Trial Outcomes & Findings for Comparative Efficacy, Safety, and Tolerability of Rivastigmine 10 and 15 cm^2 Patch in Patients With Alzheimer's Disease (AD) Showing Cognitive Decline (NCT NCT00506415)

Last Updated: 2012-09-19

Results Overview

The Alzheimer's Disease Assessment Scale-Cognitive (ADAS-cog) subscale comprises 11 items summed to a total score ranging from 0 to 70, with lower scores indicating less severe impairment. A negative change indicates an improvement from baseline.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1584 participants

Primary outcome timeframe

Baseline and week 48 of double blind period

Results posted on

2012-09-19

Participant Flow

1,584 participants were enrolled, 1582 received study drug during the initial open label period; of these, 567 were qualified to enter a double blind randomized period.

Participant milestones

Participant milestones
Measure	Initial Open Label: Rivastigmine (5 cm^2 / 10 cm^2) Rivastigmine 5 cm\^2 transdermal patch once a day during the first 4 weeks of open label treatment followed by rivastigmine 10 cm\^2 transdermal patch once a day from week 4 to week 24, 36 or 48.	Double Blind: Rivastigmine (10 cm^2) Rivastigmine transdermal patch 10 cm\^2 and placebo to rivastigmine 15 cm\^2 once daily for 48 weeks during the double blind period.	Double Blind: Rivastigmine (15 cm^2) Rivastigmine transdermal patch 15 cm\^2 and placebo to rivastigmine 10 cm\^2 once daily for 48 weeks during double blind period.	Extended Open Label (10 cm^2) Rivastigmine 10 cm\^2 transdermal patch once a day during 48 weeks (from week 48 to week 96) open label treatment.
Initial Open Label (Maximum 48 Weeks) STARTED	1584	0	0	0
Initial Open Label (Maximum 48 Weeks) Exposed to Study Drug	1582	0	0	0
Initial Open Label (Maximum 48 Weeks) COMPLETED	1085	0	0	0
Initial Open Label (Maximum 48 Weeks) NOT COMPLETED	499	0	0	0
Double Blind (Maximum 48 Weeks ) STARTED	0	286	280	0
Double Blind (Maximum 48 Weeks ) COMPLETED	0	203	207	0
Double Blind (Maximum 48 Weeks ) NOT COMPLETED	0	83	73	0
Extended Open Label (Maximum 48 Weeks) STARTED	0	0	0	457
Extended Open Label (Maximum 48 Weeks) COMPLETED	0	0	0	395
Extended Open Label (Maximum 48 Weeks) NOT COMPLETED	0	0	0	62

Reasons for withdrawal

Reasons for withdrawal
Measure	Initial Open Label: Rivastigmine (5 cm^2 / 10 cm^2) Rivastigmine 5 cm\^2 transdermal patch once a day during the first 4 weeks of open label treatment followed by rivastigmine 10 cm\^2 transdermal patch once a day from week 4 to week 24, 36 or 48.	Double Blind: Rivastigmine (10 cm^2) Rivastigmine transdermal patch 10 cm\^2 and placebo to rivastigmine 15 cm\^2 once daily for 48 weeks during the double blind period.	Double Blind: Rivastigmine (15 cm^2) Rivastigmine transdermal patch 15 cm\^2 and placebo to rivastigmine 10 cm\^2 once daily for 48 weeks during double blind period.	Extended Open Label (10 cm^2) Rivastigmine 10 cm\^2 transdermal patch once a day during 48 weeks (from week 48 to week 96) open label treatment.
Initial Open Label (Maximum 48 Weeks) Adverse Event	272	0	0	0
Initial Open Label (Maximum 48 Weeks) Abnormal laboratory value	1	0	0	0
Initial Open Label (Maximum 48 Weeks) Abnormal test procedure results	1	0	0	0
Initial Open Label (Maximum 48 Weeks) Unsatisfactory therapeutic effect	58	0	0	0
Initial Open Label (Maximum 48 Weeks) Withdrawal by Subject	88	0	0	0
Initial Open Label (Maximum 48 Weeks) Lost to Follow-up	22	0	0	0
Initial Open Label (Maximum 48 Weeks) Administrative problem	7	0	0	0
Initial Open Label (Maximum 48 Weeks) Death	22	0	0	0
Initial Open Label (Maximum 48 Weeks) Protocol Violation	28	0	0	0
Double Blind (Maximum 48 Weeks ) Adverse Event	0	33	28	0
Double Blind (Maximum 48 Weeks ) Death	0	5	3	0
Double Blind (Maximum 48 Weeks ) Unsatisfactory therapeutic effect	0	13	13	0
Double Blind (Maximum 48 Weeks ) Protocol Violation	0	5	3	0
Double Blind (Maximum 48 Weeks ) Lost to Follow-up	0	4	6	0
Double Blind (Maximum 48 Weeks ) Withdrawal by Subject	0	20	17	0
Double Blind (Maximum 48 Weeks ) Administrative problems	0	3	2	0
Double Blind (Maximum 48 Weeks ) Condition no longer requires study drug	0	0	1	0
Extended Open Label (Maximum 48 Weeks) Administrative problems	0	0	0	4
Extended Open Label (Maximum 48 Weeks) Adverse Event	0	0	0	18
Extended Open Label (Maximum 48 Weeks) Lost to Follow-up	0	0	0	8
Extended Open Label (Maximum 48 Weeks) Withdrawal by Subject	0	0	0	14
Extended Open Label (Maximum 48 Weeks) Protocol Violation	0	0	0	5
Extended Open Label (Maximum 48 Weeks) Unsatisfactory therapeutic effect	0	0	0	6
Extended Open Label (Maximum 48 Weeks) Death	0	0	0	7

Baseline Characteristics

Comparative Efficacy, Safety, and Tolerability of Rivastigmine 10 and 15 cm^2 Patch in Patients With Alzheimer's Disease (AD) Showing Cognitive Decline

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Total Patients n=1584 Participants Total number of patients enrolled in the initial open label period that may have been randomized in the double blind period or may have continued in the extended open label period.
Age Continuous	74.93 years STANDARD_DEVIATION 7.131 • n=5 Participants
Sex: Female, Male Female	992 Participants n=5 Participants
Sex: Female, Male Male	592 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and week 48 of double blind period

Population: Intent to treat population double blind (ITT-DB): included all randomized patients who received at least 1 dose of double blind study drug, and had at least 1 post-randomization assessment for both co-primary efficacy variables: Alzheimer's Disease Assessment Scale-Cognitive and Disease Cooperative Study-Instrumental Activities of Daily Living.

Outcome measures

Outcome measures
Measure	Double Blind: Rivastigmine (10 cm^2) n=268 Participants Rivastigmine transdermal patch 10 cm\^2 and placebo to rivastigmine 15 cm\^2 once daily for 48 weeks during the double blind period.	Double Blind: Rivastigmine (15 cm^2) n=264 Participants Rivastigmine transdermal patch 15 cm\^2 and placebo to rivastigmine 10 cm\^2 once daily for 48 weeks during double blind period.	Double Blind: Rivastigmine (15 cm^2) Rivastigmine transdermal patch 15c m\^2 and placebo to rivastigmine 10 cm\^2 once daily for 48 weeks during double blind period.	Extended Open Label (10 cm^2) Rivastigmine 10 cm\^2 transdermal patch once a day during 48 weeks open label treatment running in parallel to the double blind period.
Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) Subscale at Week 48 of Double Blind Period	4.9 units on a scale Standard Deviation 7.49	4.1 units on a scale Standard Deviation 8.00	—	—

PRIMARY outcome

Timeframe: Baseline and week 48 of double blind period

The Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) is a 16 item subscale of the caregiver-based ADCS-IADL scale, developed for the use in dementia studies. The ADCS-IADL total score ranges from 0 to 56, with higher scores indicating less severe impairment. A positive change indicates an improvement from baseline.

Outcome measures

Outcome measures
Measure	Double Blind: Rivastigmine (10 cm^2) n=271 Participants Rivastigmine transdermal patch 10 cm\^2 and placebo to rivastigmine 15 cm\^2 once daily for 48 weeks during the double blind period.	Double Blind: Rivastigmine (15 cm^2) n=265 Participants Rivastigmine transdermal patch 15 cm\^2 and placebo to rivastigmine 10 cm\^2 once daily for 48 weeks during double blind period.	Double Blind: Rivastigmine (15 cm^2) Rivastigmine transdermal patch 15c m\^2 and placebo to rivastigmine 10 cm\^2 once daily for 48 weeks during double blind period.	Extended Open Label (10 cm^2) Rivastigmine 10 cm\^2 transdermal patch once a day during 48 weeks open label treatment running in parallel to the double blind period.
Change in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) Subscale Score From Baseline to Week 48 of Double Blind Period	-6.2 units on a scale Standard Deviation 8.78	-4.4 units on a scale Standard Deviation 8.21	—	—

SECONDARY outcome

Timeframe: 390 days was the maximum

Functional decline was defined by either an at least 1 point decrease in the Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) subscale score in a visit and confirmed by the following visit/assessment or at least 2 points decrease from the double blind randomization baseline.

Outcome measures

Outcome measures
Measure	Double Blind: Rivastigmine (10 cm^2) n=271 Participants Rivastigmine transdermal patch 10 cm\^2 and placebo to rivastigmine 15 cm\^2 once daily for 48 weeks during the double blind period.	Double Blind: Rivastigmine (15 cm^2) n=265 Participants Rivastigmine transdermal patch 15 cm\^2 and placebo to rivastigmine 10 cm\^2 once daily for 48 weeks during double blind period.	Double Blind: Rivastigmine (15 cm^2) Rivastigmine transdermal patch 15c m\^2 and placebo to rivastigmine 10 cm\^2 once daily for 48 weeks during double blind period.	Extended Open Label (10 cm^2) Rivastigmine 10 cm\^2 transdermal patch once a day during 48 weeks open label treatment running in parallel to the double blind period.
Time to Functional Decline as Measured by Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) Subscale During the Double Blind Period	90 Time in days Interval 85.0 to 113.0	91 Time in days Interval 85.0 to 113.0	—	—

SECONDARY outcome

Timeframe: Baseline and week 48 of double blind period

Population: Intent to treat population (ITT-DB): included all randomized patients with an assessment at baseline and week 48 who received at least 1 dose of double blind study drug, and had at least 1 post-randomization assessment for both co-primary efficacy variables (ADAS-cog and ADCS-IADL).

Change from baseline to week 48 in total time to perform Trail Making Test (TMT) part A. This test provides information on visual search, scanning, speed of processing, mental flexibility, and executive functions. The TMT part A requires an individual to draw lines sequentially connecting 25 encircled numbers distributed on a sheet of paper. The score represents the amount of time required to complete the task. Total values for TMT part A range between 0 and 300 seconds. A negative change indicates an improvement from baseline.

Outcome measures

Outcome measures
Measure	Double Blind: Rivastigmine (10 cm^2) n=258 Participants Rivastigmine transdermal patch 10 cm\^2 and placebo to rivastigmine 15 cm\^2 once daily for 48 weeks during the double blind period.	Double Blind: Rivastigmine (15 cm^2) n=254 Participants Rivastigmine transdermal patch 15 cm\^2 and placebo to rivastigmine 10 cm\^2 once daily for 48 weeks during double blind period.	Double Blind: Rivastigmine (15 cm^2) Rivastigmine transdermal patch 15c m\^2 and placebo to rivastigmine 10 cm\^2 once daily for 48 weeks during double blind period.	Extended Open Label (10 cm^2) Rivastigmine 10 cm\^2 transdermal patch once a day during 48 weeks open label treatment running in parallel to the double blind period.
Change in Attention and Executive Function as Assessed by the Trail Making Test (Part A) at Week 48 of the Double Blind Period	18.2 Time in seconds Standard Deviation 62.57	16.3 Time in seconds Standard Deviation 66.09	—	—

SECONDARY outcome

Timeframe: Baseline and week 48 of double blind period

Change from baseline to week 48 in total time to perform Trail Making Test (TMT) part B. This test provides information on visual search, scanning, speed of processing, mental flexibility, and executive functions. TMT has two parts: Part A requires an individual to draw lines sequentially connecting 25 encircled numbers distributed on a sheet of paper. Task requirements are similar for TMT-Part B except the person must alternate between numbers and letters. Total values for TMT part B range between 0 and 420 seconds. A negative change from baseline indicates an improvement in condition.

Outcome measures

Outcome measures
Measure	Double Blind: Rivastigmine (10 cm^2) n=235 Participants Rivastigmine transdermal patch 10 cm\^2 and placebo to rivastigmine 15 cm\^2 once daily for 48 weeks during the double blind period.	Double Blind: Rivastigmine (15 cm^2) n=236 Participants Rivastigmine transdermal patch 15 cm\^2 and placebo to rivastigmine 10 cm\^2 once daily for 48 weeks during double blind period.	Double Blind: Rivastigmine (15 cm^2) Rivastigmine transdermal patch 15c m\^2 and placebo to rivastigmine 10 cm\^2 once daily for 48 weeks during double blind period.	Extended Open Label (10 cm^2) Rivastigmine 10 cm\^2 transdermal patch once a day during 48 weeks open label treatment running in parallel to the double blind period.
Change in Attention and Executive Function as Assessed by the Trail Making Test (Part B) at Week 48 of Double Blind Period	9.3 Time in seconds Standard Deviation 68.80	5.8 Time in seconds Standard Deviation 65.38	—	—

SECONDARY outcome

Timeframe: Baseline and week 48 of double blind period

Population: Intent to treat population double blind (ITT-DB): included all randomized patients with an assessment at baseline and week 48, who received at least 1 dose of double blind study drug, and had at least 1 post-randomization assessment for both co-primary efficacy variables (ADAS-cog, ADCS-IADL).

Change from baseline to week 48 as assessed by the Neuropsychiatric Inventory (NPI)-10 total score. The scale consists of 10 domains that are rated for both frequency (range 1-4) and severity (range 1-3). A composite score for each domain is calculated (frequency x severity) which ranges from 1 to 12. There is a leading question for each item. If the symptom is not present then the frequency, severity and distress scores are not completed. In this case the score is 0 for the item. The sum of the composite scores yields the NPI-10 total score (range 0-120). A negative change in score indicates an improvement from baseline (symptom reduction).

Outcome measures

Outcome measures
Measure	Double Blind: Rivastigmine (10 cm^2) n=271 Participants Rivastigmine transdermal patch 10 cm\^2 and placebo to rivastigmine 15 cm\^2 once daily for 48 weeks during the double blind period.	Double Blind: Rivastigmine (15 cm^2) n=265 Participants Rivastigmine transdermal patch 15 cm\^2 and placebo to rivastigmine 10 cm\^2 once daily for 48 weeks during double blind period.	Double Blind: Rivastigmine (15 cm^2) Rivastigmine transdermal patch 15c m\^2 and placebo to rivastigmine 10 cm\^2 once daily for 48 weeks during double blind period.	Extended Open Label (10 cm^2) Rivastigmine 10 cm\^2 transdermal patch once a day during 48 weeks open label treatment running in parallel to the double blind period.
Change From Baseline in Neuropsychiatric Inventory (NPI)-10 Score at Week 48 of Double Blind Period	0.9 units on a scale Standard Deviation 10.98	1.4 units on a scale Standard Deviation 11.51	—	—

SECONDARY outcome

Timeframe: 30 days after a maximum of 96 weeks treatment

Population: The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.

Outcome measures

Outcome measures
Measure	Double Blind: Rivastigmine (10 cm^2) n=1582 Participants Rivastigmine transdermal patch 10 cm\^2 and placebo to rivastigmine 15 cm\^2 once daily for 48 weeks during the double blind period.	Double Blind: Rivastigmine (15 cm^2) n=283 Participants Rivastigmine transdermal patch 15 cm\^2 and placebo to rivastigmine 10 cm\^2 once daily for 48 weeks during double blind period.	Double Blind: Rivastigmine (15 cm^2) n=280 Participants Rivastigmine transdermal patch 15c m\^2 and placebo to rivastigmine 10 cm\^2 once daily for 48 weeks during double blind period.	Extended Open Label (10 cm^2) n=457 Participants Rivastigmine 10 cm\^2 transdermal patch once a day during 48 weeks open label treatment running in parallel to the double blind period.
Number of Patients With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events	1135 Participants	193 Participants	210 Participants	263 Participants

Adverse Events

Initial Open Label: Rivastigmine (5 cm^2 / 10 cm^2)

Serious events: 227 serious events

Other events: 732 other events

Deaths: 0 deaths

Double Blind: Rivastigmine (10 cm^2)

Serious events: 44 serious events

Other events: 110 other events

Deaths: 0 deaths

Double Blind: Rivastigmine (15 cm^2)

Serious events: 44 serious events

Other events: 151 other events

Deaths: 0 deaths

Extended Open Label: Rivastigmine (10 cm^2)

Serious events: 59 serious events

Other events: 112 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis

Phone: 862 778 8300

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.
Publication restrictions are in place

Restriction type: OTHER

Measure	Initial Open Label: Rivastigmine (5 cm^2 / 10 cm^2) n=1582 participants at risk Safety population Initial Open Label (Safety-IOL) - This population consisted of all patients who received at least 1 dose of study drug during the initial open label phase and had at least 1 post baseline safety assessment during the same phase.	Double Blind: Rivastigmine (10 cm^2) n=283 participants at risk Safety population Double Blind (Safety-DB) - This population included all patients who were randomized, received at least 1 dose of study drug during the double blind phase and had at least 1 post-randomization safety assessment during the double blind phase. Patients were analyzed according to treatment received.	Double Blind: Rivastigmine (15 cm^2) n=280 participants at risk Safety population Double Blind (Safety-DB) - This population included all patients who were randomized, received at least 1 dose of study drug during the double blind phase and had at least 1 post-randomization safety assessment during the double blind phase. Patients were analyzed according to treatment received.	Extended Open Label: Rivastigmine (10 cm^2) n=457 participants at risk Safety population Extended Open Label (Safety-EOL) - This population consisted of all patients who received at least 1 dose of study drug during the extended open label phase and had at least 1 post baseline safety assessment during the same phase.
Gastrointestinal disorders Abdominal pain upper	1.1% 17/1582 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	1.1% 3/283 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	3.2% 9/280 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	0.88% 4/457 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.
Gastrointestinal disorders Diarrhoea	4.6% 73/1582 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	4.6% 13/283 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	6.4% 18/280 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	0.88% 4/457 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.
Gastrointestinal disorders Nausea	5.7% 90/1582 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	4.6% 13/283 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	11.8% 33/280 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	2.4% 11/457 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.
Gastrointestinal disorders Vomiting	4.3% 68/1582 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	4.2% 12/283 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	9.6% 27/280 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	0.22% 1/457 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.
General disorders Application site erythema	11.6% 184/1582 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	5.7% 16/283 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	6.4% 18/280 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	2.2% 10/457 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.
General disorders Application site pruritus	8.8% 139/1582 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	3.9% 11/283 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	3.9% 11/280 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	1.1% 5/457 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.
General disorders Application site rash	3.5% 56/1582 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	1.8% 5/283 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	2.1% 6/280 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	0.44% 2/457 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.
Infections and infestations Urinary tract infection	2.8% 45/1582 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	2.8% 8/283 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	3.9% 11/280 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	2.4% 11/457 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.
Injury, poisoning and procedural complications Fall	3.4% 53/1582 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	5.7% 16/283 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	6.8% 19/280 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	5.3% 24/457 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.
Investigations Weight decreased	2.8% 44/1582 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	2.8% 8/283 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	6.8% 19/280 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	2.6% 12/457 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.
Metabolism and nutrition disorders Decreased appetite	2.3% 36/1582 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	2.5% 7/283 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	5.7% 16/280 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	1.1% 5/457 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.
Nervous system disorders Dizziness	2.3% 37/1582 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	0.71% 2/283 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	3.6% 10/280 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	1.8% 8/457 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.
Nervous system disorders Headache	3.9% 62/1582 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	3.9% 11/283 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	3.9% 11/280 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	1.5% 7/457 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.
Psychiatric disorders Agitation	2.7% 42/1582 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	4.9% 14/283 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	4.3% 12/280 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	1.1% 5/457 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.
Psychiatric disorders Anxiety	3.5% 56/1582 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	2.5% 7/283 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	3.6% 10/280 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	2.2% 10/457 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.
Psychiatric disorders Depression	4.1% 65/1582 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	4.6% 13/283 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	5.0% 14/280 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	3.3% 15/457 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.
Psychiatric disorders Insomnia	2.5% 40/1582 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	2.5% 7/283 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	3.9% 11/280 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	1.3% 6/457 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.
Renal and urinary disorders Urinary incontinence	1.6% 25/1582 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	1.8% 5/283 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	3.2% 9/280 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	1.3% 6/457 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.
Vascular disorders Hypertension	3.4% 53/1582 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	2.8% 8/283 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	3.2% 9/280 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.	1.8% 8/457 • 30 days after a maximum of 96 weeks treatment The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.