EMPOWER: Phase 3 Study of Dexpramipexole in ALS

• Sponsor: Knopp Biosciences (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01281189
• Collaborator: (none)
• Enrollment: 942
• Locations: 82
• Arms: 2
• Duration (Months): 20.1
• Patients Per Site: 11.5
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether dexpramipexole (150 mg twice daily) is safe and effective in the treatment of Amyotrophic Lateral Sclerosis (ALS).

Condition or Disease	Intervention/Treatment	Phase
Amyotrophic Lateral Sclerosis	Drug: Dexpramipexole; Drug: Placebo	Phase 3

Detailed Description

Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive, degenerative disease of motor neurons in the brain and spinal cord that leads to muscle atrophy and spasticity in limb and bulbar muscles resulting in weakness and loss of ambulation, oropharyngeal dysfunction, weight loss, and ultimately respiratory failure. The purpose of this study is to determine whether dexpramipexole (150 mg twice daily) is safe and effective in the treatment of ALS.

Study Design

• Study Type: Interventional
• Actual Enrollment: 942 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study of the Safety and Efficacy of Dexpramipexole in Subjects With Amyotrophic Lateral Sclerosis
• Study Start Date: Mar 1, 2011
• Actual Primary Completion Date: Nov 1, 2012
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dexpramipexole	Drug: Dexpramipexole; Oral tablet 150mg twice daily for up to 18 months.; Other Names: KNS-760704 BIIB050
Placebo Comparator: Placebo	Drug: Placebo; Oral tablet twice daily for up to 18 months.

Outcome Measures

Primary Outcome Measures

1. Composite Assessment of Function and Survival (CAFS) at 12 Months [12 months]

   The Composite Assessment of Function and Survival (CAFS) is a between-group comparison of a single ranked clinical outcome based on (1) the change from baseline in ALS Functional Rating Scale-Revised (ALSFRS-R) score and (2) time to death. Each subject is ranked according to time-to-death (earlier deaths ranked lower than later deaths). Subjects who survive are ranked more favorably than subjects who died. Among the survivors, subjects are ranked according to change in ALSFRS-R (greater worsening of ALSFRS-R is ranked lower than less worsening or an improvement in ALSFRS-R). The ranked scores range from 001 to 941 (the number of subjects in the Efficacy Population) with larger rank score numbers associated with a better outcome. The ranks were analyzed using an ANCOVA model, which includes treatment as a fixed effect and adjusts for baseline ALSFRS-R score, duration of symptoms, site of onset, and use of riluzole. The least square mean rank score is presented for each treatment group.

2. Death up to 12 Months (CAFs Individual Component) [12 months]

   The longest duration of follow-up for this time to the death analysis was 12 months. In the study, subjects were followed for 12-18 months.

3. Change From Baseline in ALSFRS-R at 12 Months (CAFs Individual Component) [12 months]

   The ALSFRS-R (ALS functional rating scale with respiratory component) is a validated scale which measures 4 functional domains, comprising respiratory function, bulbar function, gross motor skills, and fine motor skills. There are a total of 12 questions, each scored from 0 to 4 for a total possible score of 48, with higher scores representing better function.

Secondary Outcome Measures

1. Death or Respiratory Insufficiency (DRI) up to Month 18 [18 months]

   Time to Death or Respiratory Insufficiency (DRI) is defined as receipt of a tracheostomy or the use of non-invasive ventilation (NIV) for ≥22 hours per day for at least 10 consecutive days. If NIV is used to meet the criteria for respiratory insufficiency, no measured slow vital capacity (SVC) at any subsequent assessment may be >50%. Time to DRI is calculated from the date of the first dose to the first date of one of the following events: death, tracheostomy, or the 10th day of consecutive NIV with no measured SVC >50% at any subsequent assessment.

2. Death up to 18 Months [18 months]

   Estimated time to death up to 18 months. This includes deaths reported greater than 30 days following discontinuation from the study (the time period for reporting all-cause mortality), regardless of subject disposition, up to 18 months from first dose.

3. ≤50% Predicted Upright Slow Vital Capacity (SVC) or Died up to 18 Months [18 months]

   The date of reaching ≤50% of predicted upright slow vital capacity (SVC) is defined as the date of the first visit at which a predicted upright SVC is ≤50% and continues to remain ≤50% at the subsequent visit except for the last available observation. The time to reach ≤50% of predicted upright SVC is defined as the duration between the date of reaching ≤50% of predicted upright SVC and the date of the first dose of study medication. If the subject is alive and does not reach ≤50% of predicted upright SVC, the time to reach ≤50% of predicted upright SVC will be censored and equal to the number of days from the first dose of study medication until the visit date when the subject's last available SVC assessment is performed. The earliest time (Reaching ≤50% Predicted Upright SVC or death) is used in analysis.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Aged 18 to 80 years old, inclusive, on Day 1.

• Diagnosis of sporadic or familial ALS.

• Onset of first ALS symptoms within 24 months prior to Day 1.

• World Federation of Neurology El Escorial criteria are met for a possible, laboratory-supported probable, probable, or definite ALS diagnosis.

• Upright slow vital capacity (SVC) of 65% or more at screening.

• Patients taking or not taking Riluzole are eligible for this study: if a patient has never taken Riluzole, he or she is eligible; if a patient is currently taking Riluzole, he or she must have been on a stable dose for at least 60 days; if a patient has discontinued Riluzole, he or she must have stopped taking it for at least 30 days.

• Must be able to swallow tablets at the time of study entry.

Exclusion Criteria:

• Other medically significant illness.

• Clinically significant abnormal laboratory values.

• Pregnant women or women breastfeeding.

• Prior exposure to dexpramipexole.

• Currently taking pramipexole or other dopamine agonists.

Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Barrow Neurological Institute - St. Joseph's Hospital	Phoenix	Arizona	United States	85013
2	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
3	University of California at San Francisco - Fresno	Fresno	California	United States	93701
4	University of California, Irvine	Orange	California	United States	92868
5	University of California, Davis	Sacramento	California	United States	95817
6	California Pacific Medical Center	San Francisco	California	United States	94115
7	Hospital for Special Care	New Britain	Connecticut	United States	06053
8	Mayo Clinic - Jacksonville	Jacksonville	Florida	United States	32224
9	University of Miami Miller School of Medicine	Miami	Florida	United States	33136
10	University of South Florida Medical Center	Tampa	Florida	United States	33612
11	Emory University	Atlanta	Georgia	United States	30322
12	Northwestern University	Chicago	Illinois	United States	60611
13	Indiana University	Indianapolis	Indiana	United States	46202
14	University of Iowa	Iowa City	Iowa	United States	52242
15	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
16	Johns Hopkins University School of Medicine	Baltimore	Maryland	United States	21287
17	Massachusetts General Hospital	Charlestown	Massachusetts	United States	02129
18	St. Mary's Health Care	Grand Rapids	Michigan	United States	49503
19	Hennepin County Medical Center	Minneapolis	Minnesota	United States	55404
20	Mayo Clinic - Rochester	Rochester	Minnesota	United States	55905
21	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
22	Neurology Associates, P.C.	Lincoln	Nebraska	United States	68506
23	University of Nevada School of Medicine	Las Vegas	Nevada	United States	89102
24	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
25	Columbia University	New York	New York	United States	10032
26	Research Foundation of the State University of New York	Syracuse	New York	United States	12201
27	Carolinas Medical Center	Charlotte	North Carolina	United States	28207
28	Duke University Medical Center	Durham	North Carolina	United States	27705
29	Wake Forest University	Winston-Salem	North Carolina	United States	27157
30	The Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
31	Ohio State University	Columbus	Ohio	United States	43210
32	Providence ALS Center	Portland	Oregon	United States	97213
33	Penn State Hershey Medical Center	Hershey	Pennsylvania	United States	17033
34	ALS Center at Penn	Philadelphia	Pennsylvania	United States	19107
35	Drexel University College of Medicine	Philadelphia	Pennsylvania	United States	19129
36	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213
37	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
38	Texas Neurology	Dallas	Texas	United States	75214
39	Methodist Neurological Institute	Houston	Texas	United States	77030
40	University of Texas Health Sciences Center	San Antonio	Texas	United States	78229
41	University of Utah	Salt Lake City	Utah	United States	84132
42	University of Virginia Health System	Charlottesville	Virginia	United States	22908
43	University of Washington	Seattle	Washington	United States	98195
44	Prince of Wales Hospital	Randwick	New South Wales	Australia
45	Westmead Hospital	Westmead	New South Wales	Australia	2145
46	Royal Brisbane and Women's Hospital	Herston	Queensland	Australia	4029
47	Calvary Health Care Bethlehem	Melbourne	Victoria	Australia	3121
48	AZ St-Lucas	Gent		Belgium	9000
49	UZ Leuven	Leuven		Belgium	3000
50	Univ of Calgary / Foothills MC	Calgary	Alberta	Canada	T2V 1P9
51	CHUM - Hopital Notre Dame	Montreal	Quebec	Canada	H2L 4M1
52	Mcgill University	Montreal	Quebec	Canada	H3A 2B4
53	London Health Sciences Centre	London		Canada
54	Sunnybrook and Women's College and Health Sciences Centre	Toronto		Canada	M4N 3M5
55	University of British Columbia	Vancouver		Canada
56	CHRU de Lille - Hôpital Roger Salengro	Lille		France	59037
57	CHU de Limoges - Hôpital Dupuytren	Limoges		France
58	Centre Hospitalier La Timone	Marseille		France
59	CHU Gui de Chauliac	Montpellier		France	34295
60	CHU de Nice - Hôpital de l'Archet 1	Nice		France
61	Hôpital La Pitié Salpétrière	Paris		France	75013
62	Charité - Universitätsmedizin Berlin	Berlin		Germany
63	Bergmannsheil Gmbh	Bochum		Germany
64	Medizinische Hochschule Hannover (MHH)	Hannover		Germany
65	Universitätsklinikum Jena	Jena		Germany
66	University of Ulm, RKU	Ulm		Germany
67	Beaumont Hospital	Dublin		Ireland	Dublin 9
68	Academisch Medisch Centrum	Amsterdam		Netherlands	1105 AZ
69	UMC St. Radboud	Nijmegen		Netherlands	6525 GA
70	Universitair Medisch Centrum Utrecht	Utrecht		Netherlands	3584 CX
71	Hospital Universitario de Bellvitge	Barcelona		Spain	8907
72	Hospital Vall d'Hebron	Barcelona		Spain
73	Hospital La Paz	Madrid		Spain	28046
74	Hospital Carlos III	Madrid		Spain
75	Sahlgrenska Universitetssjukhuset	Göteborg		Sweden	41345
76	Karolinska Universitetssjukhuset, Solna	Stockholm		Sweden	17176
77	Queen Elizabeth Hospital	Birmingham		United Kingdom	B15 2TH
78	Walton Centre for Neurology & Neurosurgery	Liverpool		United Kingdom	L9 7LJ
79	Kings College Hospital NHS Foundation Trust	London		United Kingdom	SE5 8AF
80	Newcastle University Hospital - Clinical Ageing Research Unit	Newcastle		United Kingdom	NE4 5PL
81	John Radcliffe Hospital	Oxford		United Kingdom
82	Sheffield Institute for Transnational Neuroscience	Sheffield		United Kingdom	S10 2HQ

Sponsors and Collaborators

• Knopp Biosciences

Investigators

• Principal Investigator: Merit Cudkowicz, MD, MSc, Professor of Neurology of the Harvard Medical School

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Knopp Biosciences
• ClinicalTrials.gov Identifier: NCT01281189
• Other Study ID Numbers: 223AS302; EUDRA CT NO: 2010-022818-19
• First Posted: Jan 21, 2011
• Last Update Posted: Jun 7, 2021
• Last Verified: May 1, 2021

• Keywords provided by Knopp Biosciences: Amyotrophic Lateral Sclerosis; ALS; Motor Neurone Disease; Motor Neuron Disease; Lou Gehrig's disease
• Additional relevant MeSH terms: Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis; Pramipexole

Study Results

Participant Flow

Recruitment Details	There were 942 participants (468 received placebo and 474 received dexpramipexole) recruited from 81 investigational sites in 11 countries worldwide. One additional participant was randomized in error and was not dosed. This subject was assigned to the placebo arm, but was removed from the intent-to-treat population as a result of the unintentional randomization performed in error by the site.

Arm/Group Title	Placebo	Dexpramipexole
Arm/Group Description	Matching Placebo: Oral tablet twice daily.	Dexpramipexole: Oral tablet 150 mg twice daily. 300 mg/day
Period Title: Overall Study
STARTED	468	474
COMPLETED	321	331
NOT COMPLETED	147	143

Baseline Characteristics

Arm/Group Title	Placebo	Dexpramipexole	Total
Arm/Group Description	Matching Placebo: Oral tablet twice daily.	Dexpramipexole: Oral tablet 150 mg twice daily. 300 mg/day	Total of all reporting groups
Overall Participants	468	474	942
Age, Customized (Count of Participants)
<50	114 24.4%	114 24.1%	228 24.2%
50-65	233 49.8%	244 51.5%	477 50.6%
>65	121 25.9%	116 24.5%	237 25.2%
Sex: Female, Male (Count of Participants)
Female	170 36.3%	167 35.2%	337 35.8%
Male	298 63.7%	307 64.8%	605 64.2%
Race/Ethnicity, Customized (Count of Participants)
Asian	7 1.5%	4 0.8%	11 1.2%
Black or African American	10 2.1%	3 0.6%	13 1.4%
White	439 93.8%	450 94.9%	889 94.4%
Not reported	7 1.5%	9 1.9%	16 1.7%
Other	5 1.1%	8 1.7%	13 1.4%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	77.76 (16.008)	77.21 (15.027)	77.48 (15.516)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	172.0 (10.22)	172.0 (9.30)	172.0 (9.77)
Body mass index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	26.15 (4.330)	26.00 (4.239)	26.08 (4.283)
ALS family history (Count of Participants)
Yes	26 5.6%	33 7%	59 6.3%
No	442 94.4%	440 92.8%	882 93.6%
Missing	0 0%	1 0.2%	1 0.1%
Time since ALS symptom onset (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	15.53 (5.411)	14.92 (5.251)	15.22 (5.337)
Site of onset (Count of Participants)
Bulbar	112 23.9%	107 22.6%	219 23.2%
Other	356 76.1%	367 77.4%	723 76.8%
Time since ALS diagnosis (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	7.62 (5.015)	7.22 (4.718)	7.42 (4.869)
El Escorial Criteria for ALS (Count of Participants)
Possible	44 9.4%	44 9.3%	88 9.3%
Probable laboratory supported	94 20.1%	98 20.7%	192 20.4%
Probable	174 37.2%	185 39%	359 38.1%
Definite	156 33.3%	147 31%	303 32.2%
Concomitant use of riluzole (Count of Participants)
Yes	349 74.6%	359 75.7%	708 75.2%
No	119 25.4%	115 24.3%	234 24.8%
Baseline ALSFRS-R total scores (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	37.9 (5.65)	38.4 (5.24)	38.2 (5.45)
Baseline predicted upright slow vital capacity (%) (Count of Participants)
<65%	27 5.8%	28 5.9%	55 5.8%
65-75%	84 17.9%	79 16.7%	163 17.3%
>75%	357 76.3%	367 77.4%	724 76.9%
Baseline predicted upright slow vital capacity (%) (%) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [%]	89.1 (17.71)	89.0 (17.57)	89.1 (17.63)

Outcome Measures

1. Primary Outcome

Title	Composite Assessment of Function and Survival (CAFS) at 12 Months
Description	The Composite Assessment of Function and Survival (CAFS) is a between-group comparison of a single ranked clinical outcome based on (1) the change from baseline in ALS Functional Rating Scale-Revised (ALSFRS-R) score and (2) time to death. Each subject is ranked according to time-to-death (earlier deaths ranked lower than later deaths). Subjects who survive are ranked more favorably than subjects who died. Among the survivors, subjects are ranked according to change in ALSFRS-R (greater worsening of ALSFRS-R is ranked lower than less worsening or an improvement in ALSFRS-R). The ranked scores range from 001 to 941 (the number of subjects in the Efficacy Population) with larger rank score numbers associated with a better outcome. The ranks were analyzed using an ANCOVA model, which includes treatment as a fixed effect and adjusts for baseline ALSFRS-R score, duration of symptoms, site of onset, and use of riluzole. The least square mean rank score is presented for each treatment group.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

The efficacy population is defined as subjects who were randomized and received at least 1 dose of study treatment and who either had at least 1 available post-dosing efficacy evaluation (ALSFRS-R) or died during the study period. Subjects were analyzed in the treatment group to which they are randomized.

Arm/Group Title	Placebo	Dexpramipexole
Arm/Group Description	Matching Placebo: Oral tablet twice daily.	Dexpramipexole: Oral tablet 150 mg twice daily. 300 mg/day
Measure Participants	468	473
Least Squares Mean (95% Confidence Interval) [units on a scale]	438.84	441.76

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dexpramipexole
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8568
	Comments
	Method	ANCOVA
	Comments	Includes treatment as a fixed effect and adjusts for baseline ALSFRS-R total score, duration from sx onset, site of onset, and use of riluzole.
Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	2.91
	Confidence Interval	(2-Sided) 95%; -28.751 to 34.576
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Death up to 12 Months (CAFs Individual Component)
Description	The longest duration of follow-up for this time to the death analysis was 12 months. In the study, subjects were followed for 12-18 months.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

The efficacy population is defined as subjects who were randomized and received at least 1 dose of study treatment and who either had at least 1 available post-dosing efficacy evaluation (ALSFRS-R) or died during the study period. Subjects were analyzed in the treatment group to which they are randomized.

Arm/Group Title	Placebo	Dexpramipexole
Arm/Group Description	Matching Placebo: Oral tablet twice daily.	Dexpramipexole: Oral tablet 150 mg twice daily. 300 mg/day
Measure Participants	468	473
Number [percentage of participants]	17.2 3.7%	16.0 3.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dexpramipexole
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8375
	Comments
	Method	Cox Proportional Hazards model
	Comments	Adjusted for baseline ALSFRS-R total score, duration from symptom onset to the first dose of study treatment, site of onset, and use of riluzole.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95%; 0.750 to 1.427
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Hazard Ratio (HR) (Dex/PBO)

3. Primary Outcome

Title	Change From Baseline in ALSFRS-R at 12 Months (CAFs Individual Component)
Description	The ALSFRS-R (ALS functional rating scale with respiratory component) is a validated scale which measures 4 functional domains, comprising respiratory function, bulbar function, gross motor skills, and fine motor skills. There are a total of 12 questions, each scored from 0 to 4 for a total possible score of 48, with higher scores representing better function.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

The efficacy population is defined as subjects who were randomized and received at least 1 dose of study treatment and who either had at least 1 available post-dosing efficacy evaluation (ALSFRS-R) or died during the study period. Subjects will be analyzed in the treatment group to which they are randomized.

Arm/Group Title	Placebo	Dexpramipexole
Arm/Group Description	Matching Placebo: Oral tablet twice daily.	Dexpramipexole: Oral tablet 150 mg twice daily. 300 mg/day
Measure Participants	468	473
Least Squares Mean (95% Confidence Interval) [units on a scale]	-13.415	-13.339

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dexpramipexole
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9019
	Comments
	Method	mixed-effects repeated-measures model
	Comments	Mixed-effects repeated-measures model with treatment, visit, treatment-by visit interaction, baseline ALSFRS-R score, baseline-by-visit interaction
Method of Estimation	Estimation Parameter	LS Mean Difference (Net)
	Estimated Value	0.076
	Confidence Interval	(2-Sided) 95%; -1.128 to 1.280
	Parameter Dispersion	Type: Value:
	Estimation Comments	The mixed-effects repeated-measures model also adjusted for the following covariates: duration from symptom onset, site of onset, and use of riluzole.

4. Secondary Outcome

Title	Death or Respiratory Insufficiency (DRI) up to Month 18
Description	Time to Death or Respiratory Insufficiency (DRI) is defined as receipt of a tracheostomy or the use of non-invasive ventilation (NIV) for ≥22 hours per day for at least 10 consecutive days. If NIV is used to meet the criteria for respiratory insufficiency, no measured slow vital capacity (SVC) at any subsequent assessment may be >50%. Time to DRI is calculated from the date of the first dose to the first date of one of the following events: death, tracheostomy, or the 10th day of consecutive NIV with no measured SVC >50% at any subsequent assessment.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

The efficacy population is defined as subjects who were randomized and received at least 1 dose of study treatment and who either had at least 1 available post-dosing efficacy evaluation (ALSFRS-R) or died during the study period. Subjects were analyzed in the treatment group to which they are randomized.

Arm/Group Title	Placebo	Dexpramipexole
Arm/Group Description	Matching Placebo: Oral tablet twice daily.	Dexpramipexole: Oral tablet 150 mg twice daily. 300 mg/day
Measure Participants	468	474
Number [percentage of participants]	27.2 5.8%	22.3 4.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dexpramipexole
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7715
	Comments
	Method	Cox Proportional Hazards model
	Comments	Adjusted for baseline ALSFRS-R total score, duration from symptom onset to the first dose of study treatment, site of onset, and use of riluzole
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.801 to 1.348
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Death up to 18 Months
Description	Estimated time to death up to 18 months. This includes deaths reported greater than 30 days following discontinuation from the study (the time period for reporting all-cause mortality), regardless of subject disposition, up to 18 months from first dose.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

Subjects who were randomized, received at least 1 dose of study treatment, had at least 1 available post-dosing efficacy evaluation (ALSFRS-R) or died during the study period. Subjects were analyzed in the treatment group to which they are randomized. An attempt was made to collect living status for each subject 18 months after randomization, regardless of the subject's disposition in the study (active or discontinued) or primary reasons for discontinuation.

Arm/Group Title	Placebo	Dexpramipexole
Arm/Group Description	Matching Placebo: Oral tablet twice daily.	Dexpramipexole: Oral tablet 150 mg twice daily. 300 mg/day
Measure Participants	468	474
Number [percentage of participants]	23.1 4.9%	20.5 4.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dexpramipexole
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9033
	Comments
	Method	Cox Proportional Hazards model
	Comments	adjusted for baseline ALSFRS-R total score, duration from symptom onset to the first dose of study treatment, site of onset, and use of riluzole
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.745 to 1.298
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	≤50% Predicted Upright Slow Vital Capacity (SVC) or Died up to 18 Months
Description	The date of reaching ≤50% of predicted upright slow vital capacity (SVC) is defined as the date of the first visit at which a predicted upright SVC is ≤50% and continues to remain ≤50% at the subsequent visit except for the last available observation. The time to reach ≤50% of predicted upright SVC is defined as the duration between the date of reaching ≤50% of predicted upright SVC and the date of the first dose of study medication. If the subject is alive and does not reach ≤50% of predicted upright SVC, the time to reach ≤50% of predicted upright SVC will be censored and equal to the number of days from the first dose of study medication until the visit date when the subject's last available SVC assessment is performed. The earliest time (Reaching ≤50% Predicted Upright SVC or death) is used in analysis.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population is defined as subjects who were randomized and received at least 1 dose of study treatment.

Arm/Group Title	Placebo	Dexpramipexole
Arm/Group Description	Matching Placebo: Oral tablet twice daily.	Dexpramipexole: Oral tablet 150 mg twice daily. 300 mg/day
Measure Participants	468	474
Number [percentage of participants]	41.9 9%	36.5 7.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dexpramipexole
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7720
	Comments
	Method	Cox Proportional Hazards model
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.789 to 1.192
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio (Dex/PBO)

Adverse Events

Time Frame	18 months
Arm/Group Title	Placebo		Dexpramipexole
Arm/Group Description	Matching Placebo: Oral tablet twice daily.		Dexpramipexole: Oral tablet 150 mg twice daily. 300 mg/day
All Cause Mortality
	Placebo		Dexpramipexole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	108/468 (23.1%)		97/474 (20.5%)
Serious Adverse Events
	Placebo		Dexpramipexole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	233/468 (49.8%)		225/474 (47.5%)
Blood and lymphatic system disorders
NEUTROPENIA	1/468 (0.2%)		9/474 (1.9%)
ANAEMIA	0/468 (0%)		1/474 (0.2%)
FEBRILE NEUTROPENIA	0/468 (0%)		1/474 (0.2%)
COAGULOPATHY	1/468 (0.2%)		0/474 (0%)
Cardiac disorders
CARDIO-RESPIRATORY ARREST	3/468 (0.6%)		5/474 (1.1%)
MYOCARDIAL INFARCTION	1/468 (0.2%)		4/474 (0.8%)
ACUTE MYOCARDIAL INFARCTION	2/468 (0.4%)		3/474 (0.6%)
ARRHYTHMIA	0/468 (0%)		2/474 (0.4%)
CARDIAC ARREST	0/468 (0%)		2/474 (0.4%)
ATRIAL FIBRILLATION	3/468 (0.6%)		1/474 (0.2%)
CARDIOGENIC SHOCK	0/468 (0%)		1/474 (0.2%)
CARDIOVASCULAR DISORDER	0/468 (0%)		1/474 (0.2%)
SINUS TACHYCARDIA	1/468 (0.2%)		1/474 (0.2%)
SUPRAVENTRICULAR EXTRASYSTOLES	0/468 (0%)		1/474 (0.2%)
SUPRAVENTRICULAR TACHYCARDIA	2/468 (0.4%)		1/474 (0.2%)
VENTRICULAR ARRHYTHMIA	0/468 (0%)		1/474 (0.2%)
CARDIOPULMONARY FAILURE	2/468 (0.4%)		0/474 (0%)
CORONARY ARTERY DISEASE	1/468 (0.2%)		0/474 (0%)
DIASTOLIC DYSFUNCTION	1/468 (0.2%)		0/474 (0%)
STRESS CARDIOMYOPATHY	1/468 (0.2%)		0/474 (0%)
TACHYCARDIA	1/468 (0.2%)		0/474 (0%)
Eye disorders
CATARACT	1/468 (0.2%)		0/474 (0%)
Gastrointestinal disorders
DYSPHAGIA	69/468 (14.7%)		62/474 (13.1%)
ABDOMINAL PAIN	2/468 (0.4%)		2/474 (0.4%)
APHAGIA	1/468 (0.2%)		2/474 (0.4%)
CONSTIPATION	4/468 (0.9%)		2/474 (0.4%)
FAECALOMA	0/468 (0%)		2/474 (0.4%)
ABDOMINAL DISTENSION	0/468 (0%)		1/474 (0.2%)
COLITIS	0/468 (0%)		1/474 (0.2%)
FLATULENCE	0/468 (0%)		1/474 (0.2%)
INTESTINAL OBSTRUCTION	1/468 (0.2%)		1/474 (0.2%)
STOMATITIS	0/468 (0%)		1/474 (0.2%)
GASTRITIS	1/468 (0.2%)		0/474 (0%)
ILEUS	2/468 (0.4%)		0/474 (0%)
OESOPHAGEAL STENOSIS	1/468 (0.2%)		0/474 (0%)
OESOPHAGITIS	1/468 (0.2%)		0/474 (0%)
RECTAL HAEMORRHAGE	2/468 (0.4%)		0/474 (0%)
General disorders
EUTHANASIA	1/468 (0.2%)		2/474 (0.4%)
NON-CARDIAC CHEST PAIN	0/468 (0%)		2/474 (0.4%)
SUDDEN DEATH	0/468 (0%)		2/474 (0.4%)
ADVERSE DRUG REACTION	0/468 (0%)		1/474 (0.2%)
ASTHENIA	0/468 (0%)		1/474 (0.2%)
CATHETER SITE HAEMORRHAGE	0/468 (0%)		1/474 (0.2%)
CHEST PAIN	0/468 (0%)		1/474 (0.2%)
COMPLICATION OF DEVICE INSERTION	0/468 (0%)		1/474 (0.2%)
DEATH	1/468 (0.2%)		1/474 (0.2%)
DEVICE MALFUNCTION	0/468 (0%)		1/474 (0.2%)
MEDICAL DEVICE COMPLICATION	0/468 (0%)		1/474 (0.2%)
PYREXIA	1/468 (0.2%)		1/474 (0.2%)
ULCER HAEMORRHAGE	0/468 (0%)		1/474 (0.2%)
DEVICE LEAKAGE	1/468 (0.2%)		0/474 (0%)
DEVICE OCCLUSION	1/468 (0.2%)		0/474 (0%)
GENERAL PHYSICAL HEALTH DETERIORATION	1/468 (0.2%)		0/474 (0%)
OEDEMA PERIPHERAL	1/468 (0.2%)		0/474 (0%)
Hepatobiliary disorders
CHOLELITHIASIS	0/468 (0%)		1/474 (0.2%)
CHOLECYSTITIS	1/468 (0.2%)		0/474 (0%)
Immune system disorders
HYPERSENSITIVITY	0/468 (0%)		1/474 (0.2%)
Infections and infestations
PNEUMONIA	19/468 (4.1%)		14/474 (3%)
LOWER RESPIRATORY TRACT INFECTION	6/468 (1.3%)		3/474 (0.6%)
URINARY TRACT INFECTION	3/468 (0.6%)		3/474 (0.6%)
BRONCHITIS	6/468 (1.3%)		2/474 (0.4%)
CELLULITIS	0/468 (0%)		2/474 (0.4%)
LUNG INFECTION	0/468 (0%)		2/474 (0.4%)
UPPER RESPIRATORY TRACT INFECTION	0/468 (0%)		2/474 (0.4%)
CATHETER SITE INFECTION	1/468 (0.2%)		1/474 (0.2%)
CLOSTRIDIUM DIFFICILE COLITIS	1/468 (0.2%)		1/474 (0.2%)
CYSTITIS ESCHERICHIA	0/468 (0%)		1/474 (0.2%)
GASTROENTERITIS VIRAL	0/468 (0%)		1/474 (0.2%)
NEUTROPENIC INFECTION	0/468 (0%)		1/474 (0.2%)
PILONIDAL CYST	0/468 (0%)		1/474 (0.2%)
PSEUDOMONAS BRONCHITIS	0/468 (0%)		1/474 (0.2%)
RHINITIS	0/468 (0%)		1/474 (0.2%)
RHINOVIRUS INFECTION	1/468 (0.2%)		1/474 (0.2%)
STAPHYLOCOCCAL INFECTION	0/468 (0%)		1/474 (0.2%)
VIRAL INFECTION	0/468 (0%)		1/474 (0.2%)
VIRAL UPPER RESPIRATORY TRACT INFECTION	0/468 (0%)		1/474 (0.2%)
BRONCHOPNEUMONIA	1/468 (0.2%)		0/474 (0%)
DEVICE RELATED INFECTION	1/468 (0.2%)		0/474 (0%)
GAS GANGRENE	1/468 (0.2%)		0/474 (0%)
GASTROENTERITIS	1/468 (0.2%)		0/474 (0%)
PNEUMONIA KLEBSIELLA	2/468 (0.4%)		0/474 (0%)
PYELONEPHRITIS	1/468 (0.2%)		0/474 (0%)
RESPIRATORY SYNCYTIAL VIRUS BRONCHITIS	1/468 (0.2%)		0/474 (0%)
RESPIRATORY TRACT INFECTION	2/468 (0.4%)		0/474 (0%)
SEPSIS	1/468 (0.2%)		0/474 (0%)
SERRATIA INFECTION	1/468 (0.2%)		0/474 (0%)
SINUSITIS	1/468 (0.2%)		0/474 (0%)
Injury, poisoning and procedural complications
FALL	11/468 (2.4%)		13/474 (2.7%)
FACIAL BONES FRACTURE	1/468 (0.2%)		2/474 (0.4%)
LACERATION	1/468 (0.2%)		2/474 (0.4%)
SUBDURAL HAEMATOMA	3/468 (0.6%)		2/474 (0.4%)
ANKLE FRACTURE	0/468 (0%)		1/474 (0.2%)
CONCUSSION	2/468 (0.4%)		1/474 (0.2%)
CRANIOCEREBRAL INJURY	1/468 (0.2%)		1/474 (0.2%)
FEMUR FRACTURE	1/468 (0.2%)		1/474 (0.2%)
FOREIGN BODY	0/468 (0%)		1/474 (0.2%)
GASTROINTESTINAL STOMA COMPLICATION	0/468 (0%)		1/474 (0.2%)
HAND FRACTURE	0/468 (0%)		1/474 (0.2%)
HIP FRACTURE	0/468 (0%)		1/474 (0.2%)
HUMERUS FRACTURE	0/468 (0%)		1/474 (0.2%)
POST PROCEDURAL HAEMORRHAGE	0/468 (0%)		1/474 (0.2%)
RADIUS FRACTURE	0/468 (0%)		1/474 (0.2%)
SPLENIC HAEMATOMA	0/468 (0%)		1/474 (0.2%)
CLAVICLE FRACTURE	1/468 (0.2%)		0/474 (0%)
CONTUSION	1/468 (0.2%)		0/474 (0%)
HEAD INJURY	1/468 (0.2%)		0/474 (0%)
INTENTIONAL OVERDOSE	1/468 (0.2%)		0/474 (0%)
POST PROCEDURAL COMPLICATION	1/468 (0.2%)		0/474 (0%)
SKELETAL INJURY	1/468 (0.2%)		0/474 (0%)
SKULL FRACTURED BASE	2/468 (0.4%)		0/474 (0%)
TRAUMATIC INTRACRANIAL HAEMORRHAGE	1/468 (0.2%)		0/474 (0%)
TRENCH FOOT	1/468 (0.2%)		0/474 (0%)
Investigations
VITAL CAPACITY DECREASED	3/468 (0.6%)		3/474 (0.6%)
WEIGHT DECREASED	1/468 (0.2%)		2/474 (0.4%)
INVESTIGATION	0/468 (0%)		1/474 (0.2%)
LIVER FUNCTION TEST ABNORMAL	0/468 (0%)		1/474 (0.2%)
DIAGNOSTIC PROCEDURE	1/468 (0.2%)		0/474 (0%)
GAMMA-GLUTAMYLTRANSFERASE INCREASED	1/468 (0.2%)		0/474 (0%)
OXYGEN SATURATION DECREASED	2/468 (0.4%)		0/474 (0%)
TOTAL LUNG CAPACITY DECREASED	1/468 (0.2%)		0/474 (0%)
Metabolism and nutrition disorders
DEHYDRATION	1/468 (0.2%)		2/474 (0.4%)
ELECTROLYTE IMBALANCE	0/468 (0%)		2/474 (0.4%)
HYPOKALAEMIA	1/468 (0.2%)		2/474 (0.4%)
HYPONATRAEMIA	0/468 (0%)		2/474 (0.4%)
DECREASED APPETITE	0/468 (0%)		1/474 (0.2%)
FAILURE TO THRIVE	0/468 (0%)		1/474 (0.2%)
MALNUTRITION	1/468 (0.2%)		1/474 (0.2%)
FLUID RETENTION	1/468 (0.2%)		0/474 (0%)
HYPOCALCAEMIA	1/468 (0.2%)		0/474 (0%)
Musculoskeletal and connective tissue disorders
MUSCULOSKELETAL CHEST PAIN	1/468 (0.2%)		2/474 (0.4%)
INTERVERTEBRAL DISC DEGENERATION	0/468 (0%)		1/474 (0.2%)
MOBILITY DECREASED	0/468 (0%)		1/474 (0.2%)
OSTEOARTHRITIS	1/468 (0.2%)		1/474 (0.2%)
POLYMYALGIA RHEUMATICA	0/468 (0%)		1/474 (0.2%)
INCLUSION BODY MYOSITIS	1/468 (0.2%)		0/474 (0%)
INTERVERTEBRAL DISC PROTRUSION	1/468 (0.2%)		0/474 (0%)
LUMBAR SPINAL STENOSIS	1/468 (0.2%)		0/474 (0%)
MUSCLE SPASMS	1/468 (0.2%)		0/474 (0%)
NOSE DEFORMITY	1/468 (0.2%)		0/474 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MALIGNANT MELANOMA	0/468 (0%)		1/474 (0.2%)
NEOPLASM MALIGNANT	0/468 (0%)		1/474 (0.2%)
CHRONIC LYMPHOCYTIC LEUKAEMIA	1/468 (0.2%)		0/474 (0%)
METASTATIC BRONCHIAL CARCINOMA	1/468 (0.2%)		0/474 (0%)
Nervous system disorders
AMYOTROPHIC LATERAL SCLEROSIS	16/468 (3.4%)		16/474 (3.4%)
MOTOR NEURONE DISEASE	7/468 (1.5%)		3/474 (0.6%)
MIGRAINE	0/468 (0%)		1/474 (0.2%)
MUSCLE SPASTICITY	0/468 (0%)		1/474 (0.2%)
SOMNOLENCE	0/468 (0%)		1/474 (0.2%)
SYNCOPE	2/468 (0.4%)		1/474 (0.2%)
TRANSIENT ISCHAEMIC ATTACK	0/468 (0%)		1/474 (0.2%)
BULBAR PALSY	1/468 (0.2%)		0/474 (0%)
CEREBELLAR INFARCTION	1/468 (0.2%)		0/474 (0%)
CEREBROVASCULAR ACCIDENT	1/468 (0.2%)		0/474 (0%)
VERTEBRAL ARTERY DISSECTION	1/468 (0.2%)		0/474 (0%)
Psychiatric disorders
SUICIDAL IDEATION	1/468 (0.2%)		1/474 (0.2%)
ALCOHOLISM	1/468 (0.2%)		0/474 (0%)
ANXIETY	1/468 (0.2%)		0/474 (0%)
COMPLETED SUICIDE	1/468 (0.2%)		0/474 (0%)
DEPRESSION	1/468 (0.2%)		0/474 (0%)
DEPRESSION SUICIDAL	1/468 (0.2%)		0/474 (0%)
PANIC ATTACK	1/468 (0.2%)		0/474 (0%)
Renal and urinary disorders
RENAL FAILURE ACUTE	0/468 (0%)		3/474 (0.6%)
URINARY RETENTION	1/468 (0.2%)		2/474 (0.4%)
HAEMATURIA	0/468 (0%)		1/474 (0.2%)
NEPHROLITHIASIS	0/468 (0%)		1/474 (0.2%)
RENAL FAILURE	0/468 (0%)		1/474 (0.2%)
URETERIC STENOSIS	1/468 (0.2%)		0/474 (0%)
Reproductive system and breast disorders
UTERINE POLYP	0/468 (0%)		1/474 (0.2%)
BREAST HAEMATOMA	1/468 (0.2%)		0/474 (0%)
VAGINAL HAEMORRHAGE	1/468 (0.2%)		0/474 (0%)
Respiratory, thoracic and mediastinal disorders
RESPIRATORY FAILURE	75/468 (16%)		69/474 (14.6%)
PNEUMONIA ASPIRATION	13/468 (2.8%)		12/474 (2.5%)
PULMONARY EMBOLISM	9/468 (1.9%)		12/474 (2.5%)
DYSPNOEA	10/468 (2.1%)		6/474 (1.3%)
ACUTE RESPIRATORY FAILURE	5/468 (1.1%)		4/474 (0.8%)
RESPIRATORY DISORDER	6/468 (1.3%)		4/474 (0.8%)
RESPIRATORY DISTRESS	6/468 (1.3%)		3/474 (0.6%)
RESPIRATORY ARREST	6/468 (1.3%)		2/474 (0.4%)
CHRONIC RESPIRATORY FAILURE	0/468 (0%)		1/474 (0.2%)
COUGH DECREASED	0/468 (0%)		1/474 (0.2%)
HYPERCAPNIA	4/468 (0.9%)		1/474 (0.2%)
HYPOVENTILATION	0/468 (0%)		1/474 (0.2%)
HYPOXIA	1/468 (0.2%)		1/474 (0.2%)
INCREASED BRONCHIAL SECRETION	1/468 (0.2%)		1/474 (0.2%)
LUNG DISORDER	3/468 (0.6%)		1/474 (0.2%)
ORTHOPNOEA	0/468 (0%)		1/474 (0.2%)
PULMONARY OEDEMA	0/468 (0%)		1/474 (0.2%)
RESPIRATORY MUSCLE WEAKNESS	0/468 (0%)		1/474 (0.2%)
RESPIRATORY TRACT CONGESTION	0/468 (0%)		1/474 (0.2%)
SLEEP APNOEA SYNDROME	0/468 (0%)		1/474 (0.2%)
UPPER AIRWAY OBSTRUCTION	0/468 (0%)		1/474 (0.2%)
ATELECTASIS	2/468 (0.4%)		0/474 (0%)
EPISTAXIS	1/468 (0.2%)		0/474 (0%)
INCREASED VISCOSITY OF BRONCHIAL SECRETION	1/468 (0.2%)		0/474 (0%)
LARYNGOSPASM	1/468 (0.2%)		0/474 (0%)
PLEURAL EFFUSION	1/468 (0.2%)		0/474 (0%)
RESPIRATORY ACIDOSIS	1/468 (0.2%)		0/474 (0%)
STRIDOR	1/468 (0.2%)		0/474 (0%)
VOCAL CORD DISORDER	1/468 (0.2%)		0/474 (0%)
Skin and subcutaneous tissue disorders
SKIN ULCER	0/468 (0%)		1/474 (0.2%)
Social circumstances
RESPITE CARE	1/468 (0.2%)		0/474 (0%)
SOCIAL STAY HOSPITALISATION	1/468 (0.2%)		0/474 (0%)
Surgical and medical procedures
SUPPORTIVE CARE	1/468 (0.2%)		0/474 (0%)
Vascular disorders
DEEP VEIN THROMBOSIS	8/468 (1.7%)		8/474 (1.7%)
ARTERIAL THROMBOSIS LIMB	0/468 (0%)		1/474 (0.2%)
HAEMATOMA	0/468 (0%)		1/474 (0.2%)
HYPERTENSION	1/468 (0.2%)		0/474 (0%)
ORTHOSTATIC HYPOTENSION	1/468 (0.2%)		0/474 (0%)
THROMBOSIS	1/468 (0.2%)		0/474 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Dexpramipexole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	447/468 (95.5%)		459/474 (96.8%)
Blood and lymphatic system disorders
NEUTROPENIA	8/468 (1.7%)		37/474 (7.8%)
Gastrointestinal disorders
CONSTIPATION	109/468 (23.3%)		129/474 (27.2%)
NAUSEA	65/468 (13.9%)		106/474 (22.4%)
DYSPHAGIA	95/468 (20.3%)		88/474 (18.6%)
DIARRHOEA	55/468 (11.8%)		44/474 (9.3%)
DRY MOUTH	20/468 (4.3%)		41/474 (8.6%)
SALIVARY HYPERSECRETION	34/468 (7.3%)		29/474 (6.1%)
General disorders
OEDEMA PERIPHERAL	72/468 (15.4%)		61/474 (12.9%)
FATIGUE	60/468 (12.8%)		57/474 (12%)
ASTHENIA	10/468 (2.1%)		23/474 (4.9%)
PYREXIA	21/468 (4.5%)		22/474 (4.6%)
Infections and infestations
NASOPHARYNGITIS	76/468 (16.2%)		69/474 (14.6%)
URINARY TRACT INFECTION	56/468 (12%)		56/474 (11.8%)
UPPER RESPIRATORY TRACT INFECTION	17/468 (3.6%)		30/474 (6.3%)
PNEUMONIA	32/468 (6.8%)		24/474 (5.1%)
BRONCHITIS	28/468 (6%)		21/474 (4.4%)
Injury, poisoning and procedural complications
FALL	198/468 (42.3%)		192/474 (40.5%)
LACERATION	31/468 (6.6%)		34/474 (7.2%)
CONTUSION	35/468 (7.5%)		31/474 (6.5%)
Investigations
WEIGHT DECREASED	48/468 (10.3%)		75/474 (15.8%)
Metabolism and nutrition disorders
DECREASED APPETITE	27/468 (5.8%)		33/474 (7%)
Musculoskeletal and connective tissue disorders
MUSCULAR WEAKNESS	44/468 (9.4%)		64/474 (13.5%)
MUSCULOSKELETAL PAIN	37/468 (7.9%)		44/474 (9.3%)
ARTHRALGIA	34/468 (7.3%)		42/474 (8.9%)
BACK PAIN	36/468 (7.7%)		39/474 (8.2%)
MUSCLE SPASMS	30/468 (6.4%)		38/474 (8%)
PAIN IN EXTREMITY	28/468 (6%)		26/474 (5.5%)
NECK PAIN	9/468 (1.9%)		24/474 (5.1%)
Nervous system disorders
HEADACHE	65/468 (13.9%)		66/474 (13.9%)
DIZZINESS	28/468 (6%)		42/474 (8.9%)
AMYOTROPHIC LATERAL SCLEROSIS	28/468 (6%)		24/474 (5.1%)
Psychiatric disorders
INSOMNIA	60/468 (12.8%)		71/474 (15%)
DEPRESSION	50/468 (10.7%)		40/474 (8.4%)
ANXIETY	34/468 (7.3%)		35/474 (7.4%)
Respiratory, thoracic and mediastinal disorders
RESPIRATORY FAILURE	81/468 (17.3%)		72/474 (15.2%)
COUGH	30/468 (6.4%)		45/474 (9.5%)
DYSPNOEA	52/468 (11.1%)		44/474 (9.3%)
Skin and subcutaneous tissue disorders
RASH	27/468 (5.8%)		27/474 (5.7%)
PRURITUS	18/468 (3.8%)		25/474 (5.3%)
Vascular disorders
HYPERTENSION	13/468 (2.8%)		23/474 (4.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Sponsor must be consulted