Trial Outcomes & Findings for Open-Label Extension Study Of Rosiglitazone XR As Adjunctive Therapy In Subjects With Mild-to-Moderate Alzheimers (NCT NCT00490568)

NCT ID: NCT00490568

Last Updated: 2017-11-13

Results Overview

An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The severity of the AE'S was categorized as mild, moderate and severe. Number of participants reporting AEs during the on treatment phase of the study.

• Recruitment status: TERMINATED
• Study phase: PHASE3
• Target enrollment: 1461 participants
• Primary outcome timeframe: Up to 76 Weeks
• Results posted on: 2017-11-13

Participant Flow

A open-label extension study to evaluate the long-term safety and tolerability of rosiglitazone extended-release (RSG XR) tablets in participants with mild-to moderate Alzheimer's Disease conducted in a total of 29 countries across 267 centers from 08 August 2007 to 30 May 2009.

Approximately 1800 participants were planned to be enrolled however a total of 1461 participants (after completing parent studies AVA102670/AVA102672) were enrolled and received open-label RSG-XR tablets.

Participant milestones

Measure	RSG XR Eligible participants who completed studies AVA102670 or AVA102672 entered in this open-label extension study. Participants received open-label RSG XR throughout the treatment period as adjunctive therapy to their existing dose of Acetylcholinesterase Inhibitor (AChEI) for Alzheimer's disease treatment. Participants took one tablet of study medication daily in the morning with or without food. All participants received oral 4 milligram (mg) once daily RSG XR for the first 4 weeks of the study (only for the first 4 weeks of the study). The RSG XR dose was then increased to 8 mg once daily from Week 4 through Week 52. The dose of RSG XR was reduced to 2mg once daily if the 8 mg dose was not well tolerated. Participants were not permitted to titrate back to 8 mg RSG XR.
Overall Study STARTED	1461
Overall Study COMPLETED	97
Overall Study NOT COMPLETED	1364

Reasons for withdrawal

Measure	RSG XR Eligible participants who completed studies AVA102670 or AVA102672 entered in this open-label extension study. Participants received open-label RSG XR throughout the treatment period as adjunctive therapy to their existing dose of Acetylcholinesterase Inhibitor (AChEI) for Alzheimer's disease treatment. Participants took one tablet of study medication daily in the morning with or without food. All participants received oral 4 milligram (mg) once daily RSG XR for the first 4 weeks of the study (only for the first 4 weeks of the study). The RSG XR dose was then increased to 8 mg once daily from Week 4 through Week 52. The dose of RSG XR was reduced to 2mg once daily if the 8 mg dose was not well tolerated. Participants were not permitted to titrate back to 8 mg RSG XR.
Overall Study Adverse Event	116
Overall Study Lost to Follow-up	13
Overall Study Protocol Violation	45
Overall Study Withdrawal by Subject	135
Overall Study Still in the study at termination	974
Overall Study Other	1
Overall Study Exclusion criteria met	1
Overall Study Caregiver related	20
Overall Study Abnormal ECG	25
Overall Study Participant refused follow-up	9
Overall Study Legal representative withdrew consent	1
Overall Study Disease progression	4
Overall Study Unmet inclusion-exclusion criteria	5
Overall Study Investigator decision	3
Overall Study Non-Compliance	7
Overall Study Efficacy related	3
Overall Study Participant died	1
Overall Study Participant withdrawal due to surgery	1

Baseline Characteristics

Open-Label Extension Study Of Rosiglitazone XR As Adjunctive Therapy In Subjects With Mild-to-Moderate Alzheimers

Baseline characteristics by cohort

Measure	RSG XR (AVA102675) n=1461 Participants Eligible participants who completed studies AVA102670 or AVA102672 entered in this open-label extension study. Participants received open-label RSG XR throughout the treatment period as adjunctive therapy to their existing dose of AChEI for Alzheimer's disease treatment. Participants took one tablet of study medication daily in the morning with or without food. All participants received 4 mg once daily RSG XR for the first 4 weeks of the study (only for the first 4 weeks of the study). The RSG XR dose was then increased to 8 mg once daily from Week 4 through Week 52. The dose of RSG XR was reduced to 2mg once daily if the 8 mg dose was not well tolerated. Participants were not permitted to titrate back to 8 mg RSG XR.
Age, Continuous	73.9 Years STANDARD_DEVIATION 7.96 • n=93 Participants
Sex: Female, Male Female	843 Participants n=93 Participants
Sex: Female, Male Male	618 Participants n=93 Participants
Race (NIH/OMB) American Indian or Alaska Native	6 Participants n=93 Participants
Race (NIH/OMB) Asian	52 Participants n=93 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants
Race (NIH/OMB) Black or African American	7 Participants n=93 Participants
Race (NIH/OMB) White	1396 Participants n=93 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants

PRIMARY outcome

Timeframe: Up to 76 Weeks

Population: All Subjects (Full population), comprised of all participants who took at least one dose of open-label study medication.

An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The severity of the AE'S was categorized as mild, moderate and severe. Number of participants reporting AEs during the on treatment phase of the study.

Outcome measures

Measure	RSG XR n=1461 Participants Eligible participants who completed studies AVA102670 or AVA102672 entered in this open-label extension study. Participants received open-label RSG XR throughout the treatment period as adjunctive therapy to their existing dose of AChEI for Alzheimer's disease treatment. Participants took one tablet of study medication daily in the morning with or without food. All participants received 4 mg once daily RSG XR for the first 4 weeks of the study (only for the first 4 weeks of the study). The RSG XR dose was then increased to 8 mg once daily from Week 4 through Week 52. The dose of RSG XR was reduced to 2mg once daily if the 8 mg dose was not well tolerated. Participants were not permitted to titrate back to 8 mg RSG XR..
Number of Participants With Any Adverse Events (AEs) and Severity of AEs Mild AE	345 Participants
Number of Participants With Any Adverse Events (AEs) and Severity of AEs Any AE	724 Participants
Number of Participants With Any Adverse Events (AEs) and Severity of AEs Moderate AE	289 Participants
Number of Participants With Any Adverse Events (AEs) and Severity of AEs Severe AE	88 Participants

SECONDARY outcome

Timeframe: Up to 76 Weeks

Population: All subject (Full population)

A SAE is defined as any untoward medical occurrence that, at any dose results in death, is a life-threatening condition, requires hospitalization or prolongation of existing hospitalization, results in disability or incapacity, or a congenital anomaly or birth defect. Number of participants with SAEs and deaths were reported for treatment duration of the study.

Outcome measures

Measure	RSG XR n=1461 Participants Eligible participants who completed studies AVA102670 or AVA102672 entered in this open-label extension study. Participants received open-label RSG XR throughout the treatment period as adjunctive therapy to their existing dose of AChEI for Alzheimer's disease treatment. Participants took one tablet of study medication daily in the morning with or without food. All participants received 4 mg once daily RSG XR for the first 4 weeks of the study (only for the first 4 weeks of the study). The RSG XR dose was then increased to 8 mg once daily from Week 4 through Week 52. The dose of RSG XR was reduced to 2mg once daily if the 8 mg dose was not well tolerated. Participants were not permitted to titrate back to 8 mg RSG XR..
Number Participants With Serious Adverse Events (SAEs) and Deaths Any SAE	126 Participants
Number Participants With Serious Adverse Events (SAEs) and Deaths Deaths	20 Participants

SECONDARY outcome

Timeframe: Up to 76 Weeks

Population: All subject (Full population)

Oedema was considered as adverse event of special interest (AESI). The process for AESI selection was based on RSG's pharmacologic class and relevant AEs potentially associated with RSG. The number of participants and their percentage for the adverse event of the various types of oedema were reported.

Outcome measures

Measure	RSG XR n=1461 Participants Eligible participants who completed studies AVA102670 or AVA102672 entered in this open-label extension study. Participants received open-label RSG XR throughout the treatment period as adjunctive therapy to their existing dose of AChEI for Alzheimer's disease treatment. Participants took one tablet of study medication daily in the morning with or without food. All participants received 4 mg once daily RSG XR for the first 4 weeks of the study (only for the first 4 weeks of the study). The RSG XR dose was then increased to 8 mg once daily from Week 4 through Week 52. The dose of RSG XR was reduced to 2mg once daily if the 8 mg dose was not well tolerated. Participants were not permitted to titrate back to 8 mg RSG XR..
Number of Participants With Adverse Event of Oedema Oedema peripheral	130 Participants
Number of Participants With Adverse Event of Oedema Face oedema	8 Participants
Number of Participants With Adverse Event of Oedema Pitting oedema	5 Participants
Number of Participants With Adverse Event of Oedema Oedema	3 Participants
Number of Participants With Adverse Event of Oedema Pulmonary oedema	1 Participants
Number of Participants With Adverse Event of Oedema Eyelid oedema	1 Participants

SECONDARY outcome

Timeframe: Up to 70 Weeks (including follow up)

Population: All subject (Full population). Only those participants available at the specified time points were analyzed.

Vital signs SBP and DBP were measured at each visit. All measurements were made on the participant non-dominant arm supported at heart level, using the same cuff size and same equipment. Blood pressure was measured once, after the participant sat quietly for at least 5 minutes. DBP was measured at the disappearance of Korotkoff sounds (Phase V). If the participant was a smoker or used tobacco products, a period of 30 minutes without tobacco was allowed before taking these measurements. Baseline for the open-label study was the latest assessment from Week 48 of parent studies to the first dose of open-label medication. Change from Baseline was measured as the blood pressure value recorded at specified visit minus the Baseline value.

Outcome measures

Measure	RSG XR n=1461 Participants Eligible participants who completed studies AVA102670 or AVA102672 entered in this open-label extension study. Participants received open-label RSG XR throughout the treatment period as adjunctive therapy to their existing dose of AChEI for Alzheimer's disease treatment. Participants took one tablet of study medication daily in the morning with or without food. All participants received 4 mg once daily RSG XR for the first 4 weeks of the study (only for the first 4 weeks of the study). The RSG XR dose was then increased to 8 mg once daily from Week 4 through Week 52. The dose of RSG XR was reduced to 2mg once daily if the 8 mg dose was not well tolerated. Participants were not permitted to titrate back to 8 mg RSG XR..
Change From Baseline in Vital Sign Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP at Week 4	-1.4 millimeters of mercury (mmHg) Standard Deviation 14.10
Change From Baseline in Vital Sign Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP at Week 8	-2.4 millimeters of mercury (mmHg) Standard Deviation 14.73
Change From Baseline in Vital Sign Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP at Week 12	-2.7 millimeters of mercury (mmHg) Standard Deviation 14.73
Change From Baseline in Vital Sign Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP at Week 16	-3.7 millimeters of mercury (mmHg) Standard Deviation 15.02
Change From Baseline in Vital Sign Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP at Week 24	-2.1 millimeters of mercury (mmHg) Standard Deviation 15.51
Change From Baseline in Vital Sign Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP at Week 36	-1.4 millimeters of mercury (mmHg) Standard Deviation 15.14
Change From Baseline in Vital Sign Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP at Week 52	-1.7 millimeters of mercury (mmHg) Standard Deviation 16.18
Change From Baseline in Vital Sign Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP at Week 64	-2.2 millimeters of mercury (mmHg) Standard Deviation 13.78
Change From Baseline in Vital Sign Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP at Follow-up	-1.8 millimeters of mercury (mmHg) Standard Deviation 15.60
Change From Baseline in Vital Sign Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP at Week 4	-1.4 millimeters of mercury (mmHg) Standard Deviation 9.41
Change From Baseline in Vital Sign Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP at Week 8	-2.0 millimeters of mercury (mmHg) Standard Deviation 9.53
Change From Baseline in Vital Sign Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP at Week 12	-2.1 millimeters of mercury (mmHg) Standard Deviation 9.74
Change From Baseline in Vital Sign Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP at Week 16	-2.4 millimeters of mercury (mmHg) Standard Deviation 9.62
Change From Baseline in Vital Sign Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP at Week 24	-2.4 millimeters of mercury (mmHg) Standard Deviation 9.48
Change From Baseline in Vital Sign Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP at Week 36	-2.0 millimeters of mercury (mmHg) Standard Deviation 9.85
Change From Baseline in Vital Sign Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP at Week 52	-3.6 millimeters of mercury (mmHg) Standard Deviation 9.94
Change From Baseline in Vital Sign Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP at Week 64	-6.3 millimeters of mercury (mmHg) Standard Deviation 6.72
Change From Baseline in Vital Sign Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP at Follow-up	-0.9 millimeters of mercury (mmHg) Standard Deviation 10.23

SECONDARY outcome

Timeframe: Up to 70 Weeks (including follow up)

Population: All subject (Full population). Only those participants available at the specified time points were analyzed.

Vital sign HR was measured at each visit. HR was measured once, after the participant sat quietly for at least 5 minutes. Baseline for the open-label study was the latest assessment from Week 48 of parent studies to the first dose of open-label medication. Change from Baseline was measured as the HR at specified visit minus the Baseline value.

Outcome measures

Measure	RSG XR n=1461 Participants Eligible participants who completed studies AVA102670 or AVA102672 entered in this open-label extension study. Participants received open-label RSG XR throughout the treatment period as adjunctive therapy to their existing dose of AChEI for Alzheimer's disease treatment. Participants took one tablet of study medication daily in the morning with or without food. All participants received 4 mg once daily RSG XR for the first 4 weeks of the study (only for the first 4 weeks of the study). The RSG XR dose was then increased to 8 mg once daily from Week 4 through Week 52. The dose of RSG XR was reduced to 2mg once daily if the 8 mg dose was not well tolerated. Participants were not permitted to titrate back to 8 mg RSG XR..
Change From Baseline in Vital Sign Heart Rate (HR) HR at Week 4	1.0 beats per minute (bpm) Standard Deviation 8.95
Change From Baseline in Vital Sign Heart Rate (HR) HR at Week 8	1.8 beats per minute (bpm) Standard Deviation 9.60
Change From Baseline in Vital Sign Heart Rate (HR) HR at Week 12	1.6 beats per minute (bpm) Standard Deviation 9.77
Change From Baseline in Vital Sign Heart Rate (HR) HR at Week 16	1.6 beats per minute (bpm) Standard Deviation 9.66
Change From Baseline in Vital Sign Heart Rate (HR) HR at Week 24	0.9 beats per minute (bpm) Standard Deviation 9.99
Change From Baseline in Vital Sign Heart Rate (HR) HR at Week 36	1.3 beats per minute (bpm) Standard Deviation 9.86
Change From Baseline in Vital Sign Heart Rate (HR) HR at Week 52	0.7 beats per minute (bpm) Standard Deviation 8.54
Change From Baseline in Vital Sign Heart Rate (HR) HR at Week 64	1.0 beats per minute (bpm) Standard Deviation 8.02
Change From Baseline in Vital Sign Heart Rate (HR) HR at Follow-up	0.9 beats per minute (bpm) Standard Deviation 10.03

SECONDARY outcome

Timeframe: Up to 70 Weeks (including follow up)

Population: All subject (Full population). Only those participants available at the specified time points were analyzed.

BW was measured at all visits, without shoes and wearing light clothing. Baseline for the open-label study was the latest assessment from Week 48 of parent studies to the first dose of open-label medication. Change from Baseline was measured as the body weight at specified visit minus the Baseline value.

Outcome measures

Measure	RSG XR n=1461 Participants Eligible participants who completed studies AVA102670 or AVA102672 entered in this open-label extension study. Participants received open-label RSG XR throughout the treatment period as adjunctive therapy to their existing dose of AChEI for Alzheimer's disease treatment. Participants took one tablet of study medication daily in the morning with or without food. All participants received 4 mg once daily RSG XR for the first 4 weeks of the study (only for the first 4 weeks of the study). The RSG XR dose was then increased to 8 mg once daily from Week 4 through Week 52. The dose of RSG XR was reduced to 2mg once daily if the 8 mg dose was not well tolerated. Participants were not permitted to titrate back to 8 mg RSG XR..
Change From Baseline in Vital Sign Body Weight (BW) BW at Week 4	0.3 kg Standard Deviation 2.04
Change From Baseline in Vital Sign Body Weight (BW) BW at Week 8	0.6 kg Standard Deviation 2.45
Change From Baseline in Vital Sign Body Weight (BW) BW at Week 12	0.6 kg Standard Deviation 2.43
Change From Baseline in Vital Sign Body Weight (BW) BW at Week 16	0.7 kg Standard Deviation 3.53
Change From Baseline in Vital Sign Body Weight (BW) BW at Week 24	0.6 kg Standard Deviation 2.95
Change From Baseline in Vital Sign Body Weight (BW) BW at Week 36	1.0 kg Standard Deviation 4.08
Change From Baseline in Vital Sign Body Weight (BW) BW at Week 52	1.2 kg Standard Deviation 3.82
Change From Baseline in Vital Sign Body Weight (BW) BW at Week 64	1.4 kg Standard Deviation 2.52
Change From Baseline in Vital Sign Body Weight (BW) BW at Follow-up	0.5 kg Standard Deviation 3.15

SECONDARY outcome

Timeframe: Up to 82 Weeks (including follow up)

Population: All subject (Full population). Only those participants available at the specified time points were analyzed.

The clinical chemistry data included non-fasting measures of lipid metabolism (TC,HDL,LDL,triglycerides). Baseline for the open-label study was the latest assessment from Week 48 of parent studies to the first dose of open-label medication. Change from Baseline was measured as the lipids (TC,HDL,LDL,triglycerides) value recorded at specified visit minus the Baseline value.

Outcome measures

Measure	RSG XR n=1461 Participants Eligible participants who completed studies AVA102670 or AVA102672 entered in this open-label extension study. Participants received open-label RSG XR throughout the treatment period as adjunctive therapy to their existing dose of AChEI for Alzheimer's disease treatment. Participants took one tablet of study medication daily in the morning with or without food. All participants received 4 mg once daily RSG XR for the first 4 weeks of the study (only for the first 4 weeks of the study). The RSG XR dose was then increased to 8 mg once daily from Week 4 through Week 52. The dose of RSG XR was reduced to 2mg once daily if the 8 mg dose was not well tolerated. Participants were not permitted to titrate back to 8 mg RSG XR..
Change From Baseline in Non-fasting Measures of Lipid Metabolism Namely Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Triglycerides TC at Week 4	0.076 millimole per litre (mmol/l) Standard Deviation 0.6828
Change From Baseline in Non-fasting Measures of Lipid Metabolism Namely Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Triglycerides TC at Week 16	0.201 millimole per litre (mmol/l) Standard Deviation 0.8666
Change From Baseline in Non-fasting Measures of Lipid Metabolism Namely Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Triglycerides TC at Week 36	0.246 millimole per litre (mmol/l) Standard Deviation 0.9649
Change From Baseline in Non-fasting Measures of Lipid Metabolism Namely Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Triglycerides TC at Week 52	0.174 millimole per litre (mmol/l) Standard Deviation 1.1437
Change From Baseline in Non-fasting Measures of Lipid Metabolism Namely Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Triglycerides TC at Week 76	-0.715 millimole per litre (mmol/l) Standard Deviation 0.3041
Change From Baseline in Non-fasting Measures of Lipid Metabolism Namely Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Triglycerides TC at follow up	0.093 millimole per litre (mmol/l) Standard Deviation 0.9377
Change From Baseline in Non-fasting Measures of Lipid Metabolism Namely Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Triglycerides HDL at Week 4	0.007 millimole per litre (mmol/l) Standard Deviation 0.2008
Change From Baseline in Non-fasting Measures of Lipid Metabolism Namely Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Triglycerides HDL at Week 16	-0.014 millimole per litre (mmol/l) Standard Deviation 0.2427
Change From Baseline in Non-fasting Measures of Lipid Metabolism Namely Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Triglycerides HDL at Week 36	-0.026 millimole per litre (mmol/l) Standard Deviation 0.2487
Change From Baseline in Non-fasting Measures of Lipid Metabolism Namely Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Triglycerides HDL at Week 52	-0.035 millimole per litre (mmol/l) Standard Deviation 0.2512
Change From Baseline in Non-fasting Measures of Lipid Metabolism Namely Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Triglycerides HDL at Week 76	0.050 millimole per litre (mmol/l) Standard Deviation NA Standard deviation could not be calculated as a single participant was analyzed.
Change From Baseline in Non-fasting Measures of Lipid Metabolism Namely Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Triglycerides HDL at follow up	-0.058 millimole per litre (mmol/l) Standard Deviation 0.2605
Change From Baseline in Non-fasting Measures of Lipid Metabolism Namely Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Triglycerides LDL at Week 4	0.062 millimole per litre (mmol/l) Standard Deviation 0.6207
Change From Baseline in Non-fasting Measures of Lipid Metabolism Namely Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Triglycerides LDL at Week 16	0.210 millimole per litre (mmol/l) Standard Deviation 0.7782
Change From Baseline in Non-fasting Measures of Lipid Metabolism Namely Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Triglycerides LDL at Week 36	0.281 millimole per litre (mmol/l) Standard Deviation 0.8863
Change From Baseline in Non-fasting Measures of Lipid Metabolism Namely Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Triglycerides LDL at Week 52	0.228 millimole per litre (mmol/l) Standard Deviation 1.0563
Change From Baseline in Non-fasting Measures of Lipid Metabolism Namely Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Triglycerides LDL at Week 76	-0.200 millimole per litre (mmol/l) Standard Deviation NA Standard deviation could not be calculated as a single participant was analyzed.
Change From Baseline in Non-fasting Measures of Lipid Metabolism Namely Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Triglycerides LDL at follow up	0.148 millimole per litre (mmol/l) Standard Deviation 0.8336
Change From Baseline in Non-fasting Measures of Lipid Metabolism Namely Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Triglycerides Triglycerides at Week 4	0.004 millimole per litre (mmol/l) Standard Deviation 0.7845
Change From Baseline in Non-fasting Measures of Lipid Metabolism Namely Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Triglycerides Triglycerides at Week 16	-0.025 millimole per litre (mmol/l) Standard Deviation 0.8053
Change From Baseline in Non-fasting Measures of Lipid Metabolism Namely Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Triglycerides Triglycerides at Week 36	-0.062 millimole per litre (mmol/l) Standard Deviation 0.8053
Change From Baseline in Non-fasting Measures of Lipid Metabolism Namely Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Triglycerides Triglycerides at Week 52	-0.092 millimole per litre (mmol/l) Standard Deviation 0.8521
Change From Baseline in Non-fasting Measures of Lipid Metabolism Namely Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Triglycerides Triglycerides at Week 76	-0.150 millimole per litre (mmol/l) Standard Deviation 0.9758
Change From Baseline in Non-fasting Measures of Lipid Metabolism Namely Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Triglycerides Triglycerides at follow up	-0.035 millimole per litre (mmol/l) Standard Deviation 0.8295

SECONDARY outcome

Timeframe: Up to 70 Weeks (including follow up)

Population: All subject (Full population). Only those participants available at the specified time points were analyzed.

The frequency of participant vital sign sitting blood pressure was obtained to check if the values lie outside of a pre-determined reference range (RR) for SBP 90-140 mmHg, DBP 50-90 mmHg or have a change from Baseline of PCC for SBP increase from Baseline (IFB) >=40, decrease from Baseline (DFB) >= 30 for and for DBP (IFB) >= 30 ,DFB >= 20. The number of participants with values of PCC at any time on treatment (ATOT) and follow up were reported.

Outcome measures

Measure	RSG XR n=1461 Participants Eligible participants who completed studies AVA102670 or AVA102672 entered in this open-label extension study. Participants received open-label RSG XR throughout the treatment period as adjunctive therapy to their existing dose of AChEI for Alzheimer's disease treatment. Participants took one tablet of study medication daily in the morning with or without food. All participants received 4 mg once daily RSG XR for the first 4 weeks of the study (only for the first 4 weeks of the study). The RSG XR dose was then increased to 8 mg once daily from Week 4 through Week 52. The dose of RSG XR was reduced to 2mg once daily if the 8 mg dose was not well tolerated. Participants were not permitted to titrate back to 8 mg RSG XR..
Number of Participants With SBP and DBP Values of Potential Clinical Concern (PCC) ATOT,SBP(RR)>140 or <90	520 Participants
Number of Participants With SBP and DBP Values of Potential Clinical Concern (PCC) ATOT,SBP(IFB)>=40	33 Participants
Number of Participants With SBP and DBP Values of Potential Clinical Concern (PCC) ATOT,SBP(DFB)>=30	179 Participants
Number of Participants With SBP and DBP Values of Potential Clinical Concern (PCC) Follow up,SBP(RR)>140 or <90	240 Participants
Number of Participants With SBP and DBP Values of Potential Clinical Concern (PCC) Follow up,SBP(IFB)>=40	13 Participants
Number of Participants With SBP and DBP Values of Potential Clinical Concern (PCC) Follow up,SBP(DFB)>=30	63 Participants
Number of Participants With SBP and DBP Values of Potential Clinical Concern (PCC) ATOT,DBP(RR)>90 or<50	141 Participants
Number of Participants With SBP and DBP Values of Potential Clinical Concern (PCC) ATOT,DBP(IFB)>=30	20 Participants
Number of Participants With SBP and DBP Values of Potential Clinical Concern (PCC) ATOT,DBP(DFB)>= 20	211 Participants
Number of Participants With SBP and DBP Values of Potential Clinical Concern (PCC) Follow up,DBP(RR)>90 or<50	54 Participants
Number of Participants With SBP and DBP Values of Potential Clinical Concern (PCC) Follow up,DBP(IFB)>=30	5 Participants
Number of Participants With SBP and DBP Values of Potential Clinical Concern (PCC) Follow up, DBP(DFB)>= 20	67 Participants

SECONDARY outcome

Timeframe: Up to 70 Weeks (including follow up)

Population: All subject (Full population). Only those participants available at the specified time points were analyzed.

HR was measured once, after the participant sat quietly for at least 5 minutes. The frequency of participant vital sign heart rate was obtained to check if the values lie outside of a pre-determined reference range (RR) 50-100 bpm or have a change from Baseline of PCC IFB >=30 and DFB >=30. The number of participants with values of PCC including follow up were reported.

Outcome measures

Measure	RSG XR n=1461 Participants Eligible participants who completed studies AVA102670 or AVA102672 entered in this open-label extension study. Participants received open-label RSG XR throughout the treatment period as adjunctive therapy to their existing dose of AChEI for Alzheimer's disease treatment. Participants took one tablet of study medication daily in the morning with or without food. All participants received 4 mg once daily RSG XR for the first 4 weeks of the study (only for the first 4 weeks of the study). The RSG XR dose was then increased to 8 mg once daily from Week 4 through Week 52. The dose of RSG XR was reduced to 2mg once daily if the 8 mg dose was not well tolerated. Participants were not permitted to titrate back to 8 mg RSG XR..
Number of Participants With HR Values of PCC ATOT ATOT,HR (RR)>100 or <50	55 Participants
Number of Participants With HR Values of PCC ATOT ATOT,HR (IFB)>=30	25 Participants
Number of Participants With HR Values of PCC ATOT ATOT,HR (DFB)>=30	14 Participants
Number of Participants With HR Values of PCC ATOT Follow up,HR (RR)>100 or <50	18 Participants
Number of Participants With HR Values of PCC ATOT Follow up,HR (IFB)>=30	11 Participants
Number of Participants With HR Values of PCC ATOT Follow up,HR (DFB)>=30	6 Participants

SECONDARY outcome

Timeframe: Up to 70 Weeks (including follow up)

Population: All subject (Full population). Only those participants available at the specified time points were analyzed.

The frequency of participant vital sign weight was obtained to check if the values have CFB of PCC IFB >=7 percent. With the exception of Week 4, when participants were first titrated to the 8mg RSG XR dose, at every time point in the study where weight was measured the percentage of participants experienced an increase in BW of PCC was approximately 2 times greater than the percentage of participants experiencing an decrease in BW of PCC DFB >=7 percent. The number of participants with values of PCC including follow up were reported.

Outcome measures

Measure	RSG XR n=1461 Participants Eligible participants who completed studies AVA102670 or AVA102672 entered in this open-label extension study. Participants received open-label RSG XR throughout the treatment period as adjunctive therapy to their existing dose of AChEI for Alzheimer's disease treatment. Participants took one tablet of study medication daily in the morning with or without food. All participants received 4 mg once daily RSG XR for the first 4 weeks of the study (only for the first 4 weeks of the study). The RSG XR dose was then increased to 8 mg once daily from Week 4 through Week 52. The dose of RSG XR was reduced to 2mg once daily if the 8 mg dose was not well tolerated. Participants were not permitted to titrate back to 8 mg RSG XR..
Number of Participants With BW Values of PCC ATOT ATOT, BW(IFB)>=7 percent	188 Participants
Number of Participants With BW Values of PCC ATOT ATOT, BW(DFB)>= 7 percent	83 Participants
Number of Participants With BW Values of PCC ATOT Follow up, BW(IFB)>=7 percent	90 Participants
Number of Participants With BW Values of PCC ATOT Follow up, BW(DFB)>= 7 percent	51 Participants

SECONDARY outcome

Timeframe: Up to Week 82 (including follow up)

Population: All subject (Full population). Only those participants available at the specified time points were analyzed.

The hematology data included eosinophils, haematocrit, haemoglobin, lymphocytes, mean corpuscular haemoglobin (MCH), mean corpuscular volume (MCV), monocytes, platelet count, red cell distribution width (RDW), red blood cell (RBC) count, segmented neutrophils (SN), total neutrophils (TN), white blood cell (WBC) count. The number of participants with values of PCC (defined as high and low) ATOT were reported.

Outcome measures

Measure	RSG XR n=1461 Participants Eligible participants who completed studies AVA102670 or AVA102672 entered in this open-label extension study. Participants received open-label RSG XR throughout the treatment period as adjunctive therapy to their existing dose of AChEI for Alzheimer's disease treatment. Participants took one tablet of study medication daily in the morning with or without food. All participants received 4 mg once daily RSG XR for the first 4 weeks of the study (only for the first 4 weeks of the study). The RSG XR dose was then increased to 8 mg once daily from Week 4 through Week 52. The dose of RSG XR was reduced to 2mg once daily if the 8 mg dose was not well tolerated. Participants were not permitted to titrate back to 8 mg RSG XR..
Number of Participants With Hematology Parameters of PCC ATOT ATOT, Eosinophils (high)	2 Participants
Number of Participants With Hematology Parameters of PCC ATOT ATOT, Haematocrit (low)	8 Participants
Number of Participants With Hematology Parameters of PCC ATOT Follow up, Haematocrit (low)	6 Participants
Number of Participants With Hematology Parameters of PCC ATOT ATOT, Haemoglobin (high)	2 Participants
Number of Participants With Hematology Parameters of PCC ATOT ATOT, Haemoglobin (low)	74 Participants
Number of Participants With Hematology Parameters of PCC ATOT Follow up, Hemoglobin (high)	2 Participants
Number of Participants With Hematology Parameters of PCC ATOT Follow up, Hemoglobin (low)	25 Participants
Number of Participants With Hematology Parameters of PCC ATOT ATOT, Lymphocytes (high)	3 Participants
Number of Participants With Hematology Parameters of PCC ATOT ATOT, Lymphocytes (low)	21 Participants
Number of Participants With Hematology Parameters of PCC ATOT Follow up, Lymphocytes (high)	3 Participants
Number of Participants With Hematology Parameters of PCC ATOT Follow up, Lymphocytes (low)	9 Participants
Number of Participants With Hematology Parameters of PCC ATOT ATOT, MCH (low)	5 Participants
Number of Participants With Hematology Parameters of PCC ATOT Follow up, MCH (low)	1 Participants
Number of Participants With Hematology Parameters of PCC ATOT ATOT, MCV (low)	1 Participants
Number of Participants With Hematology Parameters of PCC ATOT ATOT, monocytes (high)	1 Participants
Number of Participants With Hematology Parameters of PCC ATOT ATOT, monocytes (low)	61 Participants
Number of Participants With Hematology Parameters of PCC ATOT Follow up, monocytes (low)	23 Participants
Number of Participants With Hematology Parameters of PCC ATOT ATOT, platelet count (high)	7 Participants
Number of Participants With Hematology Parameters of PCC ATOT ATOT, platelet count (low)	5 Participants
Number of Participants With Hematology Parameters of PCC ATOT ATOT, RDW (high)	158 Participants
Number of Participants With Hematology Parameters of PCC ATOT Follow up, RDW (high)	45 Participants
Number of Participants With Hematology Parameters of PCC ATOT ATOT, RBC (low)	12 Participants
Number of Participants With Hematology Parameters of PCC ATOT Follow up, RBC (low)	4 Participants
Number of Participants With Hematology Parameters of PCC ATOT ATOT, SN (high)	6 Participants
Number of Participants With Hematology Parameters of PCC ATOT ATOT, SN (low)	15 Participants
Number of Participants With Hematology Parameters of PCC ATOT Follow up, SN (high)	3 Participants
Number of Participants With Hematology Parameters of PCC ATOT Follow up, SN (low)	3 Participants
Number of Participants With Hematology Parameters of PCC ATOT ATOT, TN (high)	3 Participants
Number of Participants With Hematology Parameters of PCC ATOT ATOT, TN (low)	15 Participants
Number of Participants With Hematology Parameters of PCC ATOT Follow up, TN (high)	2 Participants
Number of Participants With Hematology Parameters of PCC ATOT Follow up, TN (low)	3 Participants
Number of Participants With Hematology Parameters of PCC ATOT ATOT, WBC (high)	5 Participants
Number of Participants With Hematology Parameters of PCC ATOT ATOT, WBC (low)	22 Participants
Number of Participants With Hematology Parameters of PCC ATOT Follow up, WBC (high)	3 Participants
Number of Participants With Hematology Parameters of PCC ATOT Follow up, WBC (low)	11 Participants

SECONDARY outcome

Timeframe: Up to Week 82 (including follow up)

Population: All subject population (Full population). Only those participants available at the specified time points were analyzed.

The clinical chemistry data included alanine amino transferase (ALT), albumin, aldolase, asparatate amino transferase (AST), BUN/creatinine ratio, carbon dioxide(CO2) content, chloride, cholesterol, creatinine kinase (CK), creatinine, direct bilirubin (DB), gamma glutamyl transferase (GGT), glucose, glycosylated Hemoglobin (HbA1C), HDL, LDL, lactate dehydrogenase (LD), magnesium, potassium, sodium, total bilirubin (TB), triglycerides, troponin I, urea. The number of participants with values of PCC (defined as high and low) ATOT were reported.

Outcome measures

Measure	RSG XR n=1461 Participants Eligible participants who completed studies AVA102670 or AVA102672 entered in this open-label extension study. Participants received open-label RSG XR throughout the treatment period as adjunctive therapy to their existing dose of AChEI for Alzheimer's disease treatment. Participants took one tablet of study medication daily in the morning with or without food. All participants received 4 mg once daily RSG XR for the first 4 weeks of the study (only for the first 4 weeks of the study). The RSG XR dose was then increased to 8 mg once daily from Week 4 through Week 52. The dose of RSG XR was reduced to 2mg once daily if the 8 mg dose was not well tolerated. Participants were not permitted to titrate back to 8 mg RSG XR..
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, TB (high)	1 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT Follow up, ALT (high)	2 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT Follow up, Albumin (low)	1 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, Aldolase (high)	16 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, Aldolase (low)	78 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT Follow up, Aldolase (high)	3 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT Follow up, Aldolase (low)	14 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, AST (high)	2 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT Follow up, AST (high)	3 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, BUN/creatinine ratio (high)	87 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT Follow up, BUN/creatinine ratio (high)	37 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, CO2 content (low)	2 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT Follow up, CO2 content (low)	3 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, chloride (high)	1 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, cholesterol (high)	175 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT Follow up, cholesterol (high)	50 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, CK (high)	131 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT Follow up, CK (high)	40 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, Creatinine (high)	27 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT Follow up, creatinine (high)	10 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, DB (high)	4 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, GGT (high)	7 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT Follow up, GGT (high)	2 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, Glucose (high)	100 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, Glucose (low)	40 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT Follow up, glucose (high)	31 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT Follow up, glucose (low)	13 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, HbA1c (high)	2 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, HDL (low)	11 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT Follow up, HDL (low)	7 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, LDL (low)	469 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT Follow up, LDL (low)	211 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, LD (high)	1 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT Follow up, LD (high)	1 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, Magnesium (low)	1 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT Follow up, Magnesium (low)	1 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, Potassium (high)	17 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, Potassium (low)	1 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT Follow up, Potassium (high)	2 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT Follow up, Potassium (low)	1 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, Sodium (high)	2 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, Sodium (low)	4 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT Follow up, Sodium (low)	1 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT Follow up, TB (high)	1 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, Triglycerides (high)	1 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, Troponin I (high)	13 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT Follow up, Troponin I (high)	2 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT ATOT, Urea (high)	97 Participants
Number of Participants With Clinical Chemistry Parameters (Including Lipids) of PCC ATOT Follow up, Urea (high)	42 Participants

SECONDARY outcome

Timeframe: Baseline (Week 0) and Week 24, 52

Population: All subject (Full population). Only those participants available at the specified time points were analyzed. The analysis was done on the full population and was repeated for APOE subgroups (negative, positive, homozygotes, heterozygotes).

The 11-item ADAS-Cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Most items were evaluated by tests, but some were dependent on clinician ratings on a five point scale. Scores ranged from 0 to 70 with higher scores indicating greater dysfunction. Baseline for the open-label study was the latest assessment from Week 48 of parent studies to the first dose of open-label medication (Week 0). Change from Baseline was calculated as the Baseline value minus the value at the specified time point.

Outcome measures

Measure	RSG XR n=1461 Participants Eligible participants who completed studies AVA102670 or AVA102672 entered in this open-label extension study. Participants received open-label RSG XR throughout the treatment period as adjunctive therapy to their existing dose of AChEI for Alzheimer's disease treatment. Participants took one tablet of study medication daily in the morning with or without food. All participants received 4 mg once daily RSG XR for the first 4 weeks of the study (only for the first 4 weeks of the study). The RSG XR dose was then increased to 8 mg once daily from Week 4 through Week 52. The dose of RSG XR was reduced to 2mg once daily if the 8 mg dose was not well tolerated. Participants were not permitted to titrate back to 8 mg RSG XR..
Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Total Score as a Function of Apolipoprotein E (APOE) ε4 Status. Week 24 (Full population)	2.5 Scores on scale Standard Deviation 5.51
Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Total Score as a Function of Apolipoprotein E (APOE) ε4 Status. Week 52 (Full population)	5.1 Scores on scale Standard Deviation 6.82
Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Total Score as a Function of Apolipoprotein E (APOE) ε4 Status. Week 24 (APOE4 negatives)	2.3 Scores on scale Standard Deviation 5.28
Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Total Score as a Function of Apolipoprotein E (APOE) ε4 Status. Week 52 (APOE4 negatives)	4.8 Scores on scale Standard Deviation 6.44
Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Total Score as a Function of Apolipoprotein E (APOE) ε4 Status. Week 24 (APOE4 positives)	2.6 Scores on scale Standard Deviation 5.66
Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Total Score as a Function of Apolipoprotein E (APOE) ε4 Status. Week 52(APOE4 positives)	5.4 Scores on scale Standard Deviation 7.11
Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Total Score as a Function of Apolipoprotein E (APOE) ε4 Status. Week 24 (APOE4 E4 homozygotes)	2.7 Scores on scale Standard Deviation 5.77
Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Total Score as a Function of Apolipoprotein E (APOE) ε4 Status. Week 52 (APOE4 E4 homozygotes)	5.2 Scores on scale Standard Deviation 7.49
Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Total Score as a Function of Apolipoprotein E (APOE) ε4 Status. Week 24 (APOE4 E4 heterozygotes)	2.6 Scores on scale Standard Deviation 5.63
Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Total Score as a Function of Apolipoprotein E (APOE) ε4 Status. Week 52 (APOE4 E4 heterozygotes)	5.4 Scores on scale Standard Deviation 7.02

SECONDARY outcome

Timeframe: Baseline (Week 0) and Week 24, 52

Population: All subject population. Only those participants available at the specified time points were analyzed. The analysis was done on the full population and was repeated for APOE subgroups (negatives, positives, homozygotes, heterozygotes).

The CDR-SB is a validated clinical assessment of global function in par. with Alzheimer's disease (AD). Impairment was scored in each of 6 cognitive categories on a scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2, and severe = 3. The 6 individual category ratings, or box scores, were added together to give the CDR-Sum of Boxes which ranged from 0 to 18 (severe impairment). Baseline for the open-label study was the latest assessment from Week 48 of parent studies to the first dose of open-label medication (Week 0). Change from Baseline was calculated as the Baseline value minus the value at the specified time point.

Outcome measures

Measure	RSG XR n=1461 Participants Eligible participants who completed studies AVA102670 or AVA102672 entered in this open-label extension study. Participants received open-label RSG XR throughout the treatment period as adjunctive therapy to their existing dose of AChEI for Alzheimer's disease treatment. Participants took one tablet of study medication daily in the morning with or without food. All participants received 4 mg once daily RSG XR for the first 4 weeks of the study (only for the first 4 weeks of the study). The RSG XR dose was then increased to 8 mg once daily from Week 4 through Week 52. The dose of RSG XR was reduced to 2mg once daily if the 8 mg dose was not well tolerated. Participants were not permitted to titrate back to 8 mg RSG XR..
Change From Baseline in Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) Score as a Function of APOE ε4 Status. Week 24 (Full population)	0.7 Scores on scale Standard Deviation 1.84
Change From Baseline in Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) Score as a Function of APOE ε4 Status. Week 52 (Full population)	1.6 Scores on scale Standard Deviation 2.26
Change From Baseline in Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) Score as a Function of APOE ε4 Status. Week 24 (APOE4 negatives)	0.6 Scores on scale Standard Deviation 1.76
Change From Baseline in Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) Score as a Function of APOE ε4 Status. Week 52 (APOE4 negatives)	1.3 Scores on scale Standard Deviation 2.19
Change From Baseline in Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) Score as a Function of APOE ε4 Status. Week 24 (APOE4 positives)	0.7 Scores on scale Standard Deviation 1.89
Change From Baseline in Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) Score as a Function of APOE ε4 Status. Week 52 (APOE4 positives)	1.9 Scores on scale Standard Deviation 2.30
Change From Baseline in Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) Score as a Function of APOE ε4 Status. Week 24 (APOE4 E4 homozygotes)	0.9 Scores on scale Standard Deviation 1.90
Change From Baseline in Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) Score as a Function of APOE ε4 Status. Week 52 (APOE4 E4 homozygotes)	1.9 Scores on scale Standard Deviation 2.32
Change From Baseline in Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) Score as a Function of APOE ε4 Status. Week 24 (APOE4 E4 heterozygotes)	0.7 Scores on scale Standard Deviation 1.89
Change From Baseline in Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) Score as a Function of APOE ε4 Status. Week 52 (APOE4 E4 heterozygotes)	1.9 Scores on scale Standard Deviation 2.30

SECONDARY outcome

Timeframe: Baseline (Week 0) and Week 24, 52

Population: All subject (Full population). Only those participants available at the specified time points were analyzed. The analysis was done on the full population and was repeated for APOE subgroups (negatives, positives, homozygotes, heterozygotes).

The MMSE consisted of 11 tests of orientation, memory (recent and immediate), concentration, language and praxis. Scores ranged from 0 to 30, with lower scores indicating greater cognitive impairment. Baseline for the open-label study was the latest assessment from Week 48 of parent studies to the first dose of open-label medication (Week 0). Change from Baseline was calculated as the Baseline value minus the value at the specified time point.

Outcome measures

Measure	RSG XR n=1461 Participants Eligible participants who completed studies AVA102670 or AVA102672 entered in this open-label extension study. Participants received open-label RSG XR throughout the treatment period as adjunctive therapy to their existing dose of AChEI for Alzheimer's disease treatment. Participants took one tablet of study medication daily in the morning with or without food. All participants received 4 mg once daily RSG XR for the first 4 weeks of the study (only for the first 4 weeks of the study). The RSG XR dose was then increased to 8 mg once daily from Week 4 through Week 52. The dose of RSG XR was reduced to 2mg once daily if the 8 mg dose was not well tolerated. Participants were not permitted to titrate back to 8 mg RSG XR..
Change From Baseline in Mini Mental State Examination (MMSE) Total Score as a Function of APOE ε4 Status. Week 24 (Full population)	-1.2 Scores on scale Standard Deviation 2.84
Change From Baseline in Mini Mental State Examination (MMSE) Total Score as a Function of APOE ε4 Status. Week 52 (Full population)	-2.3 Scores on scale Standard Deviation 3.39
Change From Baseline in Mini Mental State Examination (MMSE) Total Score as a Function of APOE ε4 Status. Week 24 (APOE4 negatives)	-0.7 Scores on scale Standard Deviation 2.74
Change From Baseline in Mini Mental State Examination (MMSE) Total Score as a Function of APOE ε4 Status. Week 52 (APOE4 negatives)	-1.5 Scores on scale Standard Deviation 3.56
Change From Baseline in Mini Mental State Examination (MMSE) Total Score as a Function of APOE ε4 Status. Week 24 (APOE4 positives)	-1.5 Scores on scale Standard Deviation 2.87
Change From Baseline in Mini Mental State Examination (MMSE) Total Score as a Function of APOE ε4 Status. Week 52 (APOE4 positives)	-2.8 Scores on scale Standard Deviation 3.17
Change From Baseline in Mini Mental State Examination (MMSE) Total Score as a Function of APOE ε4 Status. Week 24 (APOE4 E4 homozygotes)	-1.5 Scores on scale Standard Deviation 3.07
Change From Baseline in Mini Mental State Examination (MMSE) Total Score as a Function of APOE ε4 Status. Week 52 (APOE4 E4 homozygotes)	-2.5 Scores on scale Standard Deviation 3.16
Change From Baseline in Mini Mental State Examination (MMSE) Total Score as a Function of APOE ε4 Status. Week 24 (APOE4 E4 heterozygotes)	-1.5 Scores on scale Standard Deviation 2.82
Change From Baseline in Mini Mental State Examination (MMSE) Total Score as a Function of APOE ε4 Status. Week 52 (APOE4 E4 heterozygotes)	-2.9 Scores on scale Standard Deviation 3.18

SECONDARY outcome

Timeframe: Baseline (Week 0) and Week 24, 52

Population: All subject (Full population). Only those participants available at the specified time points were analyzed.The analysis was done on the full population and was repeated for APOE subgroups (negatives, positives, homozygotes, heterozygotes).

DAD, assessed the ability of a participant to execute basic and instrumental activities of daily living (ADL) and leisure activities. The scale consists of 40 questions assessing basic and instrumental ADLs. This scale assesses a participant's 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. The percentage score was calculated as (DAD total score/total number of applicable items) * 100. Baseline for the open-label study was the latest assessment from Week 48 of parent studies to the first dose of open-label medication (Week 0). Change from Baseline was calculated as the Baseline value minus the value at the specified time point.

Outcome measures

Measure	RSG XR n=1461 Participants Eligible participants who completed studies AVA102670 or AVA102672 entered in this open-label extension study. Participants received open-label RSG XR throughout the treatment period as adjunctive therapy to their existing dose of AChEI for Alzheimer's disease treatment. Participants took one tablet of study medication daily in the morning with or without food. All participants received 4 mg once daily RSG XR for the first 4 weeks of the study (only for the first 4 weeks of the study). The RSG XR dose was then increased to 8 mg once daily from Week 4 through Week 52. The dose of RSG XR was reduced to 2mg once daily if the 8 mg dose was not well tolerated. Participants were not permitted to titrate back to 8 mg RSG XR..
Change From Baseline in Disability Assessment for Dementia Scale (DAD) Total Score as a Function of APOE ε4 Status. Week 24 (Full population)	-5.6 Scores on scale Standard Deviation 12.36
Change From Baseline in Disability Assessment for Dementia Scale (DAD) Total Score as a Function of APOE ε4 Status. Week 52 (Full population)	-10.8 Scores on scale Standard Deviation 15.07
Change From Baseline in Disability Assessment for Dementia Scale (DAD) Total Score as a Function of APOE ε4 Status. Week 24 (APOE4 negatives)	-4.6 Scores on scale Standard Deviation 11.57
Change From Baseline in Disability Assessment for Dementia Scale (DAD) Total Score as a Function of APOE ε4 Status. Week 52 (APOE4 negatives)	-10.9 Scores on scale Standard Deviation 14.90
Change From Baseline in Disability Assessment for Dementia Scale (DAD) Total Score as a Function of APOE ε4 Status. Week 24 (APOE4 positives)	-6.2 Scores on scale Standard Deviation 12.88
Change From Baseline in Disability Assessment for Dementia Scale (DAD) Total Score as a Function of APOE ε4 Status. Week 52 (APOE4 positives)	-10.7 Scores on scale Standard Deviation 15.26
Change From Baseline in Disability Assessment for Dementia Scale (DAD) Total Score as a Function of APOE ε4 Status. Week 24 (APOE4 E4 homozygotes)	-5.6 Scores on scale Standard Deviation 12.16
Change From Baseline in Disability Assessment for Dementia Scale (DAD) Total Score as a Function of APOE ε4 Status. Week 52 (APOE4 E4 homozygotes)	-12.6 Scores on scale Standard Deviation 11.84
Change From Baseline in Disability Assessment for Dementia Scale (DAD) Total Score as a Function of APOE ε4 Status. Week 24 (APOE4 E4 heterozygotes)	-6.4 Scores on scale Standard Deviation 13.08
Change From Baseline in Disability Assessment for Dementia Scale (DAD) Total Score as a Function of APOE ε4 Status. Week 52 (APOE4 E4 heterozygotes)	-10.1 Scores on scale Standard Deviation 16.14

SECONDARY outcome

Timeframe: Baseline (Week 0) and Week 24, 52

Population: All subject (Full population). Only those participants available at the specified time points were analyzed.The analysis was done on the full population and was repeated for APOE subgroups (negatives, positives, homozygotes, heterozygotes).

12-domain caregiver assessment of behavioral disturbances occurring in dementia: delusions, hallucinations, agitation, depression, anxiety, euphoria, apathy, disinhibition, irritability, motor disturbance, appetite, nighttime behavior. A screening question is asked about each sub-domain. If the responses to these questions=participant has problems with a particular sub-domain of behavior, the caregiver asked all the questions about that domain, rating the frequency (1=occasionally to 4=very frequently) on a 4-point scale, their severity (1=Mild to 3=Severe) on a 3-point scale, and the distress on a 5-point scale. Total score=sum of each domain score(range 0-144);higher score=greater behavioral disturbances. Baseline for the open-label study was the latest assessment from Week 48 of parent studies to the first dose of open-label medication (Week 0). Change from Baseline was calculated as the Baseline value minus the value at the specified time point.

Outcome measures

Measure	RSG XR n=1461 Participants Eligible participants who completed studies AVA102670 or AVA102672 entered in this open-label extension study. Participants received open-label RSG XR throughout the treatment period as adjunctive therapy to their existing dose of AChEI for Alzheimer's disease treatment. Participants took one tablet of study medication daily in the morning with or without food. All participants received 4 mg once daily RSG XR for the first 4 weeks of the study (only for the first 4 weeks of the study). The RSG XR dose was then increased to 8 mg once daily from Week 4 through Week 52. The dose of RSG XR was reduced to 2mg once daily if the 8 mg dose was not well tolerated. Participants were not permitted to titrate back to 8 mg RSG XR..
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score as a Function of APOE ε4 Status. Week 24 (Full population)	1.4 Score on scale Standard Deviation 7.87
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score as a Function of APOE ε4 Status. Week 52 (Full population)	3.2 Score on scale Standard Deviation 10.90
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score as a Function of APOE ε4 Status. Week 24 (APOE4 negatives)	1.0 Score on scale Standard Deviation 7.26
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score as a Function of APOE ε4 Status. Week 52 (APOE4 negatives)	2.4 Score on scale Standard Deviation 7.74
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score as a Function of APOE ε4 Status. Week 24 (APOE4 positives)	1.7 Score on scale Standard Deviation 8.29
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score as a Function of APOE ε4 Status. Week 52 (APOE4 positives)	3.8 Score on scale Standard Deviation 12.71
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score as a Function of APOE ε4 Status. Week 24 (APOE4 E4 homozygotes)	1.8 Score on scale Standard Deviation 7.75
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score as a Function of APOE ε4 Status. Week 52 (APOE4 E4 homozygotes)	4.2 Score on scale Standard Deviation 14.19
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score as a Function of APOE ε4 Status. Week 24 (APOE4 E4 heterozygotes)	1.6 Score on scale Standard Deviation 8.45
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score as a Function of APOE ε4 Status. Week 52 (APOE4 E4 heterozygotes)	3.7 Score on scale Standard Deviation 12.34

Adverse Events

RSG XR

Serious events: 126 serious events

Other events: 130 other events

Deaths: 20 deaths

Serious adverse events

Measure	RSG XR n=1461 participants at risk Eligible participants who completed studies AVA102670 or AVA102672 entered in this open-label extension study. Participants received open-label RSG XR throughout the treatment period as adjunctive therapy to their existing dose of AChEI for Alzheimer's disease treatment. Participants took one tablet of study medication daily in the morning with or without food. All participants received 4 mg once daily RSG XR for the first 4 weeks of the study (only for the first 4 weeks of the study). The RSG XR dose was then increased to 8 mg once daily from Week 4 through Week 52. The dose of RSG XR was reduced to 2mg once daily if the 8 mg dose was not well tolerated. Participants were not permitted to titrate back to 8 mg RSG XR.
Injury, poisoning and procedural complications Fall	0.27% 4/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Injury, poisoning and procedural complications Femur fracture	0.21% 3/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Injury, poisoning and procedural complications Humerus fracture	0.14% 2/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Injury, poisoning and procedural complications Skin laceration	0.14% 2/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Injury, poisoning and procedural complications Spinal compression fracture	0.14% 2/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Injury, poisoning and procedural complications Drug toxicity	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Injury, poisoning and procedural complications Femoral neck fracture	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Injury, poisoning and procedural complications Fracture	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Injury, poisoning and procedural complications Head injury	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Injury, poisoning and procedural complications Hip fracture	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Injury, poisoning and procedural complications Injury	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Injury, poisoning and procedural complications Lumbar vertebral fracture	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Injury, poisoning and procedural complications Pacemaker complication	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Injury, poisoning and procedural complications Soft tissue injury	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Injury, poisoning and procedural complications Subdural haematoma	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Injury, poisoning and procedural complications Subdural haemorrhage	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Injury, poisoning and procedural complications Traumatic fracture	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Injury, poisoning and procedural complications Upper limb fracture	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Injury, poisoning and procedural complications Wrist fracture	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Nervous system disorders Cerebrovascular accident	0.27% 4/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Nervous system disorders Syncope	0.27% 4/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Nervous system disorders Dementia	0.14% 2/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Nervous system disorders Dementia Alzheimer's type	0.14% 2/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Nervous system disorders Transient ischaemic attack	0.14% 2/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Nervous system disorders Cerebral haemorrhage	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Nervous system disorders Coma	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Nervous system disorders Convulsion	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Nervous system disorders Dizziness	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Nervous system disorders Epilepsy	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Nervous system disorders Ischaemic stroke	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Nervous system disorders Loss of consciousness	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Nervous system disorders Nerve root compression	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Nervous system disorders Optic neuritis	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Nervous system disorders Subarachnoid haemorrhage	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Nervous system disorders Thalamic infarction	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Cardiac disorders Myocardial infarction	0.21% 3/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Cardiac disorders Acute myocardial infarction	0.14% 2/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Cardiac disorders Atrial fibrillation	0.14% 2/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Cardiac disorders Angina pectoris	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Cardiac disorders Atrial flutter	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Cardiac disorders Cardiac failure congestive	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Cardiac disorders Cardio-respiratory arrest	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Cardiac disorders Coronary artery disease	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Cardiac disorders Myocardial ischaemia	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Cardiac disorders Sinus arrhythmia	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Infections and infestations Pneumonia	0.34% 5/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Infections and infestations Bronchopneumonia	0.14% 2/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Infections and infestations Urinary tract infection	0.14% 2/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Infections and infestations Cellulitis	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Infections and infestations Diverticulitis	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Infections and infestations Respiratory tract infection viral	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.14% 2/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Brain cancer metastatic	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Brain neoplasm	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Endometrial cancer	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to bone	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ovarian cancer	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Paget's disease of the breast	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Refractory anaemia	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Psychiatric disorders Aggression	0.21% 3/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Psychiatric disorders Delirium	0.14% 2/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Psychiatric disorders Agitation	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Psychiatric disorders Behavioural and psychiatric symptoms of dementia	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Psychiatric disorders Confusional state	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Psychiatric disorders Hallucination	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Psychiatric disorders Mental status changes	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Psychiatric disorders Panic disorder	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Psychiatric disorders Sleep disorder	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Blood and lymphatic system disorders Anaemia	0.34% 5/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Blood and lymphatic system disorders Iron deficiency anaemia	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Gastrointestinal disorders Haematemesis	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Gastrointestinal disorders Intestinal obstruction	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Gastrointestinal disorders Large intestine perforation	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Gastrointestinal disorders Lumbar hernia	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Gastrointestinal disorders Peritonitis	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.14% 2/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Musculoskeletal and connective tissue disorders Foot deformity	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Musculoskeletal and connective tissue disorders Osteoporotic fracture	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Musculoskeletal and connective tissue disorders Synovial disorder	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
General disorders Death	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
General disorders General physical health deterioration	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
General disorders Oedema peripheral	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Hepatobiliary disorders Bile duct stone	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Hepatobiliary disorders Cholangitis	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Hepatobiliary disorders Cholecystitis	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Vascular disorders Circulatory collapse	0.14% 2/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Vascular disorders Peripheral arterial occlusive disease	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Vascular disorders Post thrombotic syndrome	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Investigations Blood sodium increased	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Investigations Weight increased	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Metabolism and nutrition disorders Dehydration	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Metabolism and nutrition disorders Hypokalaemia	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Renal and urinary disorders Nephrotic syndrome	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Renal and urinary disorders Urinary retention	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Reproductive system and breast disorders Benign prostatic hyperplasia	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Reproductive system and breast disorders Uterine prolapse	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Respiratory, thoracic and mediastinal disorders Lung disorder	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Skin and subcutaneous tissue disorders Skin ulcer	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.
Gastrointestinal disorders Colonic polyp	0.07% 1/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.

Other adverse events

Measure

RSG XR n=1461 participants at risk Eligible participants who completed studies AVA102670 or AVA102672 entered in this open-label extension study. Participants received open-label RSG XR throughout the treatment period as adjunctive therapy to their existing dose of AChEI for Alzheimer's disease treatment. Participants took one tablet of study medication daily in the morning with or without food. All participants received 4 mg once daily RSG XR for the first 4 weeks of the study (only for the first 4 weeks of the study). The RSG XR dose was then increased to 8 mg once daily from Week 4 through Week 52. The dose of RSG XR was reduced to 2mg once daily if the 8 mg dose was not well tolerated. Participants were not permitted to titrate back to 8 mg RSG XR.

General disorders Oedema peripheral

8.9% 130/1461 • Up to 76 Weeks All subject (Full population) was used for analysis.

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