Trial Outcomes & Findings for Brivaracetam as add-on Treatment in Adolescents and Adults Suffering From Epilepsy (NCT NCT00504881)

Results Overview

An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

480 participants

Primary outcome timeframe

Week 2 to the end of the Treatment Period (Week 16)

Results posted on

2018-04-03

Participant Flow

This multicenter study was conducted in 15 countries. It started in October 2007 and concluded in December 2008.

The Participant Flow refers to the Randomized Set (RS).

Participant milestones

Participant milestones
Measure	Placebo Matching Placebo tablets administered twice a day	Brivaracetam A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Overall Study STARTED	121	359
Overall Study COMPLETED	111	323
Overall Study NOT COMPLETED	10	36

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Matching Placebo tablets administered twice a day	Brivaracetam A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Overall Study Lack of Efficacy	1	5
Overall Study Lost to Follow-up	0	2
Overall Study Withdrawal by Subject	1	4
Overall Study Non-Compliance	1	0
Overall Study No Birth Control	0	1
Overall Study Safety Visit not performed	0	1
Overall Study AE, serious fatal	0	1
Overall Study SAE, non-fatal	2	6
Overall Study AE, non-serious non-fatal	4	14
Overall Study SAE,non-fatal+AE,non-serious non-fatal	0	2
Overall Study AE of unknown type	1	0

Baseline Characteristics

Brivaracetam as add-on Treatment in Adolescents and Adults Suffering From Epilepsy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=121 Participants Matching Placebo tablets administered twice a day	Brivaracetam n=359 Participants A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day	Total Title n=480 Participants
Age, Categorical <=18 years	3 Participants n=93 Participants	5 Participants n=4 Participants	8 Participants n=27 Participants
Age, Categorical Between 18 and 65 years	116 Participants n=93 Participants	352 Participants n=4 Participants	468 Participants n=27 Participants
Age, Categorical >=65 years	2 Participants n=93 Participants	2 Participants n=4 Participants	4 Participants n=27 Participants
Age, Continuous	36.5 years STANDARD_DEVIATION 11.5 • n=93 Participants	35.6 years STANDARD_DEVIATION 11.5 • n=4 Participants	35.85 years STANDARD_DEVIATION 11.52 • n=27 Participants
Sex: Female, Male Female	52 Participants n=93 Participants	178 Participants n=4 Participants	230 Participants n=27 Participants
Sex: Female, Male Male	69 Participants n=93 Participants	181 Participants n=4 Participants	250 Participants n=27 Participants

PRIMARY outcome

Timeframe: Week 2 to the end of the Treatment Period (Week 16)

Population: The Safety Population was defined as all randomized subjects who received at least 1 dose of study medication.

An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

Outcome measures

Outcome measures
Measure	Placebo n=121 Participants Matching Placebo tablets administered twice a day	Brivaracetam n=359 Participants A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Percentage of Subjects With at Least One Adverse Event During the 16-week Treatment Period	66.1 percentage of participants	66.6 percentage of participants

PRIMARY outcome

Timeframe: Baseline (Week 0) to the end of the Treatment Period (Week 16)

Population: Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Partial (Type I) seizures can be classified into one of the following three groups: * Simple partial seizures * Complex partial seizures * Partial seizures evolving to generalized tonic-clonic convulsions. Partial Onset Seizure (POS) frequency per week over the Treatment Period (TP) was calculated as: (Total Type I seizures over the TP)\*7/(Total number of days with no missing seizure count in the TP)

Outcome measures

Outcome measures
Measure	Placebo n=108 Participants Matching Placebo tablets administered twice a day	Brivaracetam n=323 Participants A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Partial Onset Seizure (Type I) Frequency Per Week Over the 16-week Treatment Period	1.86 seizures per week Interval 1.0 to 3.98	1.74 seizures per week Interval 0.86 to 4.04

SECONDARY outcome

Timeframe: Baseline (Week 0) to the end of Treatment Period (Week 16)

Population: Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

The responder rate was presented as the percentage of responders and non-responders. A subject is a responder, if the subject has at least 50 % reduction in Partial Onset Seizure frequency per week from Baseline to Treatment Period. Subjects with zero seizure frequency per week at Baseline were considered as non-responders.

Outcome measures

Outcome measures
Measure	Placebo n=108 Participants Matching Placebo tablets administered twice a day	Brivaracetam n=323 Participants A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Responder Rate for Partial Onset Seizures (Type I) Frequency Per Week Over the 16-week Treatment Period Responders	16.7 percentage of participants	30.3 percentage of participants
Responder Rate for Partial Onset Seizures (Type I) Frequency Per Week Over the 16-week Treatment Period Non-Responders	83.3 percentage of participants	69.7 percentage of participants

SECONDARY outcome

Timeframe: Baseline (Week 0) to the end of Treatment Period (Week 16)

Population: Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

There are three different types of seizures: * Type I: Partial seizures * Type II: Generalized seizures * Type III: Unclassified epileptic seizures. All seizure frequency per week over Treatment Period (TP) was calculated as: (Total number of seizures over the TP)\*7/(Total number of days with no missing seizure count in the TP)

Outcome measures

Outcome measures
Measure	Placebo n=108 Participants Matching Placebo tablets administered twice a day	Brivaracetam n=323 Participants A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Seizure Frequency (All Seizure Types) Per Week Over the 16-week Treatment Period	1.87 number of seizures per week Interval 1.0 to 4.59	1.74 number of seizures per week Interval 0.86 to 4.04

SECONDARY outcome

Timeframe: Baseline (Week 0) to end of Treatment Period (Week 16)

Population: Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Percent change from Baseline was calculated as percent reduction by: (weekly seizure frequency Baseline - weekly seizure frequency Treatment)\*100/(weekly seizure frequency Baseline). A negative value in percent Change from Baseline indicates an improvement from Baseline. The higher the negative values for percent change in Partial Onset Seizure (POS) frequency, the higher the improvement from Baseline.

Outcome measures

Outcome measures
Measure	Placebo n=108 Participants Matching Placebo tablets administered twice a day	Brivaracetam n=323 Participants A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Percent Change From Baseline to the 16-week Treatment Period in Partial Onset Seizure (Type I) Frequency Per Week	-18.93 percent change Interval -39.05 to -7.83	-26.92 percent change Interval -55.98 to 11.44

SECONDARY outcome

Timeframe: Baseline to 16-week Treatment Period

Population: Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Subjects were classified in 1 of the following categories based on their percent reduction from Baseline to Treatment Period in Partial Onset Seizure (POS) frequency per week: \<-25 %, -25 % to \<25 %, 25 % to \<50 %, 50 % to \<75 %, 75 % to \<100 %, and 100 %. Subjects having zero for Baseline seizure frequency per week were classified in the \<-25 % category.

Outcome measures

Outcome measures
Measure	Placebo n=108 Participants Matching Placebo tablets administered twice a day	Brivaracetam n=323 Participants A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Categorized Response From Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the 16-week Treatment Period <- 25 %	14.8 percentage of participants	18.3 percentage of participants
Categorized Response From Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the 16-week Treatment Period -25 % to < 25 %	44.4 percentage of participants	29.1 percentage of participants
Categorized Response From Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the 16-week Treatment Period 25 % to < 50 %	24.1 percentage of participants	22.3 percentage of participants
Categorized Response From Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the 16-week Treatment Period 50 % to < 75 %	13.9 percentage of participants	17.0 percentage of participants
Categorized Response From Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the 16-week Treatment Period 75 % to < 100 %	2.8 percentage of participants	11.8 percentage of participants
Categorized Response From Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the 16-week Treatment Period 100 %	0 percentage of participants	1.5 percentage of participants

SECONDARY outcome

Timeframe: Baseline (Week 0) to the end of Treatment Period (Week 16)

Population: Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Subjects were considered seizure free if their seizure counts for every day over the Treatment Period (TP) was zero and if they did not discontinue before the end of the TP. Seizure freedom rate was calculated as: (total number of seizure - free subjects in treatment group during TP)/(total number of evaluable Intent-To-Treat (ITT) subjects in treatment group)

Outcome measures

Outcome measures
Measure	Placebo n=108 Participants Matching Placebo tablets administered twice a day	Brivaracetam n=323 Participants A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Seizure Freedom Rate (All Seizure Types) Over the 16-week Treatment Period Seizure-free	0 percentage of participants	1.5 percentage of participants
Seizure Freedom Rate (All Seizure Types) Over the 16-week Treatment Period No Seizure but non-completer	0 percentage of participants	0 percentage of participants
Seizure Freedom Rate (All Seizure Types) Over the 16-week Treatment Period Not Seizure free	100.0 percentage of participants	98.5 percentage of participants

SECONDARY outcome

Timeframe: Baseline to 16-week Treatment Period

Population: The Intention-to-treat (ITT) population was defined as all randomized subjects who received at least 1 dose of study medication. Type IC Population consists of those subjects with at least one Type IC seizure during the Baseline period.

The type IC/Type I seizure frequency ratio is represented by the percentage of subjects having a reduction in the ratio of Type IC seizure frequency over Type IA, IB, and IC seizure frequency from Baseline to Treatment Period.

Outcome measures

Outcome measures
Measure	Placebo n=35 Participants Matching Placebo tablets administered twice a day	Brivaracetam n=94 Participants A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Reduction of Type IC/Type I Seizure Frequency Ratio From Baseline to the 16-week Treatment Period	54.3 percentage of participants	47.9 percentage of participants

SECONDARY outcome

Timeframe: Baseline to 16-week Treatment Period

Population: Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Time to first Type I seizure during the 16-week Treatment Period was measured in days.

Outcome measures

Outcome measures
Measure	Placebo n=108 Participants Matching Placebo tablets administered twice a day	Brivaracetam n=323 Participants A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Time to First Type I Seizure During the 16-week Treatment Period	3 days Interval 2.0 to 4.0	4 days Interval 4.0 to 5.0

SECONDARY outcome

Timeframe: Baseline to 16-week Treatment Period

Population: Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Time to fifth Type I seizure during the 16-week Treatment Period was measured in days.

Outcome measures

Outcome measures
Measure	Placebo n=108 Participants Matching Placebo tablets administered twice a day	Brivaracetam n=323 Participants A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Time to Fifth Type I Seizure During the 16-week Treatment Period	14 days Interval 11.0 to 19.0	18 days Interval 16.0 to 21.0

SECONDARY outcome

Timeframe: Baseline to 16-week Treatment Period

Population: Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Time to tenth Type I seizure during the 16-week Treatment Period was measured in days.

Outcome measures

Outcome measures
Measure	Placebo n=108 Participants Matching Placebo tablets administered twice a day	Brivaracetam n=323 Participants A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Time to Tenth Type I Seizure During Treatment Period	36 days Interval 23.0 to 44.0	38 days Interval 31.0 to 43.0

SECONDARY outcome

Timeframe: Baseline to 16-week Treatment Period

Population: Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication. Only subjects who are not mentally impaired were to complete the QOLIE-31-P. Only subjects having values at baseline and at the considered visit are included.

The Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into 7 multi-item subscales: Seizure Worry (5 items), Overall Quality of Life (2 items), Emotional Well-being (5 items), Energy/Fatigue (4 items), Cognitive Functioning (6 items), Medication Effects (3 items) and Daily Activities/Social Functioning (5 items), and a Health Status item. In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking the subjects to rate the degree of 'distress' related to the topic of each subscale (ie, distress items). The QOLIE-31-P also contains an item asking about the relative importance of each subscale topic (ie, prioritization item). The subscale scores, the total score and the Health Status item score were calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function.

Outcome measures

Outcome measures
Measure	Placebo n=98 Participants Matching Placebo tablets administered twice a day	Brivaracetam n=284 Participants A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Change From Baseline to the 16-week Treatment Period in Total Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) Score	3.04 units on a scale Standard Deviation 12.58	4.22 units on a scale Standard Deviation 13.73

SECONDARY outcome

Timeframe: Baseline to 16-week Treatment Period

Population: Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication. Only subjects who are not mentally impaired were to complete the QOLIE-31-P. Only subjects having values at baseline and at the considered visit are included.

The Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into 7 multi-item subscales: Seizure Worry (5 items), Overall Quality of Life (2 items), Emotional Well-being (5 items), Energy/Fatigue (4 items), Cognitive Functioning (6 items), Medication Effects (3 items) and Daily Activities/Social Functioning (5 items), and a Health Status item. In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking the subjects to rate the degree of 'distress' related to the topic of each subscale (ie, distress items). The QOLIE-31-P also contains an item asking about the relative importance of each subscale topic (ie, prioritization item). The subscale scores, the total score and the Health Status item score were calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function.

Outcome measures

Outcome measures
Measure	Placebo n=99 Participants Matching Placebo tablets administered twice a day	Brivaracetam n=291 Participants A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Change From Baseline to the 16-week Treatment Period in Seizure Worry Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) Score	4.66 units on a scale Standard Deviation 23.23	10.29 units on a scale Standard Deviation 21.99

SECONDARY outcome

Timeframe: Baseline to 16-week Treatment Period

Population: Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication. Only subjects who are not mentally impaired were to complete the QOLIE-31-P. Only subjects having values at baseline and at the considered visit are included.

The Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into 7 multi-item subscales: Seizure Worry (5 items), Overall Quality of Life (2 items), Emotional Well-being (5 items), Energy/Fatigue (4 items), Cognitive Functioning (6 items), Medication Effects (3 items) and Daily Activities/Social Functioning (5 items), and a Health Status item. In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking the subjects to rate the degree of 'distress' related to the topic of each subscale (ie, distress items). The QOLIE-31-P also contains an item asking about the relative importance of each subscale topic (ie, prioritization item). The subscale scores, the total score and the Health Status item score were calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function.

Outcome measures

Outcome measures
Measure	Placebo n=99 Participants Matching Placebo tablets administered twice a day	Brivaracetam n=290 Participants A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Change From Baseline to the 16-week Treatment Period in Daily Activities / Social Functioning Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) Score	5.61 units on a scale Standard Deviation 21.87	2.66 units on a scale Standard Deviation 23.48

SECONDARY outcome

Timeframe: Baseline to 16-week Treatment Period

Population: Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication. Only subjects who are not mentally impaired were to complete the HADS. Only subjects having values at baseline ans at the considered visit are included.

The Hospital Anxiety and Depression Scale (HADS) was used to evaluate Anxiety and Depression. The HADS was developed as a self-administered scale to assess the presence and severity of Anxiety and Depression. It consists of 14 items that are scored on a 4-point severity scale ranging from 0 to 3. A score per dimension was calculated with each score ranging from 0 to 21 (higher scores indicating greater problems). A negative value in change from Baseline indicates an improvement from Baseline.

Outcome measures

Outcome measures
Measure	Placebo n=97 Participants Matching Placebo tablets administered twice a day	Brivaracetam n=286 Participants A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Change From Baseline to the 16-week Treatment Period in Hospital Anxiety Score	-0.57 units on a scale Standard Deviation 3.35	-0.85 units on a scale Standard Deviation 3.62

SECONDARY outcome

Timeframe: Baseline to 16-week Treatment Period

Population: Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication. Only subjects who are not mentally impaired were to complete the HADS. Only subjects having values at baseline ans at the considered visit are included.

The Hospital Anxiety and Depression Scale (HADS) was used to evaluate Anxiety and Depression.The HADS was developed as a self-administered scale to assess the presence and severity of Anxiety and Depression. It consists of 14 items that are scored on a 4-point severity scale ranging from 0 to 3. A score per dimension was calculated with each score ranging from 0 to 21 (higher scores indicating greater problems). A negative value in change from Baseline indicates an improvement from Baseline.

Outcome measures

Outcome measures
Measure	Placebo n=97 Participants Matching Placebo tablets administered twice a day	Brivaracetam n=285 Participants A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Change From Baseline to the 16-week Treatment Period in Hospital Depression Score	0.30 units on a scale Standard Deviation 3.08	-0.41 units on a scale Standard Deviation 3.54

SECONDARY outcome

Timeframe: Baseline to last visit or early discontinuation visit in the 16-week Treatment Period

Population: Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication. Evaluable subjects are subjects who completed the GES at last treatment period visit.

The Patient's Global Evaluation Scale (P-GES) is a global assessment of the disease evolution which was performed using a seven-point scale (1= Marked worsening to 7= Marked improvement) with the start of the study medication as the reference time point. The subject completed it by answering to the following: 'Overall, has there been a change in your seizures since the start of the study medication?'

Outcome measures

Outcome measures
Measure	Placebo n=99 Participants Matching Placebo tablets administered twice a day	Brivaracetam n=282 Participants A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Patient's Global Evaluation Scale (P-GES) Evaluated at Last Visit or Early Discontinuation Visit	4.73 units on a scale Standard Deviation 1.37	5.07 units on a scale Standard Deviation 1.36

SECONDARY outcome

Timeframe: Baseline to Last Visit or Early Discontinuation Visit in the 16-week Treatment Period

Population: Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication. Evaluable subjects are subjects for whom the GES was completed by the investigator at last treatment period visit.

The Investigator's Global Evaluation Scale (I-GES) is a global assessment of the disease evolution which was performed using a seven-point scale (1= Marked worsening to 7= Marked improvement) with the start of the study medication as the reference time point. The Investigator completed it by answering to the following: 'Assess the overall change in the severity of patient's illness, compared to start of study medication.'

Outcome measures

Outcome measures
Measure	Placebo n=108 Participants Matching Placebo tablets administered twice a day	Brivaracetam n=319 Participants A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Investigator's Global Evaluation Scale (I-GES) Evaluated at Last Visit or Early Discontinuation Visit	4.79 units on a scale Standard Deviation 1.14	5.00 units on a scale Standard Deviation 1.22

SECONDARY outcome

Timeframe: Baseline to 16-week Treatment Period

Population: Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication. Only subjects who are not mentally impaired were to complete the QOLIE-31-P. Only subjects having values at baseline and at the considered visit are included.

The Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into 7 multi-item subscales: Seizure Worry (5 items), Overall Quality of Life (2 items), Emotional Well-being (5 items), Energy/Fatigue (4 items), Cognitive Functioning (6 items), Medication Effects (3 items) and Daily Activities/Social Functioning (5 items), and a Health Status item. In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking the subjects to rate the degree of 'distress' related to the topic of each subscale (ie, distress items). The QOLIE-31-P also contains an item asking about the relative importance of each subscale topic (ie, prioritization item). The subscale scores, the total score and the Health Status item score were calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function.

Outcome measures

Outcome measures
Measure	Placebo n=99 Participants Matching Placebo tablets administered twice a day	Brivaracetam n=286 Participants A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Change From Baseline to the 16-week Treatment Period in Energy/Fatigue Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) Score	2.98 units on a scale Standard Deviation 18.00	3.34 units on a scale Standard Deviation 19.06

SECONDARY outcome

Timeframe: Baseline to 16-week Treatment Period

Population: Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication. Only subjects who are not mentally impaired were to complete the QOLIE-31-P. Only subjects having values at baseline and at the considered visit are included.

The Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into 7 multi-item subscales: Seizure Worry (5 items), Overall Quality of Life (2 items), Emotional Well-being (5 items), Energy/Fatigue (4 items), Cognitive Functioning (6 items), Medication Effects (3 items) and Daily Activities/Social Functioning (5 items), and a Health Status item. In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking the subjects to rate the degree of 'distress' related to the topic of each subscale (ie, distress items). The QOLIE-31-P also contains an item asking about the relative importance of each subscale topic (ie, prioritization item). The subscale scores, the total score and the Health Status item score were calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function.

Outcome measures

Outcome measures
Measure	Placebo n=99 Participants Matching Placebo tablets administered twice a day	Brivaracetam n=287 Participants A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Change From Baseline to the 16-week Treatment Period in Emotional Well-being Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) Score	1.97 units on a scale Standard Deviation 19.29	2.84 units on a scale Standard Deviation 18.07

SECONDARY outcome

Timeframe: Baseline to 16-week Treatment Period

Population: Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication. Only subjects who are not mentally impaired were to complete the QOLIE-31-P. Only subjects having values at baseline and at the considered visit are included.

The Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into 7 multi-item subscales: Seizure Worry (5 items), Overall Quality of Life (2 items), Emotional Well-being (5 items), Energy/Fatigue (4 items), Cognitive Functioning (6 items), Medication Effects (3 items) and Daily Activities/Social Functioning (5 items), and a Health Status item. In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking the subjects to rate the degree of 'distress' related to the topic of each subscale (ie, distress items). The QOLIE-31-P also contains an item asking about the relative importance of each subscale topic (ie, prioritization item). The subscale scores, the total score and the Health Status item score were calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function.

Outcome measures

Outcome measures
Measure	Placebo n=99 Participants Matching Placebo tablets administered twice a day	Brivaracetam n=290 Participants A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Change From Baseline to the 16-week Treatment Period in Cognitive Functioning Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) Score	2.28 units on a scale Standard Deviation 19.88	5.51 units on a scale Standard Deviation 18.55

SECONDARY outcome

Timeframe: Baseline to 16-week Treatment Period

Population: Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication. Only subjects who are not mentally impaired were to complete the QOLIE-31-P. Only subjects having values at baseline and at the considered visit are included.

The Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into 7 multi-item subscales: Seizure Worry (5 items), Overall Quality of Life (2 items), Emotional Well-being (5 items), Energy/Fatigue (4 items), Cognitive Functioning (6 items), Medication Effects (3 items) and Daily Activities/Social Functioning (5 items), and a Health Status item. In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking the subjects to rate the degree of 'distress' related to the topic of each subscale (ie, distress items). The QOLIE-31-P also contains an item asking about the relative importance of each subscale topic (ie, prioritization item). The subscale scores, the total score and the Health Status item score were calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function.

Outcome measures

Outcome measures
Measure	Placebo n=98 Participants Matching Placebo tablets administered twice a day	Brivaracetam n=291 Participants A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Change From Baseline to the 16-week Treatment Period in Overall Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) Score	-0.48 units on a scale Standard Deviation 17.40	4.08 units on a scale Standard Deviation 19.23

SECONDARY outcome

Timeframe: Baseline to 16-week Treatment Period

Population: Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication. Only subjects who are not mentally impaired were to complete the QOLIE-31-P. Only subjects having values at baseline and at the considered visit are included.

The Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into 7 multi-item subscales: Seizure Worry (5 items), Overall Quality of Life (2 items), Emotional Well-being (5 items), Energy/Fatigue (4 items), Cognitive Functioning (6 items), Medication Effects (3 items) and Daily Activities/Social Functioning (5 items), and a Health Status item. In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking the subjects to rate the degree of 'distress' related to the topic of each subscale (ie, distress items). The QOLIE-31-P also contains an item asking about the relative importance of each subscale topic (ie, prioritization item). The subscale scores, the total score and the Health Status item score were calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function.

Outcome measures

Outcome measures
Measure	Placebo n=99 Participants Matching Placebo tablets administered twice a day	Brivaracetam n=290 Participants A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Change From Baseline to the 16-week Treatment Period in Medication Effects Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) Score	2.83 units on a scale Standard Deviation 27.21	-0.24 units on a scale Standard Deviation 25.84

Adverse Events

Placebo

Serious events: 9 serious events

Other events: 40 other events

Deaths: 0 deaths

Brivaracetam

Serious events: 20 serious events

Other events: 139 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo n=121 participants at risk Matching Placebo tablets administered twice a day	Brivaracetam n=359 participants at risk A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Infections and infestations Nasopharyngitis	6.6% 8/121 • Number of events 10 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	3.9% 14/359 • Number of events 16 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Gastrointestinal disorders Nausea	9.1% 11/121 • Number of events 14 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	5.6% 20/359 • Number of events 26 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
General disorders Fatigue	4.1% 5/121 • Number of events 5 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	7.5% 27/359 • Number of events 31 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Musculoskeletal and connective tissue disorders Back pain	6.6% 8/121 • Number of events 9 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	3.1% 11/359 • Number of events 11 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Nervous system disorders Dizziness	5.8% 7/121 • Number of events 9 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	8.6% 31/359 • Number of events 36 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Nervous system disorders Headache	19.8% 24/121 • Number of events 45 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	14.5% 52/359 • Number of events 79 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Nervous system disorders Somnolence	4.1% 5/121 • Number of events 7 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	11.1% 40/359 • Number of events 47 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.

Additional Information

UCB (Study Director)

UCB Clinical Trial Call Center

Phone: +1 877 822 9493

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Measure	Placebo n=121 participants at risk Matching Placebo tablets administered twice a day	Brivaracetam n=359 participants at risk A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day
Infections and infestations Hepatitis B	0.83% 1/121 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.00% 0/359 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Infections and infestations Pyelonephritis acute	0.83% 1/121 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.00% 0/359 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Blood and lymphatic system disorders Neutropenia	0.00% 0/121 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.28% 1/359 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Metabolism and nutrition disorders Diabetis mellitus inadequate control	0.00% 0/121 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.28% 1/359 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Psychiatric disorders Depression	0.83% 1/121 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.28% 1/359 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Psychiatric disorders Psychotic disorder	0.00% 0/121 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.28% 1/359 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Nervous system disorders Headache	0.00% 0/121 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.28% 1/359 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Nervous system disorders Tremor	0.83% 1/121 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.00% 0/359 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Nervous system disorders Dizziness	0.00% 0/121 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.28% 1/359 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Nervous system disorders Postictal state	0.00% 0/121 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.28% 1/359 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Nervous system disorders Convulsion	0.83% 1/121 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	1.9% 7/359 • Number of events 9 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Nervous system disorders Status epilepticus	0.00% 0/121 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.28% 1/359 • Number of events 3 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Ear and labyrinth disorders Vertigo	0.00% 0/121 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.28% 1/359 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Cardiac disorders Myocardial ischaemia	0.00% 0/121 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.28% 1/359 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Gastrointestinal disorders Abdominal pain	0.00% 0/121 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.28% 1/359 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Pregnancy, puerperium and perinatal conditions Pregnancy	0.00% 0/121 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.56% 2/359 • Number of events 2 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
General disorders Chest pain	0.00% 0/121 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.28% 1/359 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
General disorders Drowning	0.00% 0/121 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.28% 1/359 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
General disorders Fatigue	0.00% 0/121 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.28% 1/359 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Injury, poisoning and procedural complications Drug toxity	0.00% 0/121 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.28% 1/359 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Injury, poisoning and procedural complications Overdose	0.00% 0/121 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.28% 1/359 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Injury, poisoning and procedural complications Ankle fracture	0.83% 1/121 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.00% 0/359 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Injury, poisoning and procedural complications Burns second degree	0.00% 0/121 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.28% 1/359 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Injury, poisoning and procedural complications Face injury	0.83% 1/121 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.00% 0/359 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Injury, poisoning and procedural complications Fall	0.83% 1/121 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.00% 0/359 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Injury, poisoning and procedural complications Head injury	0.83% 1/121 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.00% 0/359 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Injury, poisoning and procedural complications Skin laceration	0.00% 0/121 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.28% 1/359 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Injury, poisoning and procedural complications Spinal fracture	0.83% 1/121 • Number of events 1 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.	0.00% 0/359 • Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20). Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.