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Clinical Trial Results:
A Phase 3, Multi-National, Double-Blind, Randomized, Placebo-Controlled, Stratified, Parallel Group, Study to Evaluate the Safety, Tolerability and Efficacy of Tirasemtiv in Patients with Amyotrophic Lateral Sclerosis (ALS)

Summary
EudraCT number	2014-005413-23
Trial protocol	DE GB IE NL ES PT BE IT
Global end of trial date	27 Sep 2017

Results information
Results version number	v1(current)
This version publication date	12 Oct 2018
First version publication date	12 Oct 2018
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

CY4031

ISRCTN number

US NCT number

NCT02496767

WHO universal trial number (UTN)

Sponsor organisation name

Cytokinetics, Inc.

Sponsor organisation address

280 East Grand Avenue, South San Francisco, United States, CA 94080

Public contact

Medical Affairs, Cytokinetics, Inc., +1 650 624 2929, medicalaffairs@cytokinetics.com

Scientific contact

Medical Affairs, Cytokinetics, Inc., +1 650 624 2929, medicalaffairs@cytokinetics.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

27 Sep 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

27 Sep 2017

Global end of trial reached?

Yes

Global end of trial date

27 Sep 2017

Was the trial ended prematurely?

Main objective of the trial

The primary objective is to assess the effect of tirasemtiv versus placebo on respiratory function in patients with Amyotrophic Lateral Sclerosis (ALS).

Protection of trial subjects

The study was conducted in accordance with International Council on Harmonisation (ICH) guidelines and local regulations in the applicable regions in which the study was conducted. Both the US regulations and the ICH guidelines are commonly known good clinical practices (GCP) and are consistent with the Declaration of Helsinki, 1996. Written informed consent was obtained with an IRB/EC/REB-approved ICF. A master ICF was developed by the sponsor; customized for each country by Parexel; further customized for the study center by the investigator (or designee); then approved by the sponsor. The ICF was then submitted by the investigator (or designee) to the IRB/EC/REB for approval. A copy of the IRB/EC/REB approved site-specific ICF was sent to the sponsor (or designee).

Background therapy

Evidence for comparator

Actual start date of recruitment

03 Sep 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 424

Country: Number of subjects enrolled

Canada: 141

Country: Number of subjects enrolled

Netherlands: 10

Country: Number of subjects enrolled

Belgium: 15

Country: Number of subjects enrolled

France: 27

Country: Number of subjects enrolled

United Kingdom: 7

Country: Number of subjects enrolled

Germany: 34

Country: Number of subjects enrolled

Ireland: 15

Country: Number of subjects enrolled

Spain: 32

Country: Number of subjects enrolled

Italy: 35

Country: Number of subjects enrolled

Portugal: 4

Worldwide total number of subjects

744

EEA total number of subjects

179

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

541

From 65 to 84 years

202

85 years and over

Subject disposition

Top of page

Recruitment details

Participants who met all the inclusion and none of the exclusion criteria were enrolled at 79 sites in Belgium, Canada, France, Germany, Ireland, Italy, Netherlands, Portugal, Spain, the United Kingdom (UK), and the United States (US).

Screening details

Participants attended a Screening Visit before receiving their first dose of tirasemtiv. All subjects underwent inclusion exclusion criteria assessment and all eligible subjects signed the informed consent before undergoing any study-related procedures.

Period 1 title

Open-Label Phase

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Overall

Arm description

Arm type

Experimental

Investigational medicinal product name

Tirasemtiv

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

During the open-label phase of the study, all patients received one tirasemtiv tablet (125 mg) twice daily for 14 days.

Number of subjects in period 1	Overall
Started	744
Completed	565
Not completed	179
Consent withdrawn by subject	1
Adverse Event	176
Protocol deviation	2

Period 2 title

Double-Blind, Placebo-Controlled Phase

Is this the baseline period?

Yes ^[1]

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Placebo

Arm description

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

The patients randomized to the placebo group, received two tablets twice daily from Day 1 to end of Week 48. The matching placebo tablets contained excipients only.

250 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

Tirasemtiv

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

The patients received one tirasemtiv tablet (125 mg) and one placebo tablet twice daily from Day 1 through Week 48.

375 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

Tirasemtiv

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

The patients received one tirasemtiv tablet (125 mg) and one placebo tablet twice daily from Day 1 through Week 2. The target dose was escalated to 375 mg (one tirasemtiv tablet [125 mg] in the morning along with matching placebo and two tirasemtiv tables [250 mg] in the evening) from Week 3 through Week 48.

500 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

Tirasemtiv

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

The patients received one tirasemtiv tablet (125 mg) and one placebo tablet twice daily from Day 1 through Week 2. The target dose was escalated to 375 mg [One tirasemtiv tablet (125 mg) in morning along with matching placebo and two tirasemtiv tablets (250 mg) in evening] on Weeks 3 and 4. The target dose was further escalated to 500 mg [Two tirasemtiv (250 mg) tablets in morning and two tirasemtiv tablets (250 mg) in evening] from Week 5 through Week 48.

All (Tirasemtiv)

Arm description

Arm type

Experimental

Investigational medicinal product name

Tirasemtiv

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

This group includes all patients randomized to one of the 3 tirasemtiv dose groups (250 mg/day, 375 mg/day, or 500 mg/day). The patients received tirasemtiv from Week 1 through Week 48 in the double-blind, placebo-controlled phase.

Notes
[1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
Justification: Period 1 is not the baseline period as it corresponds to the open-label, lead-in phase of the study. In order to capture the baseline characteristics for placebo and treatment groups (Tirasemtiv 250mg, 375mg and 500mg), period 2 (Double-Blind, Placebo-Controlled Phase) is selected as the baseline period.

Number of subjects in period 2	Placebo	250 mg	375 mg	500 mg	All (Tirasemtiv)
Started	188	126	126	125	377
Completed	132	80	65	59	204
Not completed	56	46	61	66	173
Consent withdrawn by subject	4	3	1	2	6
Physician decision	4	1	-	-	1
Adverse Event	13	23	43	43	109
Death	10	6	2	4	12
Other	9	4	5	2	11
Progressive disease	13	9	8	14	31
Lost to follow-up	2	-	2	1	3
Protocol deviation	1	-	-	-	-

Period 3 title

Withdrawal Phase

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Placebo

Arm description

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

The patients were maintained on placebo dose given during the double-blind, placebo-controlled phase from Week 49 through Week 52.

Tirasemtiv/Placebo

Arm description

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

The patients were withdrawn from the Tirasemtiv group and were given placebo from Week 49 through Week 52.

Tirasemtiv/Tirasemtiv

Arm description

Arm type

Experimental

Investigational medicinal product name

Tirasemtiv

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

The patients were maintained on tirasemtiv dose given during the double-blind, placebo-controlled phase from Week 49 through Week 52.

Number of subjects in period 3	Placebo	Tirasemtiv/Placebo	Tirasemtiv/Tirasemtiv
Started	132	103	101
Completed	126	99	96
Not completed	6	4	5
Consent withdrawn by subject	1	1	1
Adverse Event	1	2	1
Death	-	1	2
Progressive disease	4	-	1

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Reporting group title

250 mg

Reporting group description

Reporting group title

375 mg

Reporting group description

Reporting group title

500 mg

Reporting group description

Reporting group title

All (Tirasemtiv)

Reporting group description

Reporting group values	Placebo	250 mg	375 mg	500 mg	All (Tirasemtiv)	Total
Number of subjects	188	126	126	125	377
Age categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age continuous
Units: years
arithmetic mean (standard deviation)	55.9 ( 10.63 )	57.1 ( 10.20 )	57.3 ( 9.06 )	56.4 ( 10.94 )	56.9 ( 10.08 )	-
Gender categorical
Units: Subjects
Female	65	30	42	38	110	175
Male	123	96	84	87	267	390

End points

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Reporting group title

Overall

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group title

250 mg

Reporting group description

Reporting group title

375 mg

Reporting group description

Reporting group title

500 mg

Reporting group description

Reporting group title

All (Tirasemtiv)

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group title

Tirasemtiv/Placebo

Reporting group description

Reporting group title

Tirasemtiv/Tirasemtiv

Reporting group description

Primary: Change in percent predicted slow vital capacity (SVC) from baseline to week 24

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End point title

Change in percent predicted slow vital capacity (SVC) from baseline to week 24

End point description

Respiratory assessments consisted of SVC. SVC was measured with a spirometer. Patients were instructed to take 3 to 5 regular breaths, followed by as deep an inspiration as possible, followed by a slow and steady exhalation of as much air volume as possible. Patients were to perform at least 3 SVC tests at each designated visit. Up to 2 additional SVC tests could have been performed if the variability during the first 3 tests was >10%

End point type

Primary

End point timeframe

Day 1 through Week 24

End point values	Placebo	250 mg	375 mg	500 mg	All (Tirasemtiv)
Number of subjects analysed	188	126	125	122	373
Units: Percentage (%)
least squares mean (standard error)	-14.354 ( 1.2270 )	-12.648 ( 1.5165 )	-13.742 ( 1.6076 )	-13.927 ( 1.7213 )	-13.439 ( 0.9615 )

Tirasemtiv 250mg vs. Placebo

Comparison groups

Placebo v 250 mg

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3782 ^[1]

Method

Multiple imputation, mixed model ANCOVA

Parameter type

LS mean difference vs.placebo

Point estimate

1.707

Confidence interval

level

95%

sides

2-sided

lower limit

-2.089

upper limit

5.503

Variability estimate

Standard error of the mean

Dispersion value

1.9365

Notes
[1] - Missing data were imputed using multiple imputation

Tirasemtiv 375mg vs. Placebo

Comparison groups

Placebo v 375 mg

Number of subjects included in analysis

313

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7625 ^[2]

Method

Multiple imputation, mixed model ANCOVA

Parameter type

LS mean difference vs.placebo

Point estimate

0.612

Confidence interval

level

95%

sides

2-sided

lower limit

-3.359

upper limit

4.583

Variability estimate

Standard error of the mean

Dispersion value

2.0245

Notes
[2] - Missing data were imputed using multiple imputation

Tirasemtiv 500mg vs. Placebo

Comparison groups

Placebo v 500 mg

Number of subjects included in analysis

310

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8394 ^[3]

Method

Multiple imputation, mixed model ANCOVA

Parameter type

LS mean difference vs.placebo

Point estimate

0.428

Confidence interval

level

95%

sides

2-sided

lower limit

-3.711

upper limit

4.566

Variability estimate

Standard error of the mean

Dispersion value

2.1081

Notes
[3] - Missing data were imputed using multiple imputation

All (Tirasemtiv) vs. Placebo

Comparison groups

Placebo v All (Tirasemtiv)

Number of subjects included in analysis

561

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5552 ^[4]

Method

Multiple imputation, mixed model ANCOVA

Parameter type

LS mean difference vs.placebo

Point estimate

0.915

Confidence interval

level

95%

sides

2-sided

lower limit

-2.127

upper limit

3.958

Variability estimate

Standard error of the mean

Dispersion value

1.5513

Notes
[4] - Missing data were imputed using multiple imputation

Secondary: Change in ALS Functional Rating Scale-Revised (ALSFRS-R) respiratory domain score from baseline to Week 48

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End point title

Change in ALS Functional Rating Scale-Revised (ALSFRS-R) respiratory domain score from baseline to Week 48

End point description

The ALSFRS-R consists of 12 questions, assessing a patient’s capability and independence in functional activities relevant to ALS, categorized in 4 domains: gross motor tasks, fine motor tasks, bulbar functions, and respiratory function. Each question was scored on a scale from 0 (indicating incapable or dependent) to 4 (normal).

End point type

Secondary

End point timeframe

Week 1 through Week 48

End point values	Placebo	250 mg	375 mg	500 mg	All (Tirasemtiv)
Number of subjects analysed	188	126	125	122	373
Units: Units on scale
least squares mean (standard error)	-2.26 ( 0.258 )	-1.95 ( 0.320 )	-2.41 ( 0.340 )	-2.59 ( 0.355 )	-2.29 ( 0.195 )

Tirasemtiv 250mg vs. Placebo

Comparison groups

Placebo v 250 mg

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4521

Method

Repeated measures mixed model

Parameter type

LS mean difference vs.placebo

Point estimate

0.31

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

1.12

Variability estimate

Standard error of the mean

Dispersion value

0.41

Tirasemtiv 375mg vs. Placebo

Comparison groups

Placebo v 375 mg

Number of subjects included in analysis

313

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.712

Method

Repeated measures mixed model

Parameter type

LS mean difference vs.placebo

Point estimate

-0.16

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

0.68

Variability estimate

Standard error of the mean

Dispersion value

0.426

Tirasemtiv 500mg vs. Placebo

Comparison groups

Placebo v 375 mg

Number of subjects included in analysis

313

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.451

Method

Repeated measures mixed model

Parameter type

LS mean difference vs.placebo

Point estimate

-0.33

Confidence interval

level

95%

sides

2-sided

lower limit

-1.19

upper limit

0.53

Variability estimate

Standard error of the mean

Dispersion value

0.439

All (Tirasemtiv) vs. Placebo

Comparison groups

Placebo v All (Tirasemtiv)

Number of subjects included in analysis

561

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.916

Method

Repeated measures mixed model

Parameter type

LS mean difference vs.placebo

Point estimate

-0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.67

upper limit

0.6

Variability estimate

Standard error of the mean

Dispersion value

0.323

Secondary: Slope of mega-score of muscle strength over 48 Weeks

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End point title

Slope of mega-score of muscle strength over 48 Weeks

End point description

Muscle strength as determined by the mega-score of: • Elbow flexion (bilateral) • Wrist extension (bilateral) • Knee extension (bilateral) • Ankle dorsiflexion (bilateral) • Handgrip strength (bilateral)

End point type

Secondary

End point timeframe

Week 1 through Week 48

End point values	Placebo	250 mg	375 mg	500 mg	All (Tirasemtiv)
Number of subjects analysed	188	126	125	122	373
Units: Slope
number (confidence interval 95%)	-0.1501 (-0.1729 to -0.1272)	-0.1512 (-0.1794 to -0.1230)	-0.1434 (-0.1742 to -0.1126)	-0.1413 (-0.1730 to -0.1095)	-0.1454 (-0.1628 to -0.1279)

Difference in slope Tirasemtiv 250mg vs. placebo

Comparison groups

Placebo v 250 mg

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9505

Method

Repeated measures mixed model

Parameter type

Slope

Point estimate

-0.0011

Confidence interval

level

95%

sides

2-sided

lower limit

-0.0374

upper limit

0.0351

Difference in slope Tirasemtiv 375mg vs. placebo

Comparison groups

Placebo v 375 mg

Number of subjects included in analysis

313

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7336

Method

Repeated measures mixed model

Parameter type

Slope

Point estimate

0.0066

Confidence interval

level

95%

sides

2-sided

lower limit

-0.0317

upper limit

0.045

Difference in slope Tirasemtiv 500mg vs. placebo

Comparison groups

Placebo v 500 mg

Number of subjects included in analysis

310

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6593

Method

Repeated measures mixed model

Parameter type

Slope

Point estimate

0.0088

Confidence interval

level

95%

sides

2-sided

lower limit

-0.0303

upper limit

0.0479

Difference in slope All (Tirasemtiv) vs. placebo

Comparison groups

Placebo v All (Tirasemtiv)

Number of subjects included in analysis

561

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7482

Method

Repeated measures mixed model

Parameter type

Slope

Point estimate

0.0047

Confidence interval

level

95%

sides

2-sided

lower limit

-0.024

upper limit

0.0334

Secondary: Time to the first occurrence of a decline in percent predicted SVC ≥20 percentage points or the onset of respiratory insufficiency or death from baseline to Week 48

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End point title

Time to the first occurrence of a decline in percent predicted SVC ≥20 percentage points or the onset of respiratory insufficiency or death from baseline to Week 48

End point description

To assess the time to the first occurrence of a decline from baseline in percent predicted SVC ≥ 20 percentage points or the onset of respiratory insufficiency (defined as tracheostomy or the use of non-invasive ventilation for ≥ 22 hours per day for ≥10 consecutive days) or death during all 48 weeks of double-blind, placebo-controlled treatment phase.

End point type

Secondary

End point timeframe

Day 1 through Week 48

End point values	Placebo	250 mg	375 mg	500 mg	All (Tirasemtiv)
Number of subjects analysed	188	126	125	122	373
Units: Units on scale
number (not applicable)
Death	0	0	1	0	1
Decline from baseline in percent predicted SVC	98	58	56	57	171
Non-invasive ventilation for >=22 hours per day	0	0	1	0	1

Tirasemtiv 250mg vs. Placebo

Comparison groups

Placebo v 250 mg

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2369

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.818

Confidence interval

level

95%

sides

2-sided

lower limit

0.587

upper limit

1.141

Tirasemtiv 375mg vs. Placebo

Comparison groups

Placebo v 375 mg

Number of subjects included in analysis

313

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.942

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.988

Confidence interval

level

95%

sides

2-sided

lower limit

0.711

upper limit

1.372

Tirasemtiv 500mg vs. Placebo

Comparison groups

Placebo v 500 mg

Number of subjects included in analysis

310

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6853

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.933

Confidence interval

level

95%

sides

2-sided

lower limit

0.668

upper limit

1.304

All (Tirasemtiv) vs. Placebo

Comparison groups

Placebo v All (Tirasemtiv)

Number of subjects included in analysis

561

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4642

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.91

Confidence interval

level

95%

sides

2-sided

lower limit

0.707

upper limit

1.172

Secondary: Time to the first occurrence of SVC ≤50% predicted or the onset of respiratory insufficiency or death over 48 Weeks

Top of page

End point title

Time to the first occurrence of SVC ≤50% predicted or the onset of respiratory insufficiency or death over 48 Weeks

End point description

SVC was measured with a spirometer. Patients were instructed to take 3 to 5 regular breaths, followed by as deep an inspiration as possible, followed by a slow and steady exhalation of as much air volume as possible. Patients were to perform at least 3 SVC tests at each designated visit. Up to 2 additional SVC tests could have been performed if the variability during the first 3 tests was >10%. This endpoint assessed a decline in SVC to ≤ 50% predicted or the onset of respiratory insufficiency or death during all 48 weeks of double-blind, placebo-controlled treatment.

End point type

Secondary

End point timeframe

Week 1 through Week 48

End point values	Placebo	250 mg	375 mg	500 mg	All (Tirasemtiv)
Number of subjects analysed	188	126	125	122	373
Units: Units on scale
number (not applicable)
Death	0	0	1	0	1
Decline in SVC to <=50% Predicted	54	39	27	32	98
Non-invasive ventilation for >=22 hours per day	3	0	1	0	1
Tracheostomy	0	0	1	0	1

Tirasemtiv 250mg vs. Placebo

Comparison groups

Placebo v 250 mg

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7667

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.066

Confidence interval

level

95%

sides

2-sided

lower limit

0.698

upper limit

1.627

Tirasemtiv 375mg vs. Placebo

Comparison groups

Placebo v 375 mg

Number of subjects included in analysis

313

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6619

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.904

Confidence interval

level

95%

sides

2-sided

lower limit

0.577

upper limit

1.419

Tirasemtiv 500mg vs. Placebo

Comparison groups

Placebo v 500 mg

Number of subjects included in analysis

310

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5856

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.882

Confidence interval

level

95%

sides

2-sided

lower limit

0.561

upper limit

1.386

All (Tirasemtiv) vs. Placebo

Comparison groups

Placebo v All (Tirasemtiv)

Number of subjects included in analysis

561

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7563

Method

Repeated measures mixed model

Parameter type

Hazard ratio (HR)

Point estimate

0.948

Confidence interval

level

95%

sides

2-sided

lower limit

0.678

upper limit

1.327

Secondary: Change in ALSFRS-R total score from baseline to Week 48

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End point title

Change in ALSFRS-R total score from baseline to Week 48

End point description

End point type

Secondary

End point timeframe

Week 1 through Week 48

End point values	Placebo	250 mg	375 mg	500 mg	All (Tirasemtiv)
Number of subjects analysed	188	126	125	122	373
Units: Units on scale
least squares mean (standard error)	-11.39 ( 0.695 )	-11.39 ( 0.859 )	-12.19 ( 0.903 )	-11.99 ( 0.937 )	-11.83 ( 0.519 )

Tirasemtiv 250mg vs. Placebo

Comparison groups

Placebo v 250 mg

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9991

Method

Repeated measures mixed model

Parameter type

LS mean difference vs.placebo

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2.17

upper limit

2.17

Variability estimate

Standard error of the mean

Dispersion value

1.103

Tirasemtiv 375mg vs. Placebo

Comparison groups

Placebo v 375 mg

Number of subjects included in analysis

313

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4808

Method

Repeated measures mixed model

Parameter type

LS mean difference vs.placebo

Point estimate

-0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-3.04

upper limit

1.43

Variability estimate

Standard error of the mean

Dispersion value

1.138

Tirasemtiv 500mg vs. Placebo

Comparison groups

Placebo v 500 mg

Number of subjects included in analysis

310

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6082

Method

Repeated measures mixed model

Parameter type

LS mean difference vs.placebo

Point estimate

-0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-2.89

upper limit

1.69

Variability estimate

Standard error of the mean

Dispersion value

1.165

All (Tirasemtiv) vs. Placebo

Comparison groups

Placebo v All (Tirasemtiv)

Number of subjects included in analysis

561

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6116

Method

Repeated measures mixed model

Parameter type

LS mean difference vs.placebo

Point estimate

-0.44

Confidence interval

level

95%

sides

2-sided

lower limit

-2.14

upper limit

1.26

Secondary: Time to the first use of mechanical ventilatory assistance or death over 48 Weeks

Top of page

End point title

Time to the first use of mechanical ventilatory assistance or death over 48 Weeks

End point description

To assess the time to the first use of mechanical ventilatory assistance or death during all 48 weeks of double-blind, placebo-controlled treatment. Mechanical ventilatory assistance was defined as invasive or non-invasive ventilation for at least 2 hours over a 24-hour period for at least 5 consecutive days.

End point type

Secondary

End point timeframe

Week 1 through Week 48

End point values	Placebo	250 mg	375 mg	500 mg	All (Tirasemtiv)
Number of subjects analysed	188	126	125	122	373
Units: Days
number (not applicable)
Death	11	3	5	4	12
Non-invasive ventilation for at least 2 hours	48	26	31	29	86
Tracheostomy	1	2	1	0	3

Tirasemtiv 250mg vs. Placebo

Comparison groups

Placebo v 250 mg

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2602

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.776

Confidence interval

level

95%

sides

2-sided

lower limit

0.5

upper limit

1.206

Tirasemtiv 375mg vs. Placebo

Comparison groups

Placebo v 375 mg

Number of subjects included in analysis

313

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6748

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.094

Confidence interval

level

95%

sides

2-sided

lower limit

0.72

upper limit

1.662

Tirasemtiv 500mg vs. Placebo

Comparison groups

Placebo v 500 mg

Number of subjects included in analysis

310

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7694

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.938

Confidence interval

level

95%

sides

2-sided

lower limit

0.609

upper limit

1.443

All (Tirasemtiv) vs. Placebo

Comparison groups

Placebo v All (Tirasemtiv)

Number of subjects included in analysis

561

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6454

Method

Repeated measures mixed model

Parameter type

LS mean difference vs.placebo

Point estimate

0.926

Confidence interval

level

95%

sides

2-sided

lower limit

0.668

upper limit

1.284

Adverse events

Top of page

Timeframe for reporting adverse events

From Week 2 (open-label phase) to Week 56 (follow-up visit)

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Placebo

Reporting group description

Reporting group title

250 mg

Reporting group description

Reporting group title

375 mg

Reporting group description

Reporting group title

500 mg

Reporting group description

Serious adverse events	Placebo	250 mg	375 mg	500 mg
Total subjects affected by serious adverse events
subjects affected / exposed	58 / 188 (30.85%)	34 / 126 (26.98%)	37 / 126 (29.37%)	36 / 125 (28.80%)
number of deaths (all causes)	11	7	6	7
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Genital neoplasm malignant female
subjects affected / exposed	0 / 188 (0.00%)	1 / 126 (0.79%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung cancer metastatic
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma metastatic
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Testicular cancer metastatic
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	2 / 126 (1.59%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	1 / 126 (0.79%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Device dislocation
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	1 / 126 (0.79%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Device malfunction
subjects affected / exposed	0 / 188 (0.00%)	1 / 126 (0.79%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Euthanasia
subjects affected / exposed	0 / 188 (0.00%)	1 / 126 (0.79%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Sudden death
subjects affected / exposed	2 / 188 (1.06%)	1 / 126 (0.79%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 2	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 2	1 / 1	0 / 0	0 / 1
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	0 / 188 (0.00%)	1 / 126 (0.79%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchial secretion retention
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	2 / 126 (1.59%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypercapnia
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoventilation
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Increased bronchial secretion
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	4 / 188 (2.13%)	0 / 126 (0.00%)	3 / 126 (2.38%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0
Pulmonary embolism
subjects affected / exposed	3 / 188 (1.60%)	3 / 126 (2.38%)	4 / 126 (3.17%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 4	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Respiratory depression
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	11 / 188 (5.85%)	6 / 126 (4.76%)	7 / 126 (5.56%)	6 / 125 (4.80%)
occurrences causally related to treatment / all	0 / 11	0 / 6	0 / 8	0 / 6
deaths causally related to treatment / all	0 / 6	0 / 8	0 / 4	0 / 5
Sleep apnoea syndrome
subjects affected / exposed	2 / 188 (1.06%)	1 / 126 (0.79%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Adjustment disorder with anxiety
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Completed suicide
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Hallucination, auditory
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hallucination, visual
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	2 / 125 (1.60%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Panic attack
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	2 / 126 (1.59%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abnormal behaviour
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Liver function test abnormal
subjects affected / exposed	0 / 188 (0.00%)	1 / 126 (0.79%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oxygen saturation decreased
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	1 / 126 (0.79%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary function test decreased
subjects affected / exposed	3 / 188 (1.60%)	1 / 126 (0.79%)	1 / 126 (0.79%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	2 / 188 (1.06%)	5 / 126 (3.97%)	4 / 126 (3.17%)	2 / 125 (1.60%)
occurrences causally related to treatment / all	0 / 2	1 / 5	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	1 / 126 (0.79%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Traumatic arthritis
subjects affected / exposed	0 / 188 (0.00%)	1 / 126 (0.79%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Traumatic haematoma
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	1 / 126 (0.79%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Traumatic intracranial haemorrhage
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Traumatic fracture
subjects affected / exposed	4 / 188 (2.13%)	2 / 126 (1.59%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Arteriosclerosis
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial tachycardia
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Cor pulmonale acute
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	1 / 126 (0.79%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stress cardiomyopathy
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	2 / 188 (1.06%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Amyotrophic lateral sclerosis
subjects affected / exposed	5 / 188 (2.66%)	2 / 126 (1.59%)	2 / 126 (1.59%)	4 / 125 (3.20%)
occurrences causally related to treatment / all	0 / 6	0 / 2	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 3	0 / 2	0 / 2	0 / 0
Basal ganglia stroke
subjects affected / exposed	0 / 188 (0.00%)	1 / 126 (0.79%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebellar infarction
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular insufficiency
subjects affected / exposed	0 / 188 (0.00%)	1 / 126 (0.79%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clonus
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Muscle spasticity
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Somnolence
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thalamic infarction
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Toxic encephalopathy
subjects affected / exposed	0 / 188 (0.00%)	1 / 126 (0.79%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tremor
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	1 / 126 (0.79%)	2 / 125 (1.60%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	9 / 188 (4.79%)	13 / 126 (10.32%)	10 / 126 (7.94%)	3 / 125 (2.40%)
occurrences causally related to treatment / all	0 / 9	0 / 13	0 / 10	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	3 / 125 (2.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal polyp
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	1 / 126 (0.79%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal spasm
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	1 / 126 (0.79%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	1 / 188 (0.53%)	1 / 126 (0.79%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	1 / 126 (0.79%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 188 (0.00%)	1 / 126 (0.79%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 188 (0.00%)	1 / 126 (0.79%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Cystitis interstitial
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	1 / 126 (0.79%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	1 / 126 (0.79%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	2 / 188 (1.06%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis bacterial
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	1 / 126 (0.79%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Cellulitis
subjects affected / exposed	2 / 188 (1.06%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Device related sepsis
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	1 / 126 (0.79%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Klebsiella bacteraemia
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Otitis externa
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media acute
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	4 / 188 (2.13%)	1 / 126 (0.79%)	4 / 126 (3.17%)	2 / 125 (1.60%)
occurrences causally related to treatment / all	0 / 5	0 / 1	0 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Serratia bacteraemia
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tracheobronchitis
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	1 / 126 (0.79%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 188 (0.00%)	1 / 126 (0.79%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	1 / 188 (0.53%)	0 / 126 (0.00%)	0 / 126 (0.00%)	0 / 125 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	0 / 188 (0.00%)	0 / 126 (0.00%)	0 / 126 (0.00%)	1 / 125 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Placebo	250 mg	375 mg	500 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	185 / 188 (98.40%)	126 / 126 (100.00%)	125 / 126 (99.21%)	125 / 125 (100.00%)
Vascular disorders
Hypertension
subjects affected / exposed	10 / 188 (5.32%)	5 / 126 (3.97%)	5 / 126 (3.97%)	5 / 125 (4.00%)
occurrences all number	10	7	5	5
General disorders and administration site conditions
Asthenia
subjects affected / exposed	26 / 188 (13.83%)	15 / 126 (11.90%)	22 / 126 (17.46%)	22 / 125 (17.60%)
occurrences all number	35	19	26	23
Fatigue
subjects affected / exposed	74 / 188 (39.36%)	47 / 126 (37.30%)	59 / 126 (46.83%)	57 / 125 (45.60%)
occurrences all number	94	73	88	83
Gait disturbance
subjects affected / exposed	18 / 188 (9.57%)	13 / 126 (10.32%)	10 / 126 (7.94%)	9 / 125 (7.20%)
occurrences all number	21	17	12	10
Oedema peripheral
subjects affected / exposed	21 / 188 (11.17%)	11 / 126 (8.73%)	8 / 126 (6.35%)	10 / 125 (8.00%)
occurrences all number	31	12	8	12
Peripheral swelling
subjects affected / exposed	9 / 188 (4.79%)	9 / 126 (7.14%)	0 / 126 (0.00%)	3 / 125 (2.40%)
occurrences all number	10	11	0	5
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	28 / 188 (14.89%)	13 / 126 (10.32%)	17 / 126 (13.49%)	7 / 125 (5.60%)
occurrences all number	37	16	27	8
Dyspnoea
subjects affected / exposed	41 / 188 (21.81%)	17 / 126 (13.49%)	24 / 126 (19.05%)	19 / 125 (15.20%)
occurrences all number	58	21	33	28
Nasal congestion
subjects affected / exposed	15 / 188 (7.98%)	12 / 126 (9.52%)	12 / 126 (9.52%)	8 / 125 (6.40%)
occurrences all number	15	12	12	9
Psychiatric disorders
Anxiety
subjects affected / exposed	26 / 188 (13.83%)	18 / 126 (14.29%)	14 / 126 (11.11%)	26 / 125 (20.80%)
occurrences all number	29	21	17	34
Confusional state
subjects affected / exposed	3 / 188 (1.60%)	3 / 126 (2.38%)	6 / 126 (4.76%)	6 / 125 (4.80%)
occurrences all number	4	4	6	9
Depression
subjects affected / exposed	23 / 188 (12.23%)	9 / 126 (7.14%)	25 / 126 (19.84%)	23 / 125 (18.40%)
occurrences all number	27	12	26	23
Euphoric mood
subjects affected / exposed	3 / 188 (1.60%)	8 / 126 (6.35%)	1 / 126 (0.79%)	1 / 125 (0.80%)
occurrences all number	3	9	1	1
Insomnia
subjects affected / exposed	27 / 188 (14.36%)	25 / 126 (19.84%)	25 / 126 (19.84%)	31 / 125 (24.80%)
occurrences all number	33	31	30	33
Investigations
Blood creatine phosphokinase increased
subjects affected / exposed	3 / 188 (1.60%)	3 / 126 (2.38%)	2 / 126 (1.59%)	7 / 125 (5.60%)
occurrences all number	3	3	2	8
Weight decreased
subjects affected / exposed	41 / 188 (21.81%)	41 / 126 (32.54%)	44 / 126 (34.92%)	33 / 125 (26.40%)
occurrences all number	51	50	55	38
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	36 / 188 (19.15%)	16 / 126 (12.70%)	24 / 126 (19.05%)	18 / 125 (14.40%)
occurrences all number	58	33	34	27
Head injury
subjects affected / exposed	6 / 188 (3.19%)	8 / 126 (6.35%)	3 / 126 (2.38%)	4 / 125 (3.20%)
occurrences all number	6	11	4	5
Laceration
subjects affected / exposed	17 / 188 (9.04%)	8 / 126 (6.35%)	14 / 126 (11.11%)	12 / 125 (9.60%)
occurrences all number	22	13	18	14
Ligament sprain
subjects affected / exposed	12 / 188 (6.38%)	6 / 126 (4.76%)	4 / 126 (3.17%)	2 / 125 (1.60%)
occurrences all number	16	8	6	2
Post-traumatic pain
subjects affected / exposed	28 / 188 (14.89%)	17 / 126 (13.49%)	17 / 126 (13.49%)	8 / 125 (6.40%)
occurrences all number	58	33	29	17
Skin abrasion
subjects affected / exposed	25 / 188 (13.30%)	22 / 126 (17.46%)	10 / 126 (7.94%)	13 / 125 (10.40%)
occurrences all number	51	39	13	25
Nervous system disorders
Balance disorder
subjects affected / exposed	5 / 188 (2.66%)	5 / 126 (3.97%)	4 / 126 (3.17%)	6 / 125 (4.80%)
occurrences all number	6	7	6	7
Dizziness
subjects affected / exposed	101 / 188 (53.72%)	67 / 126 (53.17%)	67 / 126 (53.17%)	73 / 125 (58.40%)
occurrences all number	143	101	108	110
Dysarthria
subjects affected / exposed	19 / 188 (10.11%)	15 / 126 (11.90%)	9 / 126 (7.14%)	12 / 125 (9.60%)
occurrences all number	24	23	12	16
Headache
subjects affected / exposed	30 / 188 (15.96%)	17 / 126 (13.49%)	26 / 126 (20.63%)	24 / 125 (19.20%)
occurrences all number	49	32	34	32
Muscle contractions involuntary
subjects affected / exposed	11 / 188 (5.85%)	16 / 126 (12.70%)	8 / 126 (6.35%)	13 / 125 (10.40%)
occurrences all number	19	18	11	14
Muscle spasticity
subjects affected / exposed	4 / 188 (2.13%)	6 / 126 (4.76%)	11 / 126 (8.73%)	9 / 125 (7.20%)
occurrences all number	4	6	13	10
Paraesthesia
subjects affected / exposed	3 / 188 (1.60%)	4 / 126 (3.17%)	2 / 126 (1.59%)	9 / 125 (7.20%)
occurrences all number	5	5	3	11
Somnolence
subjects affected / exposed	23 / 188 (12.23%)	21 / 126 (16.67%)	22 / 126 (17.46%)	27 / 125 (21.60%)
occurrences all number	30	32	37	33
Tremor
subjects affected / exposed	6 / 188 (3.19%)	7 / 126 (5.56%)	13 / 126 (10.32%)	12 / 125 (9.60%)
occurrences all number	7	7	14	16
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	10 / 188 (5.32%)	9 / 126 (7.14%)	1 / 126 (0.79%)	2 / 125 (1.60%)
occurrences all number	13	14	3	2
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	4 / 188 (2.13%)	4 / 126 (3.17%)	1 / 126 (0.79%)	8 / 125 (6.40%)
occurrences all number	4	4	1	9
Constipation
subjects affected / exposed	46 / 188 (24.47%)	27 / 126 (21.43%)	21 / 126 (16.67%)	29 / 125 (23.20%)
occurrences all number	59	36	29	34
Diarrhoea
subjects affected / exposed	24 / 188 (12.77%)	14 / 126 (11.11%)	11 / 126 (8.73%)	10 / 125 (8.00%)
occurrences all number	30	17	15	10
Dry mouth
subjects affected / exposed	14 / 188 (7.45%)	11 / 126 (8.73%)	9 / 126 (7.14%)	8 / 125 (6.40%)
occurrences all number	14	12	9	10
Dyspepsia
subjects affected / exposed	11 / 188 (5.85%)	5 / 126 (3.97%)	5 / 126 (3.97%)	7 / 125 (5.60%)
occurrences all number	11	8	6	7
Dysphagia
subjects affected / exposed	35 / 188 (18.62%)	26 / 126 (20.63%)	24 / 126 (19.05%)	14 / 125 (11.20%)
occurrences all number	43	34	31	20
Gastrooesophageal reflux disease
subjects affected / exposed	8 / 188 (4.26%)	6 / 126 (4.76%)	7 / 126 (5.56%)	6 / 125 (4.80%)
occurrences all number	11	7	7	8
Nausea
subjects affected / exposed	51 / 188 (27.13%)	25 / 126 (19.84%)	41 / 126 (32.54%)	33 / 125 (26.40%)
occurrences all number	73	33	52	53
Salivary hypersecretion
subjects affected / exposed	20 / 188 (10.64%)	15 / 126 (11.90%)	9 / 126 (7.14%)	3 / 125 (2.40%)
occurrences all number	25	19	10	5
Vomiting
subjects affected / exposed	7 / 188 (3.72%)	5 / 126 (3.97%)	5 / 126 (3.97%)	7 / 125 (5.60%)
occurrences all number	13	5	9	11
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	9 / 188 (4.79%)	5 / 126 (3.97%)	4 / 126 (3.17%)	7 / 125 (5.60%)
occurrences all number	13	5	4	7
Rash
subjects affected / exposed	12 / 188 (6.38%)	14 / 126 (11.11%)	3 / 126 (2.38%)	9 / 125 (7.20%)
occurrences all number	15	21	3	9
Renal and urinary disorders
Urinary tract infection
subjects affected / exposed	7 / 188 (3.72%)	9 / 126 (7.14%)	6 / 126 (4.76%)	8 / 125 (6.40%)
occurrences all number	8	10	7	10
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	17 / 188 (9.04%)	6 / 126 (4.76%)	7 / 126 (5.56%)	4 / 125 (3.20%)
occurrences all number	20	6	10	4
Back pain
subjects affected / exposed	20 / 188 (10.64%)	11 / 126 (8.73%)	10 / 126 (7.94%)	10 / 125 (8.00%)
occurrences all number	25	15	13	11
Muscle spasms
subjects affected / exposed	38 / 188 (20.21%)	24 / 126 (19.05%)	24 / 126 (19.05%)	19 / 125 (15.20%)
occurrences all number	48	30	31	26
Muscular weakness
subjects affected / exposed	67 / 188 (35.64%)	54 / 126 (42.86%)	46 / 126 (36.51%)	39 / 125 (31.20%)
occurrences all number	128	105	89	59
Musculoskeletal pain
subjects affected / exposed	25 / 188 (13.30%)	10 / 126 (7.94%)	10 / 126 (7.94%)	7 / 125 (5.60%)
occurrences all number	31	11	11	9
Musculoskeletal stiffness
subjects affected / exposed	8 / 188 (4.26%)	8 / 126 (6.35%)	3 / 126 (2.38%)	8 / 125 (6.40%)
occurrences all number	9	8	6	12
Myalgia
subjects affected / exposed	14 / 188 (7.45%)	6 / 126 (4.76%)	4 / 126 (3.17%)	6 / 125 (4.80%)
occurrences all number	16	8	4	6
Neck pain
subjects affected / exposed	11 / 188 (5.85%)	4 / 126 (3.17%)	4 / 126 (3.17%)	4 / 125 (3.20%)
occurrences all number	14	5	6	5
Pain in extremity
subjects affected / exposed	21 / 188 (11.17%)	9 / 126 (7.14%)	13 / 126 (10.32%)	11 / 125 (8.80%)
occurrences all number	26	18	17	16
Infections and infestations
Nasopharyngitis
subjects affected / exposed	35 / 188 (18.62%)	23 / 126 (18.25%)	20 / 126 (15.87%)	14 / 125 (11.20%)
occurrences all number	46	28	25	19
Upper respiratory tract infection
subjects affected / exposed	17 / 188 (9.04%)	3 / 126 (2.38%)	4 / 126 (3.17%)	10 / 125 (8.00%)
occurrences all number	20	3	7	13
Urinary tract infection
subjects affected / exposed	2 / 188 (1.06%)	5 / 126 (3.97%)	7 / 126 (5.56%)	1 / 125 (0.80%)
occurrences all number	2	7	9	2
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	22 / 188 (11.70%)	18 / 126 (14.29%)	19 / 126 (15.08%)	23 / 125 (18.40%)
occurrences all number	26	18	19	28

More information

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Were there any global substantial amendments to the protocol? Yes

31 Jul 2015

• Allowed patients who did not tolerate a dose level of tirasemtiv to return to a previously tolerated dose (rather than the last tolerated dose) (Note: During the conduct of the study, patients were only returned the 250-mg/day dose.) • Ensured that the language regarding patients who were not taking riluzole was consistently worded and clarified throughout the protocol • Clarified that the investigator was to be alerted if the patient had lost ≥ 5% of body weight since baseline (Week −2 visit) prior to drug administration rather than if the patient had lost ≥ 5% of body weight since the screening visit

16 Jan 2016

• Increased the number of randomized patients from approximately 360 to approximately 477 (to power the primary endpoint at 90% rather than 80%) • Revised the order of the secondary endpoints that were to be tested in a hierarchal closed testing procedure • Reclassified the secondary endpoints outside the closed testing procedure as tertiary endpoints • Removed language regarding the interim analysis of the primary endpoint (evaluated after 24 weeks of double-blind treatment) prior to completion of the study (with the last patient out at 56 weeks) • Provided clarification and details regarding acceptable contraception for male participants and female participants of childbearing potential • Clarified the blinded safety monitoring procedures

26 Jun 2017

• Revised and redefined the order of testing for the secondary endpoints • Clarified that the methodology for the closed testing procedure for the primary and secondary efficacy endpoints was fully described in the SAP • Clarified the subgroup efficacy, PK, and pharmacodynamic analyses to align with the SAP • Clarified that patients who were randomized and discontinued from the study were to be encouraged to attend the remaining study visits and complete the associated assessments • Added an additional sponsor’s medical monitor

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
A Phase 3, Multi-National, Double-Blind, Randomized, Placebo-Controlled, Stratified, Parallel Group, Study to Evaluate the Safety, Tolerability and Efficacy of Tirasemtiv in Patients with Amyotrophic Lateral Sclerosis (ALS)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change in percent predicted slow vital capacity (SVC) from baseline to week 24

Primary: Change in percent predicted slow vital capacity (SVC) from baseline to week 24

Secondary: Change in ALS Functional Rating Scale-Revised (ALSFRS-R) respiratory domain score from baseline to Week 48

Secondary: Change in ALS Functional Rating Scale-Revised (ALSFRS-R) respiratory domain score from baseline to Week 48

Secondary: Slope of mega-score of muscle strength over 48 Weeks

Secondary: Slope of mega-score of muscle strength over 48 Weeks

Secondary: Time to the first occurrence of a decline in percent predicted SVC ≥20 percentage points or the onset of respiratory insufficiency or death from baseline to Week 48

Secondary: Time to the first occurrence of a decline in percent predicted SVC ≥20 percentage points or the onset of respiratory insufficiency or death from baseline to Week 48

Secondary: Time to the first occurrence of SVC ≤50% predicted or the onset of respiratory insufficiency or death over 48 Weeks

Secondary: Time to the first occurrence of SVC ≤50% predicted or the onset of respiratory insufficiency or death over 48 Weeks

Secondary: Change in ALSFRS-R total score from baseline to Week 48

Secondary: Change in ALSFRS-R total score from baseline to Week 48

Secondary: Time to the first use of mechanical ventilatory assistance or death over 48 Weeks

Secondary: Time to the first use of mechanical ventilatory assistance or death over 48 Weeks

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A Phase 3, Multi-National, Double-Blind, Randomized, Placebo-Controlled, Stratified, Parallel Group, Study to Evaluate the Safety, Tolerability and Efficacy of Tirasemtiv in Patients with Amyotrophic Lateral Sclerosis (ALS)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change in percent predicted slow vital capacity (SVC) from baseline to week 24

Primary: Change in percent predicted slow vital capacity (SVC) from baseline to week 24

Secondary: Change in ALS Functional Rating Scale-Revised (ALSFRS-R) respiratory domain score from baseline to Week 48

Secondary: Change in ALS Functional Rating Scale-Revised (ALSFRS-R) respiratory domain score from baseline to Week 48

Secondary: Slope of mega-score of muscle strength over 48 Weeks

Secondary: Slope of mega-score of muscle strength over 48 Weeks

Secondary: Time to the first occurrence of a decline in percent predicted SVC ≥20 percentage points or the onset of respiratory insufficiency or death from baseline to Week 48

Secondary: Time to the first occurrence of a decline in percent predicted SVC ≥20 percentage points or the onset of respiratory insufficiency or death from baseline to Week 48

Secondary: Time to the first occurrence of SVC ≤50% predicted or the onset of respiratory insufficiency or death over 48 Weeks

Secondary: Time to the first occurrence of SVC ≤50% predicted or the onset of respiratory insufficiency or death over 48 Weeks

Secondary: Change in ALSFRS-R total score from baseline to Week 48

Secondary: Change in ALSFRS-R total score from baseline to Week 48

Secondary: Time to the first use of mechanical ventilatory assistance or death over 48 Weeks

Secondary: Time to the first use of mechanical ventilatory assistance or death over 48 Weeks

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 3, Multi-National, Double-Blind, Randomized, Placebo-Controlled, Stratified, Parallel Group, Study to Evaluate the Safety, Tolerability and Efficacy of Tirasemtiv in Patients with Amyotrophic Lateral Sclerosis (ALS)