Trial Outcomes & Findings for Efficacy of Vortioxetine (Lu AA21004) in the Prevention of Relapse of Major Depressive Episodes (NCT NCT00596817)

Last Updated: 2014-03-31

Results Overview

The Montgomery Åsberg Depression Rating Scale (MADRS) is a depression rating scale consisting of 10 items, each rated 0 (no symptom) to 6 (severe symptom). The 10 items represent the core symptoms of depressive illness. The rating should be based on a clinical interview with the patient, moving from broadly phrased questions about symptoms to more detailed ones, which allow a precise rating of severity, covering the last 7 days. Total score from 0 to 60. The higher the score, the more severe.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

639 participants

Primary outcome timeframe

Within first 24 weeks of the double-blind period

Results posted on

2014-03-31

Participant Flow

Patients were in- and outpatients from psychiatric settings.

The study consisted of two consecutive periods: a 12-week open-label treatment period with Vortioxetine and a double-blind, fixed-dose, placebo-controlled treatment period of at least 24 weeks.

Participant milestones

Participant milestones
Measure	Placebo Placebo : capsules, daily, orally	Vortioxetine: 5 or 10 mg Vortioxetine (Lu AA21004) : encapsulated tablets, daily, orally
Open-label Period STARTED	0	639
Open-label Period COMPLETED	0	492
Open-label Period NOT COMPLETED	0	147
Open-label Period to Double-blind Period STARTED	0	492
Open-label Period to Double-blind Period COMPLETED	0	400
Open-label Period to Double-blind Period NOT COMPLETED	0	92
Double-blind Period STARTED	192	204
Double-blind Period COMPLETED	104	125
Double-blind Period NOT COMPLETED	88	79

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Placebo : capsules, daily, orally	Vortioxetine: 5 or 10 mg Vortioxetine (Lu AA21004) : encapsulated tablets, daily, orally
Open-label Period Adverse Event	0	49
Open-label Period Lack of Efficacy	0	33
Open-label Period Other Reasons	0	65
Open-label Period to Double-blind Period Adverse Event	0	5
Open-label Period to Double-blind Period Lack of Efficacy	0	24
Open-label Period to Double-blind Period Not Eligible	0	49
Open-label Period to Double-blind Period Other Reasons	0	14
Double-blind Period Adverse Event	5	16
Double-blind Period Lack of Efficacy	52	28
Double-blind Period Non-compliance With Study Product	3	4
Double-blind Period Protocol Violation	11	8
Double-blind Period Withdrawal of Consent	7	3
Double-blind Period Lost to Follow-up	0	2
Double-blind Period Other Reasons	10	18

Baseline Characteristics

Efficacy of Vortioxetine (Lu AA21004) in the Prevention of Relapse of Major Depressive Episodes

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Open-label Period (APTS) n=639 Participants	Placebo - Double-blind Period (FAS) n=192 Participants Placebo : capsules, daily, orally	Vortioxetine: 5 or 10 mg - Double-blind Period (FAS) n=204 Participants Vortioxetine (Lu AA21004) : encapsulated tablets, daily, orally	Total n=1035 Participants Total of all reporting groups
Age, Continuous	44.6 years STANDARD_DEVIATION 12.4 • n=5 Participants	45.1 years STANDARD_DEVIATION 12.1 • n=7 Participants	44.8 years STANDARD_DEVIATION 12.4 • n=5 Participants	45.0 years STANDARD_DEVIATION 12.3 • n=4 Participants
Sex/Gender, Customized Female (Open-label Period)	397 participants n=5 Participants	NA participants n=7 Participants	NA participants n=5 Participants	NA participants n=4 Participants
Sex/Gender, Customized Male (Open-label Period)	242 participants n=5 Participants	NA participants n=7 Participants	NA participants n=5 Participants	NA participants n=4 Participants
Sex/Gender, Customized Female (Double-blind Period)	0 participants n=5 Participants	120 participants n=7 Participants	130 participants n=5 Participants	250 participants n=4 Participants
Sex/Gender, Customized Male (Double-blind Period)	0 participants n=5 Participants	72 participants n=7 Participants	74 participants n=5 Participants	146 participants n=4 Participants
MADRS	32.3 units on a scale STANDARD_DEVIATION 4.1 • n=5 Participants	4.66 units on a scale STANDARD_DEVIATION 3.16 • n=7 Participants	4.89 units on a scale STANDARD_DEVIATION 3.00 • n=5 Participants	4.78 units on a scale STANDARD_DEVIATION 3.08 • n=4 Participants
HAM-D-17	22.8 units on a scale STANDARD_DEVIATION 4.5 • n=5 Participants	3.96 units on a scale STANDARD_DEVIATION 3.15 • n=7 Participants	4.46 units on a scale STANDARD_DEVIATION 3.27 • n=5 Participants	4.21 units on a scale STANDARD_DEVIATION 3.21 • n=4 Participants
HAM-A	22.6 units on a scale STANDARD_DEVIATION 6.6 • n=5 Participants	4.60 units on a scale STANDARD_DEVIATION 3.60 • n=7 Participants	5.09 units on a scale STANDARD_DEVIATION 3.83 • n=5 Participants	4.85 units on a scale STANDARD_DEVIATION 3.72 • n=4 Participants
CGI-S	4.8 units on a scale STANDARD_DEVIATION 0.7 • n=5 Participants	1.54 units on a scale STANDARD_DEVIATION 0.69 • n=7 Participants	1.56 units on a scale STANDARD_DEVIATION 0.68 • n=5 Participants	1.55 units on a scale STANDARD_DEVIATION 0.69 • n=4 Participants
SDS	20.8 units on a scale STANDARD_DEVIATION 5.7 • n=5 Participants	8.37 units on a scale STANDARD_DEVIATION 7.44 • n=7 Participants	8.95 units on a scale STANDARD_DEVIATION 7.09 • n=5 Participants	8.66 units on a scale STANDARD_DEVIATION 7.27 • n=4 Participants

PRIMARY outcome

Timeframe: Within first 24 weeks of the double-blind period

Population: FAS

Outcome measures

Outcome measures
Measure	Placebo n=192 Participants capsules, daily, orally	Vortioxetine: 5 or 10 mg n=204 Participants encapsulated tablets, daily, orally
Relapse Within First 24 Weeks of the Double-blind Period Based on a MADRS Total Score >=22 or an Unsatisfactory Treatment Effect (Lack of Efficacy) as Judged by the Investigator	26.0 percentage of patients who relapsed	13.2 percentage of patients who relapsed

SECONDARY outcome

Timeframe: Within 64 weeks of the double-blind period

Population: FAS

Outcome measures

Outcome measures
Measure	Placebo n=192 Participants capsules, daily, orally	Vortioxetine: 5 or 10 mg n=204 Participants encapsulated tablets, daily, orally
Relapse During the Entire Double-blind Period Based on a MADRS Total Score >=22 or an Unsatisfactory Treatment Effect (Lack of Efficacy) as Judged by the Investigator	30.2 percentage of patients who relapsed	15.2 percentage of patients who relapsed

SECONDARY outcome

Timeframe: Double-blind Baseline and Week 24 of the double-blind period

Population: FAS; observed cases (OC)

Outcome measures

Outcome measures
Measure	Placebo n=132 Participants capsules, daily, orally	Vortioxetine: 5 or 10 mg n=151 Participants encapsulated tablets, daily, orally
Change From Double-blind Baseline in MADRS Total Score After 24 Weeks of Double-blind Treatment	1.45 units on a scale Standard Error 0.55	-0.62 units on a scale Standard Error 0.51

SECONDARY outcome

Timeframe: Double-blind Baseline and Week 24 of the double-blind period

Population: FAS; OC

The Hamilton Depression Scale - 17 items (HAM-D-17) measures depression severity. Items are rated on a scale from 0 (symptoms not present) to a maximum of 2 to 4 (symptom extremely severe) for a total score range of 0 to 52. The higher the score, the more severe.

Outcome measures

Outcome measures
Measure	Placebo n=136 Participants capsules, daily, orally	Vortioxetine: 5 or 10 mg n=158 Participants encapsulated tablets, daily, orally
Change From Double-blind Baseline in HAM-D-17 Total Score After 24 Weeks of Double-blind Treatment	1.61 units on a scale Standard Error 0.46	0.30 units on a scale Standard Error 0.42

SECONDARY outcome

Timeframe: Double-blind Baseline and Week 24 of the double-blind period

Population: FAS; OC

The Hamilton Anxiety Rating Scale (HAM-A) consists of 14 items that assess anxious mood, tension, fear, insomnia, intellectual (cognitive) symptoms, depressed mood, behaviour at interview, somatic (sensory), cardiovascular, respiratory, gastrointestinal, genitourinary, autonomic, and somatic (muscular) symptoms. Each symptom is rated from 0 (absent) to 4 (maximum severity). Total score from 0 to 56. The higher the score, the more severe.

Outcome measures

Outcome measures
Measure	Placebo n=136 Participants capsules, daily, orally	Vortioxetine: 5 or 10 mg n=158 Participants encapsulated tablets, daily, orally
Change From Double-blind Baseline in HAM-A Total Score After 24 Weeks of Double-blind Treatment	0.89 units on a scale Standard Error 0.50	-0.23 units on a scale Standard Error 0.46

SECONDARY outcome

Timeframe: Double-blind Baseline and Week 24 of the double-blind period

Population: FAS; OC

The Clinical Global Impression - Severity of Illness (CGI-S) is a 7-point scale rated from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). The investigator should use his/her total clinical experience with this patient population to judge how mentally ill the patient is at the time of rating.

Outcome measures

Outcome measures
Measure	Placebo n=132 Participants capsules, daily, orally	Vortioxetine: 5 or 10 mg n=151 Participants encapsulated tablets, daily, orally
Change From Double-blind Baseline in CGI-S Score After 24 Weeks of Double-blind Treatment	0.24 units on a scale Standard Error 0.08	-0.14 units on a scale Standard Error 0.08

SECONDARY outcome

Timeframe: Week 24 of the double-blind period (Counted From Open-label Baseline)

Population: FAS; OC

Outcome measures

Outcome measures
Measure	Placebo n=132 Participants capsules, daily, orally	Vortioxetine: 5 or 10 mg n=151 Participants encapsulated tablets, daily, orally
Proportion of Responders at Week 24 of the Double-blind Period (Response Defined as a >=50% Reduction in MADRS Total Score From Open-label Baseline)	91.7 percentage of patients	98.0 percentage of patients

SECONDARY outcome

Timeframe: Week 24 of the double-blind period

Population: FAS; OC

Outcome measures

Outcome measures
Measure	Placebo n=132 Participants capsules, daily, orally	Vortioxetine: 5 or 10 mg n=151 Participants encapsulated tablets, daily, orally
Proportion of Remitters at Week 24 of the Double-blind Period (Remission Defined as a MADRS Total Score <=10)	82.6 percentage of patients	94.7 percentage of patients

SECONDARY outcome

Timeframe: Week 24 of the double-blind period (Counted From Double-blind Baseline)

Population: FAS; OC

The Sheehan Disability Scale (SDS) comprises self-rated items designed to measure impairment. The patient rates the extent to which his or her (1) work, (2) social life or leisure activities and (3) home life or family responsibilities are impaired on a 10-point visual analogue scales, on which 0 = normal functioning and 10 = severe functional impairment. The three items may be summed into a single dimensional measure of global functional impairment that ranges from 0 (unimpaired) to 30 (highly impaired). The higher the score, the more severe.

Outcome measures

Outcome measures
Measure	Placebo n=118 Participants capsules, daily, orally	Vortioxetine: 5 or 10 mg n=135 Participants encapsulated tablets, daily, orally
Change From Double-blind Baseline in SDS Total Score at Week 24 of the Double-blind Period	0.14 units on a scale Standard Error 0.58	-0.53 units on a scale Standard Error 0.57

Adverse Events

Open-label Period (APTS)

Serious events: 14 serious events

Other events: 337 other events

Deaths: 0 deaths

Placebo - Double-blind Period (FAS)

Serious events: 6 serious events

Other events: 73 other events

Deaths: 0 deaths

Vortioxetine: 5 or 10 mg - Double-blind Period (FAS)

Serious events: 7 serious events

Other events: 79 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Open-label Period (APTS) n=639 participants at risk	Placebo - Double-blind Period (FAS) n=192 participants at risk	Vortioxetine: 5 or 10 mg - Double-blind Period (FAS) n=204 participants at risk
Gastrointestinal disorders Dry mouth	6.4% 41/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	2.0% 4/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Gastrointestinal disorders Nausea	25.7% 164/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	3.1% 6/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	8.8% 18/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
General disorders Fatigue	5.0% 32/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	2.1% 4/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	2.0% 4/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Infections and infestations Gastroenteritis	1.9% 12/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	3.1% 6/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	5.4% 11/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Infections and infestations Influenza	1.1% 7/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	4.7% 9/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	6.9% 14/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Infections and infestations Nasopharyngitis	8.1% 52/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	13.5% 26/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	10.8% 22/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Injury, poisoning and procedural complications Accidental overdose	5.6% 36/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	7.8% 15/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	7.8% 16/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Nervous system disorders Dizziness	6.9% 44/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	3.6% 7/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	2.9% 6/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Nervous system disorders Headache	18.3% 117/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	13.0% 25/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	12.3% 25/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Psychiatric disorders Insomnia	5.6% 36/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	1.6% 3/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	2.5% 5/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.

Additional Information

H. Lundbeck A/S

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The main publication has to be published before any sub-publications. H. Lundbeck A/S follows the Vancouver declaration with respect to authorship.
Publication restrictions are in place

Restriction type: OTHER

Measure	Open-label Period (APTS) n=639 participants at risk	Placebo - Double-blind Period (FAS) n=192 participants at risk	Vortioxetine: 5 or 10 mg - Double-blind Period (FAS) n=204 participants at risk
Cardiac disorders Stress cardiomyopathy	0.16% 1/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Gastrointestinal disorders Abdominal pain	0.16% 1/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Gastrointestinal disorders Gastritis	0.00% 0/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.49% 1/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
General disorders Non-cardiac chest pain	0.16% 1/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Hepatobiliary disorders Cholelithiasis	0.00% 0/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.52% 1/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Infections and infestations Bronchitis	0.16% 1/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Infections and infestations Cystitis	0.16% 1/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Infections and infestations Influenza	0.00% 0/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.52% 1/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Infections and infestations Nasopharyngitis	0.00% 0/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.52% 1/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Infections and infestations Pneumonia	0.16% 1/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Infections and infestations Streptococcal infection	0.00% 0/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.49% 1/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Infections and infestations Upper respiratory tract infection	0.00% 0/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.52% 1/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Injury, poisoning and procedural complications Accidental overdose	0.16% 1/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Injury, poisoning and procedural complications Alcohol poisoning	0.00% 0/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.52% 1/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.49% 1/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Injury, poisoning and procedural complications Joint dislocation	0.00% 0/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.52% 1/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Injury, poisoning and procedural complications Road traffic accident	0.00% 0/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.98% 2/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Injury, poisoning and procedural complications Upper limb fracture	0.00% 0/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.52% 1/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Metabolism and nutrition disorders Hypoglycaemia	0.16% 1/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.16% 1/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Pancreatic carcinoma	0.16% 1/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Sebaceous carcinoma	0.16% 1/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Nervous system disorders Loss of consciousness	0.00% 0/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.52% 1/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Nervous system disorders Serotonin syndrome	0.16% 1/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Pregnancy, puerperium and perinatal conditions Abortion incomplete	0.00% 0/397 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/120 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.77% 1/130 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Psychiatric disorders Alcohol abuse	0.16% 1/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Psychiatric disorders Depression	0.31% 2/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.52% 1/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Psychiatric disorders Suicide attempt	0.16% 1/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.
Social circumstances Social stay hospitalisation	0.00% 0/639 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.00% 0/192 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.	0.49% 1/204 • Serious Adverse Events: 12-week open-label period, 24-week double-blind period and 4-week safety follow-up period. Other Adverse Events: 12-week open-label period and 24-week double-blind period.