Trial Outcomes & Findings for Efficacy and Safety Study of Oral Edaravone Administered in Subjects With ALS (NCT NCT04569084)

Last Updated: 2025-12-30

Results Overview

CAFS ranks patients' clinical outcomes based on survival time and change in the ALSFRS-R score. To calculate a patient's CAFS, each patient is compared individually to all other patients in the study. The summary score for each patient is the sum of the comparisons ( 1, 0, 1) against all other patients. After that, patients' summary scores are ranked. The CAFS rank is 1-383 and a higher CAFS rank indicates a better outcome than does a lower CAFS. Since CAFS were calculated using the imputed ALSFRS-R scores with multiple imputation method, and the maximum varies for each simulation, 383 is the maximum possible value of full range for measure of dispersion.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

384 participants

Primary outcome timeframe

up to 48 Weeks

Results posted on

2025-12-30

Participant Flow

Participant milestones

Participant milestones
Measure	Edaravone 105 mg (Once Daily) Oral edaravone 105 mg administered once daily (regimen denoted as Once Daily) in Cycles 1 through 12	Edaravone 105mg (2 Weeks On/Off ) Oral edaravone 105 mg administered for 14 days, followed by placebo for 14 days in Cycle 1. Subsequently, repeat oral edaravone 105 mg administered for 10 days followed by placebo for 18 days (regimen denoted as On/Off) in Cycles 2 through 12
Overall Study STARTED	192	192
Overall Study COMPLETED	125	121
Overall Study NOT COMPLETED	67	71

Reasons for withdrawal

Reasons for withdrawal
Measure	Edaravone 105 mg (Once Daily) Oral edaravone 105 mg administered once daily (regimen denoted as Once Daily) in Cycles 1 through 12	Edaravone 105mg (2 Weeks On/Off ) Oral edaravone 105 mg administered for 14 days, followed by placebo for 14 days in Cycle 1. Subsequently, repeat oral edaravone 105 mg administered for 10 days followed by placebo for 18 days (regimen denoted as On/Off) in Cycles 2 through 12
Overall Study Adverse Event	10	14
Overall Study Death	2	3
Overall Study Lost to Follow-up	1	1
Overall Study Physician Decision	3	3
Overall Study Protocol Violation	2	1
Overall Study Withdrawal by Subject	20	21
Overall Study Study terminated by sponsor	26	23
Overall Study Other	3	5

Baseline Characteristics

Efficacy and Safety Study of Oral Edaravone Administered in Subjects With ALS

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Edaravone 105 mg (Once Daily) n=192 Participants Oral edaravone 105 mg administered once daily (regimen denoted as Once Daily) in Cycles 1 through 12	Edaravone 105mg (2 Weeks On/Off ) n=192 Participants Oral edaravone 105 mg administered for 14 days, followed by placebo for 14 days in Cycle 1. Subsequently, repeat oral edaravone 105 mg administered for 10 days followed by placebo for 18 days (regimen denoted as On/Off) in Cycles 2 through 12	Total n=384 Participants Total of all reporting groups
Age, Customized 18-64 years	134 Participants n=174 Participants	122 Participants n=166 Participants	256 Participants n=167 Participants
Age, Customized 65-84 years	58 Participants n=174 Participants	70 Participants n=166 Participants	128 Participants n=167 Participants
Sex: Female, Male Female	69 Participants n=174 Participants	70 Participants n=166 Participants	139 Participants n=167 Participants
Sex: Female, Male Male	123 Participants n=174 Participants	122 Participants n=166 Participants	245 Participants n=167 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	9 Participants n=174 Participants	5 Participants n=166 Participants	14 Participants n=167 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	183 Participants n=174 Participants	187 Participants n=166 Participants	370 Participants n=167 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=174 Participants	0 Participants n=166 Participants	0 Participants n=167 Participants

PRIMARY outcome

Timeframe: up to 48 Weeks

Population: One subject randomized to the On/Off treatment group was excluded from this analysis because the subject did not receive any study treatment.

Outcome measures

Outcome measures
Measure	Edaravone 105mg (2 Weeks On/Off ) n=191 Participants Oral edaravone 105 mg administered for 14 days, followed by placebo for 14 days in Cycle 1. Subsequently, repeat oral edaravone 105 mg administered for 10 days followed by placebo for 18 days (regimen denoted as On/Off) in Cycles 2 through 12	Edaravone 105 mg (Once Daily) n=192 Participants Oral edaravone 105 mg administered once daily (regimen denoted as Once Daily) in Cycles 1 through 12
CAFS Score at Week 48	184.2 Units on a scale Interval 1.0 to 383.0	187.2 Units on a scale Interval 4.0 to 383.0

SECONDARY outcome

Timeframe: up to 48 Weeks

Population: Those patients reached to Week 48 and conducted SVC assessment.

SVC measurements will be conducted in clinic at around the same time of day where possible with the subject in sitting upright position. Subjects should make at least 3 attempts to generate acceptable and reproducible SVC data. The highest value was selected and recorded.

Outcome measures

Outcome measures
Measure	Edaravone 105mg (2 Weeks On/Off ) n=117 Participants Oral edaravone 105 mg administered for 14 days, followed by placebo for 14 days in Cycle 1. Subsequently, repeat oral edaravone 105 mg administered for 10 days followed by placebo for 18 days (regimen denoted as On/Off) in Cycles 2 through 12	Edaravone 105 mg (Once Daily) n=116 Participants Oral edaravone 105 mg administered once daily (regimen denoted as Once Daily) in Cycles 1 through 12
Change From Baseline in % Slow Vital Capacity (SVC) at Week 48	-22.15 percentage of SVC Standard Error 2.48	-26.94 percentage of SVC Standard Error 2.45

SECONDARY outcome

Timeframe: up to 48 Weeks

Population: Those patients reached to Week 48 and conducted ALSAQ-40 assessment.

The ALSAQ-40 is a questionnaire that consists of 40 questions/items with 5 discrete scales: physical mobility, activities of daily living and independence, eating and drinking, communication, emotional reactions, ranging from 0 (best health as assessed by the scale) to 100 (worse health as assessed by the measure).

Outcome measures

Outcome measures
Measure	Edaravone 105mg (2 Weeks On/Off ) n=125 Participants Oral edaravone 105 mg administered for 14 days, followed by placebo for 14 days in Cycle 1. Subsequently, repeat oral edaravone 105 mg administered for 10 days followed by placebo for 18 days (regimen denoted as On/Off) in Cycles 2 through 12	Edaravone 105 mg (Once Daily) n=128 Participants Oral edaravone 105 mg administered once daily (regimen denoted as Once Daily) in Cycles 1 through 12
Change From Baseline in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ)40 at Week 48	1.79 Point Standard Error 0.25	2.35 Point Standard Error 0.25

SECONDARY outcome

Timeframe: up to 48 Weeks

Outcome measures

Outcome measures
Measure	Edaravone 105mg (2 Weeks On/Off ) n=192 Participants Oral edaravone 105 mg administered for 14 days, followed by placebo for 14 days in Cycle 1. Subsequently, repeat oral edaravone 105 mg administered for 10 days followed by placebo for 18 days (regimen denoted as On/Off) in Cycles 2 through 12	Edaravone 105 mg (Once Daily) n=192 Participants Oral edaravone 105 mg administered once daily (regimen denoted as Once Daily) in Cycles 1 through 12
Time to Death, Tracheostomy or Permanent Assisted Mechanical Ventilation (≥ 23 Hours/Day)	NA Months The median survival time to death, tracheostomy, or PAMV at 50% survival probability timepoint could not be calculated (K-M analysis) in either group due to the low number of events (Once Daily group: 11 events; On/Off group: 17 events), resulting in 181 and 175 censored observations in respective group.	NA Months The median survival time to death, tracheostomy, or PAMV at 50% survival probability timepoint could not be calculated (K-M analysis) in either group due to the low number of events (Once Daily group: 11 events; On/Off group: 17 events), resulting in 181 and 175 censored observations in respective group.

SECONDARY outcome

Timeframe: up to 48 Weeks

Outcome measures

Outcome measures
Measure	Edaravone 105mg (2 Weeks On/Off ) n=192 Participants Oral edaravone 105 mg administered for 14 days, followed by placebo for 14 days in Cycle 1. Subsequently, repeat oral edaravone 105 mg administered for 10 days followed by placebo for 18 days (regimen denoted as On/Off) in Cycles 2 through 12	Edaravone 105 mg (Once Daily) n=192 Participants Oral edaravone 105 mg administered once daily (regimen denoted as Once Daily) in Cycles 1 through 12
Time to Death or PAMV (≥ 23 Hours/Day)	NA Months The median survival time to death or PAMV at 50% survival probability timepoint could not be calculated (K-M analysis) in either group due to the low number of events (Once Daily group: 10 events; On/Off group: 17 events).	NA Months The median survival time to death or PAMV at 50% survival probability timepoint could not be calculated (K-M analysis) in either group due to the low number of events (Once Daily group: 10 events; On/Off group: 17 events).

SECONDARY outcome

Timeframe: up to 48 Weeks

Outcome measures

Outcome measures
Measure	Edaravone 105mg (2 Weeks On/Off ) n=192 Participants Oral edaravone 105 mg administered for 14 days, followed by placebo for 14 days in Cycle 1. Subsequently, repeat oral edaravone 105 mg administered for 10 days followed by placebo for 18 days (regimen denoted as On/Off) in Cycles 2 through 12	Edaravone 105 mg (Once Daily) n=192 Participants Oral edaravone 105 mg administered once daily (regimen denoted as Once Daily) in Cycles 1 through 12
Time to Death	NA Months The median survival time to death at 50% survival probability timepoint could not be calculated (K-M analysis) in either group due to the low number of events (Once Daily group: 9 events; On/Off group: 16 events).	NA Months The median survival time to death at 50% survival probability timepoint could not be calculated (K-M analysis) in either group due to the low number of events (Once Daily group: 9 events; On/Off group: 16 events).

Adverse Events

Edaravone 105 mg (Once Daily)

Serious events: 52 serious events

Other events: 118 other events

Deaths: 9 deaths

Edaravone 105mg (2 Weeks On/Off )

Serious events: 55 serious events

Other events: 131 other events

Deaths: 16 deaths

Serious adverse events

Other adverse events

Additional Information

Clinical Trials, Information Desk

Tanabe Pharma America, Inc.

Phone: 908-607-1980

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Edaravone 105 mg (Once Daily) n=192 participants at risk Oral edaravone 105 mg administered once daily (regimen denoted as Once Daily) in Cycles 1 through 12	Edaravone 105mg (2 Weeks On/Off ) n=191 participants at risk Oral edaravone 105 mg administered for 14 days, followed by placebo for 14 days in Cycle 1. Subsequently, repeat oral edaravone 105 mg administered for 10 days followed by placebo for 18 days (regimen denoted as On/Off) in Cycles 2 through 12
Cardiac disorders Cardiac arrest	0.52% 1/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	1.0% 2/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Congenital, familial and genetic disorders Benign familial pemphigus	0.52% 1/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.00% 0/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Gastrointestinal disorders Dysphagia	8.3% 16/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	7.9% 15/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Gastrointestinal disorders Salivary hypersecretion	0.52% 1/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.00% 0/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Gastrointestinal disorders Vomiting	0.52% 1/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.00% 0/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
General disorders Death	1.0% 2/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.52% 1/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
General disorders Sudden death	0.00% 0/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.52% 1/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Infections and infestations Abdominal wall abscess	0.52% 1/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.00% 0/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Infections and infestations COVID-19	2.1% 4/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	2.1% 4/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Infections and infestations COVID-19 pneumonia	0.52% 1/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.52% 1/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Infections and infestations Coronavirus infection	0.52% 1/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.00% 0/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Infections and infestations Pneumonia	1.0% 2/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.52% 1/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Infections and infestations Urinary tract infection	0.52% 1/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.52% 1/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Injury, poisoning and procedural complications Ankle fracture	0.52% 1/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.00% 0/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Injury, poisoning and procedural complications Clavicle fracture	0.52% 1/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.00% 0/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Injury, poisoning and procedural complications Facial bones fracture	0.52% 1/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.00% 0/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Injury, poisoning and procedural complications Fall	0.52% 1/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.52% 1/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Injury, poisoning and procedural complications Foot fracture	0.52% 1/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.00% 0/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Injury, poisoning and procedural complications Hip fracture	0.52% 1/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.00% 0/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Injury, poisoning and procedural complications Ligament injury	0.52% 1/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.00% 0/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Injury, poisoning and procedural complications Procedural pain	0.52% 1/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.00% 0/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Injury, poisoning and procedural complications Rib fracture	0.52% 1/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.00% 0/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Injury, poisoning and procedural complications Subdural haematoma	0.00% 0/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.52% 1/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Injury, poisoning and procedural complications Upper limb fracture	0.00% 0/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.52% 1/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Investigations Pulmonary function test decreased	0.00% 0/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.52% 1/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Investigations Swallow study	0.00% 0/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.52% 1/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Investigations Vital capacity decreased	0.52% 1/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.00% 0/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Investigations Weight decreased	0.52% 1/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.52% 1/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Metabolism and nutrition disorders Decreased appetite	0.00% 0/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.52% 1/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Musculoskeletal and connective tissue disorders Back pain	0.52% 1/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.00% 0/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Musculoskeletal and connective tissue disorders Muscular weakness	0.00% 0/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.52% 1/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Musculoskeletal and connective tissue disorders Musculoskeletal stiffness	0.52% 1/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.00% 0/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.00% 0/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.52% 1/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colorectal cancer	0.00% 0/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.52% 1/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Nervous system disorders Amyotrophic lateral sclerosis	0.52% 1/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	2.6% 5/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Nervous system disorders Syncope	0.52% 1/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	1.0% 2/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Product Issues Embedded device	0.52% 1/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.00% 0/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Psychiatric disorders Delirium	0.52% 1/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.00% 0/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Psychiatric disorders Suicide attempt	0.00% 0/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.52% 1/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Respiratory, thoracic and mediastinal disorders Apnoea	0.00% 0/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	0.52% 1/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.

Other adverse events
Measure	Edaravone 105 mg (Once Daily) n=192 participants at risk Oral edaravone 105 mg administered once daily (regimen denoted as Once Daily) in Cycles 1 through 12	Edaravone 105mg (2 Weeks On/Off ) n=191 participants at risk Oral edaravone 105 mg administered for 14 days, followed by placebo for 14 days in Cycle 1. Subsequently, repeat oral edaravone 105 mg administered for 10 days followed by placebo for 18 days (regimen denoted as On/Off) in Cycles 2 through 12
Gastrointestinal disorders Constipation	12.5% 24/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	14.1% 27/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Gastrointestinal disorders Diarrhoea	10.4% 20/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	7.3% 14/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Gastrointestinal disorders Dysphagia	5.7% 11/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	6.3% 12/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
General disorders Fatigue	6.2% 12/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	5.2% 10/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
General disorders Oedema peripheral	5.2% 10/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	4.7% 9/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Infections and infestations COVID-19	12.5% 24/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	13.6% 26/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Infections and infestations Nasopharyngitis	5.7% 11/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	4.2% 8/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Injury, poisoning and procedural complications Contusion	8.9% 17/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	7.3% 14/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Injury, poisoning and procedural complications Fall	18.8% 36/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	17.8% 34/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Musculoskeletal and connective tissue disorders Back pain	4.2% 8/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	10.5% 20/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Musculoskeletal and connective tissue disorders Muscle spasms	1.6% 3/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	5.2% 10/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Musculoskeletal and connective tissue disorders Muscular weakness	7.8% 15/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	6.8% 13/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	5.2% 10/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	4.7% 9/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Musculoskeletal and connective tissue disorders Pain in extremity	2.1% 4/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	5.2% 10/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Nervous system disorders Headache	7.8% 15/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	4.7% 9/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Psychiatric disorders Depression	4.7% 9/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	5.2% 10/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Psychiatric disorders Insomnia	5.7% 11/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	7.3% 14/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Respiratory, thoracic and mediastinal disorders Cough	7.8% 15/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	5.8% 11/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Skin and subcutaneous tissue disorders Pruritus	5.7% 11/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	4.2% 8/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.
Skin and subcutaneous tissue disorders Rash	6.8% 13/192 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.	2.1% 4/191 • Up to 3 years The safety analysis set (SAF) is defined as all randomized subjects who received at least 1 dose of study medication. One subject randomized to the on/off treatment group was excluded from the arm because the subject did not receive any study treatment. Therefore, serious, and other AE were analyzed by SAF which is 2weeks on/off Group: 191, whereas the number at Risk for All-Cause Mortality is Randomized set which is 2weeks on/off Group: 192, considering the definition of ClinicalTrials.gov.