Outcome measures

Outcome measures
Measure	Placebo n=165 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=166 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=165 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=83 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Change From Baseline (W0) in Body Weight Week 4, n=160, 161, 153, 79	0.1 Kilogram (Kg) Standard Deviation 1.59	0.4 Kilogram (Kg) Standard Deviation 1.76	0.3 Kilogram (Kg) Standard Deviation 1.61	-0.1 Kilogram (Kg) Standard Deviation 1.39
Change From Baseline (W0) in Body Weight Week 8, n=150, 157, 147, 66	-0.0 Kilogram (Kg) Standard Deviation 2.56	0.5 Kilogram (Kg) Standard Deviation 1.73	0.8 Kilogram (Kg) Standard Deviation 2.16	-0.4 Kilogram (Kg) Standard Deviation 1.46
Change From Baseline (W0) in Body Weight Week 12, n=143, 149, 136, 61	0.0 Kilogram (Kg) Standard Deviation 2.12	0.6 Kilogram (Kg) Standard Deviation 2.06	0.9 Kilogram (Kg) Standard Deviation 2.03	-0.9 Kilogram (Kg) Standard Deviation 1.71
Change From Baseline (W0) in Body Weight Week 16, n=143, 146, 132, 61	-0.0 Kilogram (Kg) Standard Deviation 2.05	0.7 Kilogram (Kg) Standard Deviation 2.20	1.1 Kilogram (Kg) Standard Deviation 2.08	-1.0 Kilogram (Kg) Standard Deviation 2.05
Change From Baseline (W0) in Body Weight Week 24, 133, 132, 125, 55	-0.3 Kilogram (Kg) Standard Deviation 2.53	0.8 Kilogram (Kg) Standard Deviation 2.63	0.8 Kilogram (Kg) Standard Deviation 2.54	-0.8 Kilogram (Kg) Standard Deviation 2.28

SECONDARY outcome

Timeframe: Baseline (W0) and up to W24

Population: Safety Population. Only those par. available at the specified time points were analyzed (represented as n=x,x,x,x in the category titles).

Hematology parameters were assessed at Baseline, W4, W12 and W24. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0.

Outcome measures

Outcome measures
Measure	Placebo n=165 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=166 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=165 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=83 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Change From Baseline (W0) in Hemoglobin Week 4, n=152, 152, 138, 76	0.1 Grams per liter (G/L) Standard Deviation 5.84	-2.8 Grams per liter (G/L) Standard Deviation 7.04	-3.9 Grams per liter (G/L) Standard Deviation 7.57	-0.4 Grams per liter (G/L) Standard Deviation 6.03
Change From Baseline (W0) in Hemoglobin Week 12, n=132, 142, 132, 60	-0.2 Grams per liter (G/L) Standard Deviation 6.55	-4.5 Grams per liter (G/L) Standard Deviation 8.65	-10.5 Grams per liter (G/L) Standard Deviation 8.67	-0.6 Grams per liter (G/L) Standard Deviation 6.59
Change From Baseline (W0) in Hemoglobin Week 24, n=128, 124, 115, 54	-1.3 Grams per liter (G/L) Standard Deviation 7.54	-4.2 Grams per liter (G/L) Standard Deviation 8.34	-11.9 Grams per liter (G/L) Standard Deviation 10.58	0.2 Grams per liter (G/L) Standard Deviation 6.51

SECONDARY outcome

Timeframe: Baseline (W0) and Up to W24

Population: Safety Population. Only those par. available at the specified time points were analyzed (represented as n=x,x,x,x in the category titles).

Hematology parameters were assessed at Baseline, W4, W12 and W24. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0.

Outcome measures

Outcome measures
Measure	Placebo n=165 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=166 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=165 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=83 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Change From Baseline (W0) in Hematocrit Week 4, n=152, 152, 138, 76	-0.0011 Percentage of red blood cells in blood Standard Deviation 0.01886	-0.0088 Percentage of red blood cells in blood Standard Deviation 0.02285	-0.0125 Percentage of red blood cells in blood Standard Deviation 0.02322	-0.0024 Percentage of red blood cells in blood Standard Deviation 0.01829
Change From Baseline (W0) in Hematocrit Week 12, n=132, 142, 132, 60	-0.0007 Percentage of red blood cells in blood Standard Deviation 0.02137	-0.0152 Percentage of red blood cells in blood Standard Deviation 0.02813	-0.0316 Percentage of red blood cells in blood Standard Deviation 0.02629	-0.0055 Percentage of red blood cells in blood Standard Deviation 0.01932
Change From Baseline (W0) in Hematocrit Week 24, n=128, 124, 115, 54	-0.0010 Percentage of red blood cells in blood Standard Deviation 0.02500	-0.0123 Percentage of red blood cells in blood Standard Deviation 0.02304	-0.0326 Percentage of red blood cells in blood Standard Deviation 0.03195	-0.0001 Percentage of red blood cells in blood Standard Deviation 0.02135

SECONDARY outcome

Timeframe: Baseline (W0) and up to W24

Population: Safety Population. Only those par. available at the specified time points were analyzed (represented as n=x,x,x,x in the category titles).

HbA1c assessment was performed par. with type 2 diabetes mellitus or HbA1c \>=6.5% at Screening only. HbA1c levels were assessed at Baseline, W12 and W24. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0.

Outcome measures

Outcome measures
Measure	Placebo n=165 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=166 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=165 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=83 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Change From Baseline (W0) in Periodic HbA1c Assessment Week 12, n=48, 46, 38, 22	-0.1 Percentage Standard Deviation 0.56	0.2 Percentage Standard Deviation 0.62	0.1 Percentage Standard Deviation 0.41	-0.2 Percentage Standard Deviation 0.81
Change From Baseline (W0) in Periodic HbA1c Assessment Week 24, n=123, 120, 117, 52	0.1 Percentage Standard Deviation 0.52	0.2 Percentage Standard Deviation 0.66	0.1 Percentage Standard Deviation 0.52	0.0 Percentage Standard Deviation 0.56

SECONDARY outcome

Timeframe: Up to W24

Population: Safety Population. Only those par. available at the specified time points were analyzed (represented as n=x,x,x,x in the category titles).

Haematology parameters were identified as of PCC (high \[H\], low \[L\]), if the values were out of the reference range (RR). The range for parameters was: platelet (100AV-500AV), red blood cell (RBC, 0.8-1.2), hemoglobin (L: female \[F\]:10, male \[M\]:11; H: F:16.5-AV, M:18), hematocrit (0.8-1.2), white blood cell (WBC, 3-15), neutrophils (0.75-1.5), lymphocytes (0.75-1.5), monocytes (0.75-2), eosinophils (none-2), basophils (none-2), mean corpuscle volume (MCV, 0.8-1.2), mean corpuscular hemoglobin (MCH, 0.8-1.2), mean corpuscular hemoglobin concentration (MCHC, 0.8-1.2), red cell distribution width (RDW, 0.8-1.2). Data for mean platelet volume (reference range not established) not reported

Outcome measures

Outcome measures
Measure	Placebo n=165 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=166 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=165 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=83 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Number of Par. With Hematology Data of Potential Clinical Concern Any Time on Treatment WBC H, n=157, 161,151, 76	0 Participants	0 Participants	1 Participants	1 Participants
Number of Par. With Hematology Data of Potential Clinical Concern Any Time on Treatment Platelet H, n=157, 160,150, 76	1 Participants	0 Participants	0 Participants	0 Participants
Number of Par. With Hematology Data of Potential Clinical Concern Any Time on Treatment Eosinophils H, n=156, 161, 151, 72	2 Participants	0 Participants	1 Participants	0 Participants
Number of Par. With Hematology Data of Potential Clinical Concern Any Time on Treatment Hematocrit H, n=157, 161,151, 76	0 Participants	1 Participants	0 Participants	0 Participants
Number of Par. With Hematology Data of Potential Clinical Concern Any Time on Treatment Hematocrit L, n=157, 161,151, 76	0 Participants	0 Participants	1 Participants	0 Participants
Number of Par. With Hematology Data of Potential Clinical Concern Any Time on Treatment Hemoglobin H, n=157, 161,151, 76	0 Participants	2 Participants	0 Participants	0 Participants
Number of Par. With Hematology Data of Potential Clinical Concern Any Time on Treatment Hemoglobin L, n=157, 161,151, 76	0 Participants	3 Participants	8 Participants	0 Participants
Number of Par. With Hematology Data of Potential Clinical Concern Any Time on Treatment Lymphocytes L, n=156, 161,151, 76	2 Participants	2 Participants	2 Participants	0 Participants
Number of Par. With Hematology Data of Potential Clinical Concern Any Time on Treatment MCH H, n=157, 161,151, 76	0 Participants	0 Participants	0 Participants	1 Participants
Number of Par. With Hematology Data of Potential Clinical Concern Any Time on Treatment MCH L, n=157, 161,151, 76	0 Participants	1 Participants	0 Participants	0 Participants
Number of Par. With Hematology Data of Potential Clinical Concern Any Time on Treatment MCV L, n=156, 161,151, 76	0 Participants	0 Participants	0 Participants	1 Participants
Number of Par. With Hematology Data of Potential Clinical Concern Any Time on Treatment Monocytes H, n=156, 161,151, 76	0 Participants	0 Participants	0 Participants	1 Participants
Number of Par. With Hematology Data of Potential Clinical Concern Any Time on Treatment Monocytes L, n=156, 161,151, 76	9 Participants	10 Participants	15 Participants	4 Participants
Number of Par. With Hematology Data of Potential Clinical Concern Any Time on Treatment Platelet L, n=157, 160,150, 76	2 Participants	1 Participants	0 Participants	0 Participants
Number of Par. With Hematology Data of Potential Clinical Concern Any Time on Treatment RDW H, n=157, 161,151, 76	4 Participants	6 Participants	10 Participants	1 Participants
Number of Par. With Hematology Data of Potential Clinical Concern Any Time on Treatment RBC L, n=157, 161,151, 76	0 Participants	1 Participants	1 Participants	1 Participants
Number of Par. With Hematology Data of Potential Clinical Concern Any Time on Treatment Total neutrophil H, n=156, 161, 151, 76	0 Participants	0 Participants	1 Participants	1 Participants
Number of Par. With Hematology Data of Potential Clinical Concern Any Time on Treatment Total neutrophil L, n=156, 161, 151, 76	2 Participants	5 Participants	7 Participants	3 Participants
Number of Par. With Hematology Data of Potential Clinical Concern Any Time on Treatment WBC L, n=157, 161,151, 76	4 Participants	4 Participants	7 Participants	0 Participants

SECONDARY outcome

Timeframe: Up to W24

Population: Safety Population. Only those par. available at the specified time points were analyzed (represented as n=x,x,x,x in the category titles).

Clinical chemistry parameters were identified as of PCC (H, L), if values were out of RR: Alanine aminotransferase (ALT, none-120 \[250% upper limit of RR, ULRR\]), Albumin (0.75-2), Aspartate aminotransferase (AST,none-105 (3-64y), 137.5 (65+y), \>250%ULRR), Alkaline phosphatase (ALP,none-312.5 (20+y), \>250%ULRR), blood urea nitrogen (BUN)/Creatinine ratio (none-1.25), BUN (none-11), Chloride (80-115), Calcium (0.75-1.25), Carbon dioxide (CO2, 15-40) content, Creatinine (22, \<50% lower limit of RR \[LLRR\]-155, \>125%ULRR), Creatine phosphokinase (CPK, none-1.25), Gamma glutamyl transferase (GGT,none-2.5), Glucose (3.6-7.8), High density lipoprotein (HDL,0.65-none), Lactate dehydrogenase (LDH,none-1.25), Low density lipoprotein (LDL,none-2), Magnesium (0.5-2), Potassium (3-5.5), Phosphorus inorganic (0.5-1.5), Sodium (130-150), Total protein (0.8-1.5), Total cholesterol (none-1.25), Total bilirubin (none-1.95), Triglycerides (none-9). Data for Creatinine clearance not reported.

Outcome measures

Outcome measures
Measure	Placebo n=165 Participants Par. randomized to this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=166 Participants Par. randomized to this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=165 Participants Par. randomized to this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=83 Participants Par. randomized to this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
Number of Par. With Clinical Chemistry Values of Potential Clinical Concern Any Time on Treatment ALT H, n=156, 162, 151, 77	2 Participants	0 Participants	0 Participants	0 Participants
Number of Par. With Clinical Chemistry Values of Potential Clinical Concern Any Time on Treatment AST H, n=156, 162, 151, 77	2 Participants	0 Participants	0 Participants	0 Participants
Number of Par. With Clinical Chemistry Values of Potential Clinical Concern Any Time on Treatment BUN/Creatinine ratio H, n=156, 162, 151, 77	8 Participants	8 Participants	19 Participants	9 Participants
Number of Par. With Clinical Chemistry Values of Potential Clinical Concern Any Time on Treatment Cholesterol H, n=141, 148, 137, 62	7 Participants	17 Participants	29 Participants	1 Participants
Number of Par. With Clinical Chemistry Values of Potential Clinical Concern Any Time on Treatment Creatinine H, n=156, 162, 151, 77	5 Participants	1 Participants	4 Participants	3 Participants
Number of Par. With Clinical Chemistry Values of Potential Clinical Concern Any Time on Treatment CPK H, n=156, 162, 151, 77	5 Participants	13 Participants	11 Participants	5 Participants
Number of Par. With Clinical Chemistry Values of Potential Clinical Concern Any Time on Treatment GGT H, n=156, 162, 151, 77	2 Participants	1 Participants	0 Participants	1 Participants
Number of Par. With Clinical Chemistry Values of Potential Clinical Concern Any Time on Treatment Glucose H, n=156, 162, 151, 77	12 Participants	19 Participants	9 Participants	8 Participants
Number of Par. With Clinical Chemistry Values of Potential Clinical Concern Any Time on Treatment Glucose L, n=156, 162, 151, 77	3 Participants	5 Participants	4 Participants	1 Participants
Number of Par. With Clinical Chemistry Values of Potential Clinical Concern Any Time on Treatment LDL H, n=141, 147, 136, 62	36 Participants	51 Participants	55 Participants	10 Participants
Number of Par. With Clinical Chemistry Values of Potential Clinical Concern Any Time on Treatment Phosphorus L, n=156, 162, 151, 77	0 Participants	0 Participants	1 Participants	0 Participants
Number of Par. With Clinical Chemistry Values of Potential Clinical Concern Any Time on Treatment Potassium H, n=156, 162, 150, 77	4 Participants	2 Participants	2 Participants	2 Participants
Number of Par. With Clinical Chemistry Values of Potential Clinical Concern Any Time on Treatment Sodium H, n=156, 162, 151, 77	0 Participants	0 Participants	0 Participants	1 Participants
Number of Par. With Clinical Chemistry Values of Potential Clinical Concern Any Time on Treatment Sodium L, n=156, 162, 151, 77	0 Participants	0 Participants	1 Participants	2 Participants
Number of Par. With Clinical Chemistry Values of Potential Clinical Concern Any Time on Treatment BUN H, n=156, 162, 151, 77	7 Participants	5 Participants	12 Participants	5 Participants
Number of Par. With Clinical Chemistry Values of Potential Clinical Concern Any Time on Treatment Total Bilirubin H, n=156, 162, 151, 77	0 Participants	1 Participants	0 Participants	0 Participants

Adverse Events

Placebo

Serious events: 10 serious events

Other events: 13 other events

Deaths: 1 deaths

RSG XR 2 mg

Serious events: 7 serious events

Other events: 25 other events

Deaths: 0 deaths

RSG XR 8 mg

Serious events: 8 serious events

Other events: 30 other events

Deaths: 1 deaths

Donepezil 10 mg

Serious events: 6 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo n=165 participants at risk Par. in this arm received RSG placebo tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 2 mg n=166 participants at risk Par. in this arm received RSGXR 2 milligram (mg) tablet along with dummy donepezil capsule once daily for 24W. For par. in this arm, the dosage were remain constant throughout the 24W treatment period. Study treatment were taken in the evening with or without food.	RSG XR 8 mg n=165 participants at risk Par. in this arm received RSGXR 4 mg tablet along with dummy donepezil capsule once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received 8 mg RSGXR tablet along with dummy donepezil capsule once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.	Donepezil 10 mg n=83 participants at risk Par. in this arm received donepezil 5 mg capsule along with dummy RSGXR tablet once daily for the first 4 weeks of treatment. From Visit 4 (Week 4) onwards, these par. received donepezil 10 mg capsule along with dummy RSGXR tablet once daily for the remaining 20W of double-blind treatment. Study treatment were taken in the evening with or without food.
General disorders Oedema peripheral	5.5% 9/165 • Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication up to W24. The safety population (full population cohort) was used.	3.6% 6/166 • Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication up to W24. The safety population (full population cohort) was used.	14.5% 24/165 • Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication up to W24. The safety population (full population cohort) was used.	3.6% 3/83 • Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication up to W24. The safety population (full population cohort) was used.
Infections and infestations Nasopharyngitis	2.4% 4/165 • Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication up to W24. The safety population (full population cohort) was used.	6.6% 11/166 • Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication up to W24. The safety population (full population cohort) was used.	2.4% 4/165 • Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication up to W24. The safety population (full population cohort) was used.	1.2% 1/83 • Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication up to W24. The safety population (full population cohort) was used.
Metabolism and nutrition disorders Hyperlipidaemia	0.61% 1/165 • Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication up to W24. The safety population (full population cohort) was used.	5.4% 9/166 • Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication up to W24. The safety population (full population cohort) was used.	0.61% 1/165 • Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication up to W24. The safety population (full population cohort) was used.	2.4% 2/83 • Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication up to W24. The safety population (full population cohort) was used.
Nervous system disorders Headache	0.00% 0/165 • Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication up to W24. The safety population (full population cohort) was used.	1.2% 2/166 • Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication up to W24. The safety population (full population cohort) was used.	1.2% 2/165 • Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication up to W24. The safety population (full population cohort) was used.	8.4% 7/83 • Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication up to W24. The safety population (full population cohort) was used.

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Publication restrictions are in place

Restriction type: OTHER