Trial Outcomes & Findings for Safety and Efficacy of Oral Fampridine-Sustained Release (SR) for the Treatment of Spasticity Resulting From Spinal Cord Injury (NCT NCT01683838)

Last Updated: 2017-08-25

Results Overview

The Ashworth evaluates the functioning of two lower extremity muscle groups, the hamstring and quadriceps muscles, while in the supine position. The test measures extension of the right and left hamstring muscle and flexion of the right and left quadriceps muscle using the following 5-point grading scale: 1=no increased tone; 2=slight increase in tone, giving a "catch" when the affected part is moved in flexion or extension; 3=more marked increase in tone, but affected part is easily flexed; 4=considerable increase in tone, passive movement is difficult; 5=affected part is rigid in flexion and extension. The Ashworth Score was determined by adding all individual scores for each muscle group and dividing by four. Higher Ashworth Scores indicated greater spasticity.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

204 participants

Primary outcome timeframe

Baseline (visits 2,3) average score days 7,14 and double-blind treatment period (visits 4-7) average score days 28-98

Results posted on

2017-08-25

Participant Flow

The randomization schedule was created prior to the start of the study, and was blocked and stratified by site and by concomitant anti-spasmodic medication status to ensure treatment balance between patients who were treated with anti-spasmodic medications upon entry into the study and those who were not.

Investigational drug assignments were communicated through an Interactive Voice Response System (IVRS).

Participant milestones

Participant milestones
Measure	Fampridine-SR 50mg/Day Fampridine-SR : 25mg bid (twice daily)	Placebo Placebo : Placebo
Overall Study STARTED	104	100
Overall Study Intent to Treat (ITT) Population	103	100
Overall Study Safety Population	103	100
Overall Study Efficacy Population	89	93
Overall Study COMPLETED	78	88
Overall Study NOT COMPLETED	26	12

Reasons for withdrawal

Reasons for withdrawal
Measure	Fampridine-SR 50mg/Day Fampridine-SR : 25mg bid (twice daily)	Placebo Placebo : Placebo
Overall Study Adverse Event	12	2
Overall Study Protocol Violation	3	1
Overall Study Withdrawal by Subject	6	5
Overall Study Lost to Follow-up	1	1
Overall Study Other	4	3

Baseline Characteristics

Safety and Efficacy of Oral Fampridine-Sustained Release (SR) for the Treatment of Spasticity Resulting From Spinal Cord Injury

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Fampridine-SR 50mg/Day n=103 Participants Fampridine-SR : 25mg bid (twice daily)	Placebo n=100 Participants Placebo : Placebo	Total n=203 Participants Total of all reporting groups
Age, Continuous	41.3 Years STANDARD_DEVIATION 11.79 • n=5 Participants	40.5 Years STANDARD_DEVIATION 12.25 • n=7 Participants	40.9 Years STANDARD_DEVIATION 12.00 • n=5 Participants
Sex: Female, Male Female	17 Participants n=5 Participants	14 Participants n=7 Participants	31 Participants n=5 Participants
Sex: Female, Male Male	86 Participants n=5 Participants	86 Participants n=7 Participants	172 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	92 participants n=5 Participants	87 participants n=7 Participants	179 participants n=5 Participants
Race/Ethnicity, Customized Black or African American	8 participants n=5 Participants	10 participants n=7 Participants	18 participants n=5 Participants
Race/Ethnicity, Customized Asian/Pacific Islander	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Race/Ethnicity, Customized Other	2 participants n=5 Participants	3 participants n=7 Participants	5 participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline (visits 2,3) average score days 7,14 and double-blind treatment period (visits 4-7) average score days 28-98

Population: Intent to Treat (ITT) Population. Number of participants analyzed is number of patients with available data at both baseline and double-blind treatment period.

Outcome measures

Outcome measures
Measure	Fampridine-SR 50mg/Day n=102 Participants Fampridine-SR : 25mg bid (twice daily)	Placebo n=98 Participants Placebo : Placebo
Double-blind Change From Baseline in Ashworth Score Evaluating Spasticity	-0.28 units on a scale Standard Error 0.046	-0.16 units on a scale Standard Error 0.047

PRIMARY outcome

Timeframe: Baseline (visits 2,3) average score days 7,14 and double-blind treatment period (visits 4-7) average score days 28-98

Population: ITT population. Number of participants analyzed is number of patients with available data at both baseline and double-blind treatment period.

The SGI is a 7-unit ordinal scale used by the subject to evaluate the effects of study medication on his/her quality of life during the preceding week, with higher scores denoting greater satisfaction. A positive change score in SGI signifies improved outcome. The questionnaire consisted of one question (How do you feel about the effects of the investigational drug over the past 7 days?). The answer was based on a numerical rating scale where 1=terrible; 2=unhappy; 3=mostly dissatisfied; 4=neutral/mixed; 5=mostly satisfied; 6=pleased; 7=delighted.

Outcome measures

Outcome measures
Measure	Fampridine-SR 50mg/Day n=102 Participants Fampridine-SR : 25mg bid (twice daily)	Placebo n=98 Participants Placebo : Placebo
Double-blind Change From Baseline in Mean Subject's Global Impression (SGI) Scores	-0.0 units on a scale Standard Error 0.07	0.1 units on a scale Standard Error 0.08

SECONDARY outcome

Timeframe: Baseline (visits 2,3) average score days 7,14 and double-blind treatment period (visits 4-7) average score days 28-98

Population: ITT Population. Number of participants analyzed is number of patients with available data at both baseline and double-blind treatment period.

The Spasm Frequency score is the average rating by the clinician of the left and right arm(s) and leg(s), each evaluated on a 4-point scale (from 0=no spasms to 4=spontaneous spasms occurring more than ten times per hour), with higher scores denoting a greater degree of muscle spasms. The Spasm Severity score is the average rating of the left and right arm(s) and leg(s), each evaluated on a three-point scale (mild, moderate, or severe) as rated by the clinician on the basis of patient self-report. On both, a negative change in score signifies improvement in muscle spasms. The average Spasm Frequency/Spasm Severity Score was calculated as the average of the left and right non-missing scores.

Outcome measures

Outcome measures
Measure	Fampridine-SR 50mg/Day n=102 Participants Fampridine-SR : 25mg bid (twice daily)	Placebo n=98 Participants Placebo : Placebo
Double-blind Change From Baseline in Mean Spasm Frequency/Severity Scores Arm Spasm Frequency	-0.13 units on a scale Standard Error 0.051	0.02 units on a scale Standard Error 0.053
Double-blind Change From Baseline in Mean Spasm Frequency/Severity Scores Leg Spasm Frequency	-0.12 units on a scale Standard Error 0.051	-0.10 units on a scale Standard Error 0.052
Double-blind Change From Baseline in Mean Spasm Frequency/Severity Scores Arm Spasm Severity	-0.09 units on a scale Standard Error 0.034	-0.02 units on a scale Standard Error 0.035
Double-blind Change From Baseline in Mean Spasm Frequency/Severity Scores Leg Spasm Severity	-0.14 units on a scale Standard Error 0.040	-0.07 units on a scale Standard Error 0.041

SECONDARY outcome

Timeframe: Baseline (visits 2,3) average of days 7-14 and double-blind treatment period (visits 4-7) average of days 28-98)

Population: ITT Population. Number of participants analyzed is number of patients with available data at both baseline and double-blind treatment period.

The supervising clinician rated the patient's neurological condition following treatment as compared to the screening visit on a seven-point scale (from 1=very much improved to 7=very much worse). The assessment was based on the clinician's overall impression of the patient's neurological status (specifically bowel, bladder, and sexual function; spasticity; and other neurological functions) and general state of health related to his or her participation in the study. Negative change scores indicated a change for the better.

Outcome measures

Outcome measures
Measure	Fampridine-SR 50mg/Day n=102 Participants Fampridine-SR : 25mg bid (twice daily)	Placebo n=98 Participants Placebo : Placebo
Double-blind Change From Baseline in Mean Clinician's Global Impression (CGI) Scores	-0.2 units on a scale Standard Error 0.06	-0.2 units on a scale Standard Error 0.06

SECONDARY outcome

Timeframe: Baseline (visits 2,3) average score days 7,14 and stable-dose treatment period (visits 5-7) average score days 56-98

Population: ITT Population. Number of participants analyzed is number of patients with available data at both baseline and stable-blind treatment period.

Ten key muscle groups for the right and left sides were rated on a 0 (absent) to 5 (normal) scale, with a possible total score of 100. Higher positive change scores indicate improved motor function.

Outcome measures

Outcome measures
Measure	Fampridine-SR 50mg/Day n=87 Participants Fampridine-SR : 25mg bid (twice daily)	Placebo n=92 Participants Placebo : Placebo
Stable-dose Change From Baseline in Mean American Spinal Injury Association(ASIA) Total Motor Score	0.4 units on a scale Standard Error 0.51	0.7 units on a scale Standard Error 0.49

SECONDARY outcome

Timeframe: Baseline (visit 1) average score obtained at day 1 and stable treatment period (visit 7) average score day 98

Population: ITT Population. N = number of participants analyzed with available data at both baseline and stable treatment period.

Male patients were asked to complete the IIEF questionnaire on sexual function. The IIEF is a brief, reliable, and valid self-administered questionnaire of 15 questions (items) that were categorized into five domains: Erectile Function (EF) scores: 0-6 Severe dysfunction, 7-12 Moderate dysfunction, 13-18 Mild to moderate dysfunction, 19-24 Mild dysfunction, 25-30 No dysfunction. Orgasmic Function (OF) score range: 0-2 Severe dysfunction to 9-10 No dysfunction, Sexual Desire (SD) score range: 0-2 Severe dysfunction to 9-10 No dysfunction, Intercourse Satisfaction (IS) score range: 0-3 Severe dysfunction to 13-15 No dysfunction, and Overall Satisfaction (OS) score range: 0-2 Severe dysfunction to 9-10 No dysfunction. Domain scores were derived by summing the individual items within a given domain. Final scale ranges from 0 (negative) to 5 (positive). A positive change in IIEF domain scores signifies improvement.

Outcome measures

Outcome measures
Measure	Fampridine-SR 50mg/Day n=65 Participants Fampridine-SR : 25mg bid (twice daily)	Placebo n=77 Participants Placebo : Placebo
Change From Baseline in Mean International Index of Erectile Function (IIEF) Score EF (Fampridine-SR Number (N) =65, Placebo N=77)	0.8 units on a scale Standard Error 1.09	1.6 units on a scale Standard Error 1.01
Change From Baseline in Mean International Index of Erectile Function (IIEF) Score OF (Fampridine-SR N=64, Placebo N=76)	0.3 units on a scale Standard Error 0.36	0.0 units on a scale Standard Error 0.33
Change From Baseline in Mean International Index of Erectile Function (IIEF) Score SD (Fampridine-SR N=64, Placebo N=75)	-0.0 units on a scale Standard Error 0.23	0.0 units on a scale Standard Error 0.21
Change From Baseline in Mean International Index of Erectile Function (IIEF) Score IS (Fampridine-SR N=64, N=76)	0.4 units on a scale Standard Error 0.55	0.4 units on a scale Standard Error 0.50
Change From Baseline in Mean International Index of Erectile Function (IIEF) Score OS (Fampridine-SR N=51, Placebo N=66)	0.4 units on a scale Standard Error 0.27	0.3 units on a scale Standard Error 0.24

SECONDARY outcome

Timeframe: Baseline (visit 1) average score obtained at day 1 and stable treatment period (visits 4-7) average score days 28-98

The FSFI is a brief, reliable, and valid self-administered questionnaire of 19 questions (items). It contains six domains: Desire (2 items score range: 1 Very low or none at all to 5 Very high), Arousal (4 items score range: 0 No sexual activity to 5 Almost always or always), Lubrication (4 items score range: 0 No sexual activity to 5 Almost always or always), Orgasm (3 items score range: 0 No sexual activity to 5 Almost always or always), Satisfaction (3 items score range: 0 No sexual activity to 5 Very satisfied) and Pain (3 items score range: 0 Did not attempt intercourse to 5 Almost never or never). A positive change signifies improvement.

Outcome measures

Outcome measures
Measure	Fampridine-SR 50mg/Day n=14 Participants Fampridine-SR : 25mg bid (twice daily)	Placebo n=13 Participants Placebo : Placebo
Change From Baseline in Mean Female Sexual Function Index (FSFI) Scores Desire	0.7 units on a scale Standard Error 0.26	0.2 units on a scale Standard Error 0.28
Change From Baseline in Mean Female Sexual Function Index (FSFI) Scores Arousal	0.6 units on a scale Standard Error 0.37	0.2 units on a scale Standard Error 0.40
Change From Baseline in Mean Female Sexual Function Index (FSFI) Scores Lubrication	0.7 units on a scale Standard Error 0.45	-0.2 units on a scale Standard Error 0.48
Change From Baseline in Mean Female Sexual Function Index (FSFI) Scores Orgasm	0.2 units on a scale Standard Error 0.18	0.4 units on a scale Standard Error 0.19
Change From Baseline in Mean Female Sexual Function Index (FSFI) Scores Satisfaction (Fampridine-SR N=13, Placebo N=12)	0.4 units on a scale Standard Error 0.25	0.3 units on a scale Standard Error 0.26
Change From Baseline in Mean Female Sexual Function Index (FSFI) Scores Pain	0.7 units on a scale Standard Error 0.47	-0.1 units on a scale Standard Error 0.50

SECONDARY outcome

Timeframe: Baseline (visit 1) average score obtained at day 1 and double-blind treatment period (visits 4-7) average score days 28-98

Population: ITT Population. Number of participants analyzed is number of patients with available data at both baseline and double-blind treatment period.

Bowel/bladder questions pertaining to the average number of times per day the patient experienced accidental urination/leakage and the average number of bowel movements per day were asked of all patients daily. A negative change in patient bladder/bowel function diary score signifies improvement.

Outcome measures

Outcome measures
Measure	Fampridine-SR 50mg/Day n=103 Participants Fampridine-SR : 25mg bid (twice daily)	Placebo n=99 Participants Placebo : Placebo
Adjusted Mean Change in Subject Bladder/Bowel Function Diary Scores Number of Accidental Urination or Leakage	-0.2 episodes Standard Error 0.20	-0.2 episodes Standard Error 0.21
Adjusted Mean Change in Subject Bladder/Bowel Function Diary Scores Number of Bowel Movements	0.1 episodes Standard Error 0.03	-0.0 episodes Standard Error 0.03

SECONDARY outcome

Timeframe: Baseline (visit 1) average score obtained at day 1 and double-blind treatment period (visits 4-7) average score days 28-98

Population: ITT Population. Number of participants analyzed is number of patients with available data at both baseline and double-blind treatment period.

Bowel questions pertaining to the average number of minutes per day spent on bowel routine were asked of all patients daily. A negative change in patient bowel function diary score signifies improvement.

Outcome measures

Outcome measures
Measure	Fampridine-SR 50mg/Day n=103 Participants Fampridine-SR : 25mg bid (twice daily)	Placebo n=99 Participants Placebo : Placebo
Adjusted Mean Change in Subject Bowel Function Diary Scores	-0.7 minutes Standard Error 0.90	0.3 minutes Standard Error 0.93

Adverse Events

Fampridine-SR 50mg/Day

Serious events: 8 serious events

Other events: 24 other events

Deaths: 0 deaths

Placebo

Serious events: 9 serious events

Other events: 17 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Chief Scientific Officer

Acorda Therapeutics, Inc.

Phone: 914-347-4300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Sponsor (Acorda) has right to review and comment on proposed publications within a specified time frame, up to 60 days; multi-center trials require joint publication unless specifically permitted otherwise.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Fampridine-SR 50mg/Day n=103 participants at risk Fampridine-SR : 25mg bid (twice daily)	Placebo n=100 participants at risk Placebo : Placebo
Injury, poisoning and procedural complications Accidental Injury	0.00% 0/103 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.	1.0% 1/100 • Number of events 2 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.
Infections and infestations Cellulitis	0.97% 1/103 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.	1.0% 1/100 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.
Nervous system disorders Headache	0.97% 1/103 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.	0.00% 0/100 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.
Infections and infestations Hypothermia	0.97% 1/103 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.	0.00% 0/100 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.
Psychiatric disorders Overdose	0.00% 0/103 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.	1.0% 1/100 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.
Blood and lymphatic system disorders Sepsis	0.00% 0/103 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.	1.0% 1/100 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.
Cardiac disorders Atrial Fibrillation	0.97% 1/103 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.	0.00% 0/100 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.
Cardiac disorders Bradycardia	0.97% 1/103 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.	0.00% 0/100 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.
Cardiac disorders Coronary Artery Disorder	0.00% 0/103 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.	1.0% 1/100 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.
Vascular disorders Hemorrhage	0.97% 1/103 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.	0.00% 0/100 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.
Vascular disorders Hypertension	0.00% 0/103 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.	1.0% 1/100 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.
Cardiac disorders Myocardial Infarct	0.97% 1/103 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.	0.00% 0/100 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.
Gastrointestinal disorders Intestinal Obstruction	0.97% 1/103 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.	0.00% 0/100 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.
Musculoskeletal and connective tissue disorders Pathological Fracture	0.97% 1/103 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.	1.0% 1/100 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.
Musculoskeletal and connective tissue disorders Tendon Disorder	0.00% 0/103 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.	1.0% 1/100 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.
Nervous system disorders Dysautonomia	0.97% 1/103 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.	3.0% 3/100 • Number of events 3 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.
Nervous system disorders Neuropathy	0.00% 0/103 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.	1.0% 1/100 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.
Nervous system disorders Paresthesia	0.00% 0/103 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.	1.0% 1/100 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.
Nervous system disorders Somnolence	0.97% 1/103 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.	0.00% 0/100 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.
Nervous system disorders Speech Disorder	0.97% 1/103 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.	0.00% 0/100 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.
Respiratory, thoracic and mediastinal disorders Bronchitis	0.00% 0/103 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.	1.0% 1/100 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.
Infections and infestations Pneumonia	0.97% 1/103 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.	0.00% 0/100 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.
Skin and subcutaneous tissue disorders Skin Ulcer	0.97% 1/103 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.	0.00% 0/100 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.
Eye disorders Amblyopia	0.00% 0/103 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.	1.0% 1/100 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.
Infections and infestations Urinary Tract Infection	0.97% 1/103 • Number of events 1 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.	0.00% 0/100 • Treatment-emergent adverse events (TEAE) include AEs with date of onset (or worsening) on or after the start of treatment and no more than 14 days after the last dose of investigational drug. Adverse events were recorded at every study visit. Results are presented for the Safety population defined as all randomized patients who received at least one dose of study treatment.