Trial Outcomes & Findings for Levetiracetam Versus Oxcarbazepine as Monotherapy to Evaluate Efficacy and Safety in Subjects With Newly or Recently Diagnosed Partial Epilepsy (NCT NCT01498822)

Last Updated: 2015-08-20

Results Overview

Treatment failure is defined as (1) Dropout due to related intolerable adverse event, lack of efficacy or need for addition of another Antiepileptic Drug (AED), or (2) need of a 1-step down-Titration, within 50 weeks from the first dose of study medication.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

353 participants

Primary outcome timeframe

Week 0 (First Dose) to Week 50

Results posted on

2015-08-20

Participant Flow

This study started to enroll subjects in June 2011. A total of 27 investigators enrolled 353 subjects at 23 sites in Korea.

Participant Flow refers to the Randomized Set, consisting of all subjects who were randomized in this study.

Participant milestones

Participant milestones
Measure	Levetiracetam Levetiracetam twice a day treatment Group 250 mg and 500 mg Levetiracetam tablet, 1000 mg-3000 mg/day, maximum 50 weeks including initial up titration of 500 mg/day for 2 weeks	Oxcarbazepine Oxcarbazepine twice a day treatment Group 150 mg and 300 mg Oxcarbazepine tablet, 900 mg-2400 mg/day, maximum 50 weeks including 2 weeks of up titration (300 mg/day 1 week then 600 mg/day 1 week)
Overall Study STARTED	175	178
Overall Study COMPLETED	121	122
Overall Study NOT COMPLETED	54	56

Reasons for withdrawal

Reasons for withdrawal
Measure	Levetiracetam Levetiracetam twice a day treatment Group 250 mg and 500 mg Levetiracetam tablet, 1000 mg-3000 mg/day, maximum 50 weeks including initial up titration of 500 mg/day for 2 weeks	Oxcarbazepine Oxcarbazepine twice a day treatment Group 150 mg and 300 mg Oxcarbazepine tablet, 900 mg-2400 mg/day, maximum 50 weeks including 2 weeks of up titration (300 mg/day 1 week then 600 mg/day 1 week)
Overall Study Protocol Violation	8	4
Overall Study Other Reason	5	2
Overall Study Lack of Efficacy	7	2
Overall Study AE, non-serious non-fatal	8	17
Overall Study SAE, non-fatal	2	2
Overall Study Adverse Event, serious fatal	1	1
Overall Study Withdrawal by Subject	15	25
Overall Study Lost to Follow-up	8	3

Baseline Characteristics

Levetiracetam Versus Oxcarbazepine as Monotherapy to Evaluate Efficacy and Safety in Subjects With Newly or Recently Diagnosed Partial Epilepsy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Levetiracetam n=175 Participants Levetiracetam twice a day treatment Group 250 mg and 500 mg Levetiracetam tablet, 1000 mg-3000 mg/day, maximum 50 weeks including initial up titration of 500 mg/day for 2 weeks	Oxcarbazepine n=178 Participants Oxcarbazepine twice a day treatment Group 150 mg and 300 mg Oxcarbazepine tablet, 900 mg-2400 mg/day, maximum 50 weeks including 2 weeks of up titration (300 mg/day 1 week then 600 mg/day 1 week)	Total Title n=353 Participants
Age, Categorical <=18 years	14 Participants n=5 Participants	13 Participants n=7 Participants	27 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	145 Participants n=5 Participants	143 Participants n=7 Participants	288 Participants n=5 Participants
Age, Categorical >=65 years	16 Participants n=5 Participants	22 Participants n=7 Participants	38 Participants n=5 Participants
Age, Continuous	39.5 years STANDARD_DEVIATION 16.7 • n=5 Participants	42.7 years STANDARD_DEVIATION 17.3 • n=7 Participants	41.1 years STANDARD_DEVIATION 17.0 • n=5 Participants
Sex: Female, Male Female	84 Participants n=5 Participants	79 Participants n=7 Participants	163 Participants n=5 Participants
Sex: Female, Male Male	91 Participants n=5 Participants	99 Participants n=7 Participants	190 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	174 Participants n=5 Participants	178 Participants n=7 Participants	352 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 0 (First Dose) to Week 50

Population: Per Protocol Set (PPS) consisted of all subjects who received at least 1 (partial) dose of study mediaction, returned at least 1 post-Baseline seizure diary and had no important protocol deviations. Subjects who discontinued the study before Week 50 for any reason other than treatment failure were excluded from the PPS.

Outcome measures

Outcome measures
Measure	Per Protocol Set (LEV Treated Subjects) n=118 Participants 250 mg and 500 mg Levetiracetam tablet, 1000 mg-3000 mg/day, maximum 50 weeks including initial up titration of 500 mg/day for 2 weeks	Per Protocol Set (OXC Treated Subjects) n=128 Participants 150 mg and 300 mg Oxcarbazepine tablet, 900 mg-2400 mg/day, maximum 50 weeks including 2 weeks of up titration (300 mg/day 1 week then 600 mg/day 1 week)
Percentage of Subjects With a Treatment Failure	12.7 percentage of subjects	23.4 percentage of subjects

SECONDARY outcome

Timeframe: From Week 2 to Week 50 (During Treatment Period )

Population: The Full Analysis Set (FAS) consisted of all subjects who received at least 1 (partial) dose of study mediaction and returned at least 1 post-Baseline seizure diary. A randomized subject was only excluded from the FAS when there was clear evidence that the subject did not take any study medication.

Outcome measures

Outcome measures
Measure	Per Protocol Set (LEV Treated Subjects) n=173 Participants 250 mg and 500 mg Levetiracetam tablet, 1000 mg-3000 mg/day, maximum 50 weeks including initial up titration of 500 mg/day for 2 weeks	Per Protocol Set (OXC Treated Subjects) n=171 Participants 150 mg and 300 mg Oxcarbazepine tablet, 900 mg-2400 mg/day, maximum 50 weeks including 2 weeks of up titration (300 mg/day 1 week then 600 mg/day 1 week)
Time to the First Seizure Defined as the Time From the First Dose of Medication to the Occurrence of the First Seizure During the 48 Weeks Treatment Period	7.556 months Dispersion measures for this statistic were not part of the analysis (or it's specification).	NA months Kaplan-Meier estimation of percentage of event-free subjects does not fall to or below 50 %, therefore no median time to event could be estimated for the OXC group.

SECONDARY outcome

Timeframe: From Week 2 to Week 50 (During Treatment Period )

24-week Seizure Freedom (rate) defined as the number and percentage of subjects who achieved seizure freedom for 24 consecutive weeks during the Treatment Period at any time

Outcome measures

Outcome measures
Measure	Per Protocol Set (LEV Treated Subjects) n=173 Participants 250 mg and 500 mg Levetiracetam tablet, 1000 mg-3000 mg/day, maximum 50 weeks including initial up titration of 500 mg/day for 2 weeks	Per Protocol Set (OXC Treated Subjects) n=171 Participants 150 mg and 300 mg Oxcarbazepine tablet, 900 mg-2400 mg/day, maximum 50 weeks including 2 weeks of up titration (300 mg/day 1 week then 600 mg/day 1 week)
Percentage of Subjects Who Achieved Seizure Freedom for 24 Consecutive Weeks During the 48 Weeks Treatment Period at Any Time	53.8 percentage of subjects	58.5 percentage of subjects

SECONDARY outcome

Timeframe: From Week 2 to Week 50 (During Treatment Period )

48-week Seizure Freedom (rate) defined as the number and percentage of subjects who achieved seizure freedom during the Treatment Period

Outcome measures

Outcome measures
Measure	Per Protocol Set (LEV Treated Subjects) n=173 Participants 250 mg and 500 mg Levetiracetam tablet, 1000 mg-3000 mg/day, maximum 50 weeks including initial up titration of 500 mg/day for 2 weeks	Per Protocol Set (OXC Treated Subjects) n=171 Participants 150 mg and 300 mg Oxcarbazepine tablet, 900 mg-2400 mg/day, maximum 50 weeks including 2 weeks of up titration (300 mg/day 1 week then 600 mg/day 1 week)
Percentage of Subjects Who Achieved Seizure Freedom During the 48 Weeks Treatment Period	34.7 percentage of subjects	40.9 percentage of subjects

Adverse Events

Levetiracetam

Serious events: 15 serious events

Other events: 67 other events

Deaths: 0 deaths

Oxcarbazepine

Serious events: 15 serious events

Other events: 93 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Levetiracetam n=173 participants at risk Levetiracetam twice a day treatment Group 250 mg and 500 mg Levetiracetam tablet, 1000 mg-3000 mg/day, maximum 50 weeks including initial up titration of 500 mg/day for 2 weeks	Oxcarbazepine n=174 participants at risk Oxcarbazepine twice a day treatment Group 150 mg and 300 mg Oxcarbazepine tablet, 900 mg-2400 mg/day, maximum 50 weeks including 2 weeks of up titration (300 mg/day 1 week then 600 mg/day 1 week)
Infections and infestations Nasopharyngitis	8.1% 14/173 • Number of events 15 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	10.9% 19/174 • Number of events 21 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
Nervous system disorders Dizziness	14.5% 25/173 • Number of events 30 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	28.7% 50/174 • Number of events 70 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
Nervous system disorders Headache	14.5% 25/173 • Number of events 29 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	20.7% 36/174 • Number of events 53 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
Nervous system disorders Somnolence	12.7% 22/173 • Number of events 30 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	13.8% 24/174 • Number of events 30 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
Skin and subcutaneous tissue disorders Rash	1.7% 3/173 • Number of events 3 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	7.5% 13/174 • Number of events 16 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.

Additional Information

UCB (Study Director)

UCB Clinical Trial Call Center

Phone: +1 887 822 9493

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Measure	Levetiracetam n=173 participants at risk Levetiracetam twice a day treatment Group 250 mg and 500 mg Levetiracetam tablet, 1000 mg-3000 mg/day, maximum 50 weeks including initial up titration of 500 mg/day for 2 weeks	Oxcarbazepine n=174 participants at risk Oxcarbazepine twice a day treatment Group 150 mg and 300 mg Oxcarbazepine tablet, 900 mg-2400 mg/day, maximum 50 weeks including 2 weeks of up titration (300 mg/day 1 week then 600 mg/day 1 week)
Cardiac disorders Cardiac arrest	0.00% 0/173 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	1.1% 2/174 • Number of events 2 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
Gastrointestinal disorders Abdominal pain	0.58% 1/173 • Number of events 1 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	0.00% 0/174 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
Gastrointestinal disorders Diarrhoea	0.58% 1/173 • Number of events 1 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	0.00% 0/174 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/173 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	0.57% 1/174 • Number of events 1 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
General disorders Chest discomfort	0.58% 1/173 • Number of events 1 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	0.00% 0/174 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
Injury, poisoning and procedural complications Fibula fracture	0.58% 1/173 • Number of events 1 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	0.00% 0/174 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
Injury, poisoning and procedural complications Thermal burn	0.58% 1/173 • Number of events 1 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	0.00% 0/174 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
Injury, poisoning and procedural complications Tibia fracture	0.58% 1/173 • Number of events 1 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	0.00% 0/174 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
Injury, poisoning and procedural complications Ankle fracture	0.00% 0/173 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	0.57% 1/174 • Number of events 1 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
Injury, poisoning and procedural complications Comminuted fracture	0.00% 0/173 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	0.57% 1/174 • Number of events 1 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/173 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	0.57% 1/174 • Number of events 1 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
Musculoskeletal and connective tissue disorders Back pain	0.58% 1/173 • Number of events 1 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	0.57% 1/174 • Number of events 1 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
Musculoskeletal and connective tissue disorders Flank pain	0.58% 1/173 • Number of events 1 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	0.00% 0/174 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
Musculoskeletal and connective tissue disorders Myalgia	0.00% 0/173 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	0.57% 1/174 • Number of events 1 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
Musculoskeletal and connective tissue disorders Neck pain	0.00% 0/173 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	0.57% 1/174 • Number of events 1 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
Nervous system disorders Convulsion	2.3% 4/173 • Number of events 4 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	2.9% 5/174 • Number of events 5 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
Nervous system disorders Dizziness	0.58% 1/173 • Number of events 1 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	0.00% 0/174 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
Nervous system disorders Status epilepticus	0.58% 1/173 • Number of events 1 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	0.57% 1/174 • Number of events 1 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
Nervous system disorders Encephalopathy	0.00% 0/173 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	0.57% 1/174 • Number of events 1 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
Reproductive system and breast disorders Endometriosis	0.58% 1/173 • Number of events 1 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	0.00% 0/174 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
Respiratory, thoracic and mediastinal disorders Upper airway obstruction	0.58% 1/173 • Number of events 1 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	0.00% 0/174 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/173 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	0.57% 1/174 • Number of events 1 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
Surgical and medical procedures Abortion induced	0.58% 1/173 • Number of events 1 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.	0.57% 1/174 • Number of events 1 • Adverse Events were collected up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit). Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.