Trial Outcomes & Findings for Trial to Assess Lacosamide as the First add-on Anti-epileptic Drug Treatment in Patients With Partial-onset Seizures (NCT NCT00955357)

Last Updated: 2018-07-17

Results Overview

A subject will be considered seizure-free if the subject completes the first 12 weeks of the Maintenance Phase, reports zero seizures, and has no seizure data missing for any day during the period of time. This study was intended to assess the efficacy outcomes in the First Add-On Group and the Later Add-On Group individually relative to historical data. Comparisons between the 2 groups should not be attempted and conclusions should not be drawn.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

461 participants

Primary outcome timeframe

From Week 7 (end of Week 6) to end of Week 18

Results posted on

2018-07-17

Participant Flow

An estimated 656 subjects were to be enrolled in the study at approximately 130 sites in the US, Europe, and the rest of the world.

Overall 461 subjects were enrolled. The Participant Flow refers to the Safety Set (SS) which was defined as all enrolled subjects who took at least 1 dose of Lacosamide. Reasons for discontinuation were only calculated for the SS. 456 subjects were included in the Safety Set.

Participant milestones

Participant milestones
Measure	First Add-on Lacosamide added to first adequate monotherapy (no history of Anti-Epileptic Drug \[AED\] polytherapy) and epilepsy diagnosis \< or = 24 months at Screening. Lacosamide: oral tablet Subjects Titration Phase (6 Weeks): Week 1 - 50 mg tablet twice daily (bid); Week 2 - 100 mg tablet bid; Week 3 - 150 mg tablet bid; Week 4 - 200 mg tablet bid; Week 5 - 200 mg tablet bid; Week 6 - 150 mg tablet bid OR Week 6 - 200 mg tablet bid Maintenance Phase (24 Weeks): 200 mg tablet bid OR 150 mg tablet bid Taper Phase (1 - 3 Weeks): 50 mg tablet bid for 1 week OR 100 mg tablet bid for 1 week OR 150 mg tablet bid for 1 week	Later Add-on Lacosamide added to 1 to 3 Anti-Epileptic Drugs (AEDs) (with tentatives of at least 2 prior AED treatment regimens) and epilepsy diagnosis \> or = 5 years at Screening. Lacosamide: oral tablet Subjects Titration Phase (6 Weeks): Week 1 - 50 mg tablet twice daily (bid); Week 2 - 100 mg tablet bid; Week 3 - 150 mg tablet bid; Week 4 - 200 mg tablet bid; Week 5 - 200 mg tablet bid; Week 6 - 150 mg tablet bid OR Week 6 - 200 mg tablet bid Maintenance Phase (24 Weeks): 200 mg tablet bid OR 150 mg tablet bid Taper Phase (1 - 3 Weeks): 50 mg tablet bid for 1 week OR 100 mg tablet bid for 1 week OR 150 mg tablet bid for 1 week
Titration Phase STARTED	96	360
Titration Phase COMPLETED	80	294
Titration Phase NOT COMPLETED	16	66
Maintenance Phase STARTED	80	294
Maintenance Phase COMPLETED	68	249
Maintenance Phase NOT COMPLETED	12	45

Reasons for withdrawal

Reasons for withdrawal
Measure	First Add-on Lacosamide added to first adequate monotherapy (no history of Anti-Epileptic Drug \[AED\] polytherapy) and epilepsy diagnosis \< or = 24 months at Screening. Lacosamide: oral tablet Subjects Titration Phase (6 Weeks): Week 1 - 50 mg tablet twice daily (bid); Week 2 - 100 mg tablet bid; Week 3 - 150 mg tablet bid; Week 4 - 200 mg tablet bid; Week 5 - 200 mg tablet bid; Week 6 - 150 mg tablet bid OR Week 6 - 200 mg tablet bid Maintenance Phase (24 Weeks): 200 mg tablet bid OR 150 mg tablet bid Taper Phase (1 - 3 Weeks): 50 mg tablet bid for 1 week OR 100 mg tablet bid for 1 week OR 150 mg tablet bid for 1 week	Later Add-on Lacosamide added to 1 to 3 Anti-Epileptic Drugs (AEDs) (with tentatives of at least 2 prior AED treatment regimens) and epilepsy diagnosis \> or = 5 years at Screening. Lacosamide: oral tablet Subjects Titration Phase (6 Weeks): Week 1 - 50 mg tablet twice daily (bid); Week 2 - 100 mg tablet bid; Week 3 - 150 mg tablet bid; Week 4 - 200 mg tablet bid; Week 5 - 200 mg tablet bid; Week 6 - 150 mg tablet bid OR Week 6 - 200 mg tablet bid Maintenance Phase (24 Weeks): 200 mg tablet bid OR 150 mg tablet bid Taper Phase (1 - 3 Weeks): 50 mg tablet bid for 1 week OR 100 mg tablet bid for 1 week OR 150 mg tablet bid for 1 week
Titration Phase Adverse Event	9	46
Titration Phase Lack of Efficacy	0	2
Titration Phase Protocol Violation	3	7
Titration Phase Lost to Follow-up	1	3
Titration Phase Withdrawal by Subject	3	5
Titration Phase Prohibited Antiepileptic Drug change	0	1
Titration Phase Study medication not tolerated	0	1
Titration Phase Non compliance to study procedures	0	1
Maintenance Phase Adverse Event	3	23
Maintenance Phase Lack of Efficacy	0	4
Maintenance Phase Protocol Violation	2	6
Maintenance Phase Lost to Follow-up	2	7
Maintenance Phase Withdrawal by Subject	4	4
Maintenance Phase Patient moving out of area	0	1
Maintenance Phase Non compliance to study procedures	1	0

Baseline Characteristics

Trial to Assess Lacosamide as the First add-on Anti-epileptic Drug Treatment in Patients With Partial-onset Seizures

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	First Add-on n=96 Participants Lacosamide added to first adequate monotherapy (no history of AED polytherapy) and epilepsy diagnosis \< or = 24 months at Screening. Lacosamide: oral tablet Subjects Titration Phase (6 Weeks): Week 1 - 50 mg tablet twice daily (bid); Week 2 - 100 mg tablet bid; Week 3 - 150 mg tablet bid; Week 4 - 200 mg tablet bid; Week 5 - 200 mg tablet bid; Week 6 - 150 mg tablet bid OR Week 6 - 200 mg tablet bid Maintenance Phase (24 Weeks): 200 mg tablet bid OR 150 mg tablet bid Taper Phase (1 - 3 Weeks): 50 mg tablet bid for 1 week OR 100 mg tablet bid for 1 week OR 150 mg tablet bid for 1 week	Later-Add-on n=360 Participants Lacosamide added to 1 to 3 AEDs (with tentatives of at least 2 prior AED treatment regimens) and epilepsy diagnosis \> or = 5 years at Screening. Lacosamide: oral tablet Subjects Titration Phase (6 Weeks): Week 1 - 50 mg tablet twice daily (bid); Week 2 - 100 mg tablet bid; Week 3 - 150 mg tablet bid; Week 4 - 200 mg tablet bid; Week 5 - 200 mg tablet bid; Week 6 - 150 mg tablet bid OR Week 6 - 200 mg tablet bid Maintenance Phase (24 Weeks): 200 mg tablet bid OR 150 mg tablet bid Taper Phase (1 - 3 Weeks): 50 mg tablet bid for 1 week OR 100 mg tablet bid for 1 week OR 150 mg tablet bid for 1 week	Total n=456 Participants Total of all reporting groups
Age, Continuous	37.5 years n=99 Participants	38.0 years n=107 Participants	38.0 years n=206 Participants
Age, Categorical <=18 years	4 Participants n=99 Participants	7 Participants n=107 Participants	11 Participants n=206 Participants
Age, Categorical Between 18 and 65 years	82 Participants n=99 Participants	349 Participants n=107 Participants	431 Participants n=206 Participants
Age, Categorical >=65 years	10 Participants n=99 Participants	4 Participants n=107 Participants	14 Participants n=206 Participants
Sex: Female, Male Female	53 Participants n=99 Participants	180 Participants n=107 Participants	233 Participants n=206 Participants
Sex: Female, Male Male	43 Participants n=99 Participants	180 Participants n=107 Participants	223 Participants n=206 Participants
Race (NIH/OMB) American Indian or Alaska Native	11 Participants n=99 Participants	6 Participants n=107 Participants	17 Participants n=206 Participants
Race (NIH/OMB) Asian	0 Participants n=99 Participants	12 Participants n=107 Participants	12 Participants n=206 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Black or African American	1 Participants n=99 Participants	19 Participants n=107 Participants	20 Participants n=206 Participants
Race (NIH/OMB) White	79 Participants n=99 Participants	278 Participants n=107 Participants	357 Participants n=206 Participants
Race (NIH/OMB) More than one race	5 Participants n=99 Participants	45 Participants n=107 Participants	50 Participants n=206 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	24 Participants n=99 Participants	99 Participants n=107 Participants	123 Participants n=206 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	72 Participants n=99 Participants	261 Participants n=107 Participants	333 Participants n=206 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Weight	71.8 kilogram n=99 Participants	73.0 kilogram n=107 Participants	73.0 kilogram n=206 Participants
Height	166.5 centimeter n=99 Participants	167.6 centimeter n=107 Participants	167.6 centimeter n=206 Participants
BMI	25.3 kilogram per m^2 n=99 Participants	25.5 kilogram per m^2 n=107 Participants	25.4 kilogram per m^2 n=206 Participants

PRIMARY outcome

Timeframe: From Week 7 (end of Week 6) to end of Week 18

Population: The Analysis Population refers to the Completer Set (CS) which includes all subjects who were enrolled, received at least one dose of Lacosamide and completed the first 12 weeks of the Maintenance Phase.

Outcome measures

Outcome measures
Measure	First Add-on n=72 Participants Lacosamide added to first adequate monotherapy (no history of AED polytherapy) and epilepsy diagnosis \< or = 24 months at Screening. Lacosamide: oral tablet Subjects Titration Phase (6 Weeks): Week 1 - 50 mg tablet twice daily (bid); Week 2 - 100 mg tablet bid; Week 3 - 150 mg tablet bid; Week 4 - 200 mg tablet bid; Week 5 - 200 mg tablet bid; Week 6 - 150 mg tablet bid OR Week 6 - 200 mg tablet bid Maintenance Phase (24 Weeks): 200 mg tablet bid OR 150 mg tablet bid Taper Phase (1 - 3 Weeks): 50 mg tablet bid for 1 week OR 100 mg tablet bid for 1 week OR 150 mg tablet bid for 1 week	Later Add-on n=261 Participants Lacosamide added to 1 to 3 AEDs (with tentatives of at least 2 prior AED treatment regimens) and epilepsy diagnosis \> or = 5 years at Screening. Lacosamide: oral tablet Subjects Titration Phase (6 Weeks): Week 1 - 50 mg tablet twice daily (bid); Week 2 - 100 mg tablet bid; Week 3 - 150 mg tablet bid; Week 4 - 200 mg tablet bid; Week 5 - 200 mg tablet bid; Week 6 - 150 mg tablet bid OR Week 6 - 200 mg tablet bid Maintenance Phase (24 Weeks): 200 mg tablet bid OR 150 mg tablet bid Taper Phase (1 - 3 Weeks): 50 mg tablet bid for 1 week OR 100 mg tablet bid for 1 week OR 150 mg tablet bid for 1 week
The Proportion of Subjects Who Achieved "Seizure-free Status" During the First 12 Weeks of the Maintenance Phase	37.5 percentage of subjects	14.9 percentage of subjects

Adverse Events

First Add-on

Serious events: 8 serious events

Other events: 53 other events

Deaths: 0 deaths

Later Add-on

Serious events: 19 serious events

Other events: 212 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	First Add-on n=96 participants at risk Lacosamide added to first adequate monotherapy (no history of AED polytherapy) and epilepsy diagnosis \< or = 24 months at Screening. Lacosamide: oral tablet Subjects Titration Phase (6 Weeks): Week 1 - 50 mg tablet Twice daily (bid); Week 2 - 100 mg tablet bid; Week 3 - 150 mg tablet bid; Week 4 - 200 mg tablet bid; Week 5 - 200 mg tablet bid; Week 6 - 150 mg tablet bid OR Week 6 - 200 mg tablet bid Maintenance Phase (24 Weeks): 200 mg tablet bid OR 150 mg tablet bid Taper Phase (1 - 3 Weeks): 50 mg tablet bid for 1 week OR 100 mg tablet bid for 1 week OR 150 mg tablet bid for 1 week	Later Add-on n=360 participants at risk Lacosamide added to 1 to 3 AEDs (with tentatives of at least 2 prior AED treatment regimens) and epilepsy diagnosis \> or = 5 years at Screening. Lacosamide: oral tablet Subjects Titration Phase (6 Weeks): Week 1 - 50 mg tablet Twice daily (bid); Week 2 - 100 mg tablet bid; Week 3 - 150 mg tablet bid; Week 4 - 200 mg tablet bid; Week 5 - 200 mg tablet bid; Week 6 - 150 mg tablet bid OR Week 6 - 200 mg tablet bid Maintenance Phase (24 Weeks): 200 mg tablet bid OR 150 mg tablet bid Taper Phase (1 - 3 Weeks): 50 mg tablet bid for 1 week OR 100 mg tablet bid for 1 week OR 150 mg tablet bid for 1 week
Ear and labyrinth disorders Vertigo	9.4% 9/96 • Number of events 11 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	6.1% 22/360 • Number of events 22 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Eye disorders Vision blurred	2.1% 2/96 • Number of events 3 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	6.7% 24/360 • Number of events 28 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Eye disorders Diplopia	7.3% 7/96 • Number of events 7 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	4.7% 17/360 • Number of events 17 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Gastrointestinal disorders Nausea	8.3% 8/96 • Number of events 8 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	6.7% 24/360 • Number of events 27 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Infections and infestations Influenza	5.2% 5/96 • Number of events 5 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	1.1% 4/360 • Number of events 4 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Nervous system disorders Dizziness	31.2% 30/96 • Number of events 37 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	33.1% 119/360 • Number of events 159 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Nervous system disorders Somnolence	6.2% 6/96 • Number of events 8 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	15.0% 54/360 • Number of events 65 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Nervous system disorders Headache	13.5% 13/96 • Number of events 19 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	11.4% 41/360 • Number of events 57 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Nervous system disorders Tremor	3.1% 3/96 • Number of events 3 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	6.1% 22/360 • Number of events 23 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Psychiatric disorders Anxiety	6.2% 6/96 • Number of events 6 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	1.1% 4/360 • Number of events 4 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.

Additional Information

UCB Clinical Trial Call Center

UCB

Phone: +1 877 822 9493

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Measure	First Add-on n=96 participants at risk Lacosamide added to first adequate monotherapy (no history of AED polytherapy) and epilepsy diagnosis \< or = 24 months at Screening. Lacosamide: oral tablet Subjects Titration Phase (6 Weeks): Week 1 - 50 mg tablet Twice daily (bid); Week 2 - 100 mg tablet bid; Week 3 - 150 mg tablet bid; Week 4 - 200 mg tablet bid; Week 5 - 200 mg tablet bid; Week 6 - 150 mg tablet bid OR Week 6 - 200 mg tablet bid Maintenance Phase (24 Weeks): 200 mg tablet bid OR 150 mg tablet bid Taper Phase (1 - 3 Weeks): 50 mg tablet bid for 1 week OR 100 mg tablet bid for 1 week OR 150 mg tablet bid for 1 week	Later Add-on n=360 participants at risk Lacosamide added to 1 to 3 AEDs (with tentatives of at least 2 prior AED treatment regimens) and epilepsy diagnosis \> or = 5 years at Screening. Lacosamide: oral tablet Subjects Titration Phase (6 Weeks): Week 1 - 50 mg tablet Twice daily (bid); Week 2 - 100 mg tablet bid; Week 3 - 150 mg tablet bid; Week 4 - 200 mg tablet bid; Week 5 - 200 mg tablet bid; Week 6 - 150 mg tablet bid OR Week 6 - 200 mg tablet bid Maintenance Phase (24 Weeks): 200 mg tablet bid OR 150 mg tablet bid Taper Phase (1 - 3 Weeks): 50 mg tablet bid for 1 week OR 100 mg tablet bid for 1 week OR 150 mg tablet bid for 1 week
Blood and lymphatic system disorders Agranulocytosis	0.00% 0/96 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.28% 1/360 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Cardiac disorders Angina pectoris	1.0% 1/96 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.00% 0/360 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Eye disorders Diplopia	0.00% 0/96 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.28% 1/360 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
General disorders Pyrexia	0.00% 0/96 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.56% 2/360 • Number of events 2 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
General disorders Chest discomfort	0.00% 0/96 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.28% 1/360 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Infections and infestations Pneumonia	1.0% 1/96 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.00% 0/360 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Infections and infestations Tooth abscess	0.00% 0/96 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.28% 1/360 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Infections and infestations Urinary tract infection	1.0% 1/96 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.00% 0/360 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Injury, poisoning and procedural complications Arthropod bite	0.00% 0/96 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.28% 1/360 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Injury, poisoning and procedural complications Femoral neck fracture	1.0% 1/96 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.00% 0/360 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Injury, poisoning and procedural complications Hip fracture	1.0% 1/96 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.00% 0/360 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Injury, poisoning and procedural complications Humerus fracture	1.0% 1/96 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.00% 0/360 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Injury, poisoning and procedural complications Joint dislocation	0.00% 0/96 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.28% 1/360 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Injury, poisoning and procedural complications Subdural haematoma	1.0% 1/96 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.00% 0/360 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Investigations Electrocardiogram ST segment elevation	0.00% 0/96 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.28% 1/360 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Metabolism and nutrition disorders Hypochloraemia	0.00% 0/96 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.28% 1/360 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/96 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.28% 1/360 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Nervous system disorders Convulsion	2.1% 2/96 • Number of events 2 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.56% 2/360 • Number of events 2 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Nervous system disorders Dizziness	0.00% 0/96 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.56% 2/360 • Number of events 2 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Nervous system disorders Complex partial seizures	0.00% 0/96 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.28% 1/360 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Nervous system disorders Coordination abnormal	0.00% 0/96 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.28% 1/360 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Nervous system disorders Dysarthria	0.00% 0/96 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.28% 1/360 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Nervous system disorders Dyskinesia	0.00% 0/96 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.28% 1/360 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Nervous system disorders Epilepsy	0.00% 0/96 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.28% 1/360 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Nervous system disorders Grand mal convulsion	0.00% 0/96 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.28% 1/360 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Nervous system disorders Headache	0.00% 0/96 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.28% 1/360 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Nervous system disorders Lacunar infarction	0.00% 0/96 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.28% 1/360 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Nervous system disorders Partial seizures with secondary generalisation	0.00% 0/96 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.28% 1/360 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Psychiatric disorders Panic attack	0.00% 0/96 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.28% 1/360 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Psychiatric disorders Suicide attempt	1.0% 1/96 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.00% 0/360 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.
Surgical and medical procedures Abortion induced	1.0% 1/96 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.	0.28% 1/360 • Number of events 1 • Treatment Emergent Adverse Events were collected from Screening (Week -1) until the end of the study ( up to Week 33). Treatment Emergent Adverse Events started on/after the date of first dose and within 30 days of the date of last dose.