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Clinical Trial Results:
A Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of BIIB067 Administered to Adult Subjects with Amyotrophic Lateral Sclerosis and Confirmed Superoxide Dismutase 1 Mutation

Summary
EudraCT number	2015-004098-33
Trial protocol	SE DE GB BE DK PL
Global end of trial date	16 Jul 2021

Results information
Results version number	v2(current)
This version publication date	24 Aug 2023
First version publication date	31 Jul 2022
Other versions	v1
Version creation reason	Correction of full data set Updated '99999' explanations and added number of subjects analysed for Day 85 for endpoints: Cmax and Tmax.

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

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Trial information

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Sponsor protocol code

233AS101

ISRCTN number

US NCT number

NCT02623699

WHO universal trial number (UTN)

Sponsor organisation name

Biogen

Sponsor organisation address

225 Binney Street, Cambridge, United States, 02142

Public contact

Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com

Scientific contact

Biogen Study Medical Director, Biogen, clinicaltrials@biogen.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

16 Jul 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

16 Jul 2021

Was the trial ended prematurely?

Main objective of the trial

The primary objectives of Parts A and B of this study are to evaluate the safety, tolerability, and pharmacokinetics (PK) of ascending doses of BIIB067 (tofersen) in adults with ALS and a documented superoxide dismutase 1 (SOD1) mutation. The secondary objective of Parts A and B of this study is to evaluate the effects of BIIB067 on levels of total SOD1 protein in the cerebrospinal fluid (CSF). The primary objective of Part C of this study is to evaluate the clinical efficacy of BIIB067 administered to adults with ALS and a confirmed SOD1 mutation. The secondary objectives of Part C are to evaluate the safety, tolerability, pharmacodynamic (PD), and biomarker effects of BIIB067.

Protection of trial subjects

Written informed consent was obtained from each subject or subject’s legally authorized representative (e.g., legal guardian), as applicable, prior to evaluations performed for eligibility. Subjects or the subject’s legally authorized representative were given adequate time to review the information in the informed consent/assent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study.

Background therapy

Evidence for comparator

Actual start date of recruitment

20 Jan 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

France: 8

Country: Number of subjects enrolled

Canada: 27

Country: Number of subjects enrolled

Japan: 7

Country: Number of subjects enrolled

United States: 93

Country: Number of subjects enrolled

Germany: 11

Country: Number of subjects enrolled

Italy: 5

Country: Number of subjects enrolled

Belgium: 14

Country: Number of subjects enrolled

Denmark: 1

Country: Number of subjects enrolled

United Kingdom: 12

Worldwide total number of subjects

178

EEA total number of subjects

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)

156

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects were enrolled at the investigative sites in the Belgium, Canada, Denmark, France, Germany, Italy, Japan, United Kingdom, and the United States from 20 January 2016 to 16 July 2021.

Screening details

Study included SAD (Part A), MAD (Part B) and pivotal portions (Part C). Total 176 subjects were enrolled 20 into Part A, 50 into Part B including 2 subjects who completed Part A, were re-enrolled in Part B after 12-week washout period, hence 2 subjects were analysed in both Parts A, B (for total of 68 in Parts A, B), Part C enrolled 108 subjects.

Period 1 title

Parts A, B, and C (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer

Are arms mutually exclusive

Yes

Part A-SAD: Combined Placebo

Arm description

Subjects were administered BIIB067-matching placebo once by intrathecal bolus injection on Day 1 of Cohorts 1, 2, 3, and 4 respectively.

Arm type

Placebo

Investigational medicinal product name

BIIB067-matching Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

Subjects were administered BIIB067-matching placebo as specified in treatment arm.

Part A-SAD: Cohort 1: BIIB067 10 mg

Arm description

Subjects were administered BIIB067 10 mg once by intrathecal bolus injection on Day 1.

Arm type

Experimental

Investigational medicinal product name

BIIB067

Investigational medicinal product code

ISIS666853

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

Subjects were administered BIIB067 10 mg as specified in the treatment arm.

Part A-SAD: Cohort 2: BIIB067 20 mg

Arm description

Subjects were administered BIIB067 20 mg once by intrathecal bolus injection on Day 1 of Cohort 2 after the safety review of Cohort 1.

Arm type

Experimental

Investigational medicinal product name

BIIB067

Investigational medicinal product code

ISIS666853

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

Subjects were administered BIIB067 20 mg as specified in the treatment arm.

Part A-SAD: Cohort 3: BIIB067 40 mg

Arm description

Subjects were administered BIIB067 40 mg once by intrathecal bolus injection on Day 1 of Cohort 3 after the safety review of Cohort 2.

Arm type

Experimental

Investigational medicinal product name

BIIB067

Investigational medicinal product code

ISIS666853

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

Subjects were administered BIIB067 40 mg as specified in the treatment arm.

Part A-SAD: Cohort 4: BIIB067 60 mg

Arm description

Subjects were administered BIIB067 60 mg once by intrathecal bolus injection on Day 1 of Cohort 4 after the safety review of Cohort 3.

Arm type

Experimental

Investigational medicinal product name

BIIB067

Investigational medicinal product code

ISIS666853

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

Subjects were administered BIIB067 60 mg as specified in the treatment arm.

Part B-MAD: Combined Placebo

Arm description

Subjects were administered BIIB067-matching placebo, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection.

Arm type

Placebo

Investigational medicinal product name

BIIB067-matching Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

Subjects were administered BIIB067-matching placebo as specified in treatment arm.

Part B-MAD: Cohort 5: BIIB067 20 mg

Arm description

Subjects were administered BIIB067 20 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection.

Arm type

Experimental

Investigational medicinal product name

BIIB067

Investigational medicinal product code

ISIS666853

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

Subjects were administered BIIB067 20 mg as specified in the treatment arm.

Part B-MAD: Cohort 6: BIIB067 40 mg

Arm description

Subjects were administered BIIB067 40 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection after the safety and PK review of Cohort 5.

Arm type

Experimental

Investigational medicinal product name

BIIB067

Investigational medicinal product code

ISIS666853

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

Subjects were administered BIIB067 40 mg as specified in the treatment arm.

Part B-MAD: Cohort 7: BIIB067 60 mg

Arm description

Subjects were administered BIIB067 60 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection after the safety, PK review and superoxide dismutase 1 (SOD1) PD review of Cohort 6.

Arm type

Experimental

Investigational medicinal product name

BIIB067

Investigational medicinal product code

ISIS666853

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

Subjects were administered BIIB067 60 mg as specified in the treatment arm.

Part B-MAD: Cohort 8: BIIB067 100 mg

Arm description

Subjects were administered BIIB067 100 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection after the safety, PK review and SOD1 PD review of Cohort 7.

Arm type

Experimental

Investigational medicinal product name

BIIB067

Investigational medicinal product code

ISIS666853

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

Subjects were administered BIIB067 100 mg as specified in the treatment arm.

Part C-Pivotal: Placebo

Arm description

Subjects were administered BIIB067-matching placebo, 3 loading doses administered once every 2 weeks on Days 1, 15, 29 followed by 5 maintenance doses administered once every 4 weeks on Days 57, 85, 113, 141, 169 up to 24 weeks by intrathecal bolus injection.

Arm type

Placebo

Investigational medicinal product name

BIIB067-matching Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

Subjects were administered BIIB067-matching placebo as specified in treatment arm.

Part C-Pivotal: BIIB067 100 mg

Arm description

Subjects were administered BIIB067 100 mg, 3 loading doses administered once every 2 weeks on Days 1, 15, 29 followed by 5 maintenance doses administered once every 4 weeks on Days 57, 85, 113, 141, 169 up to 24 weeks by intrathecal bolus injection.

Arm type

Experimental

Investigational medicinal product name

BIIB067

Investigational medicinal product code

ISIS666853

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

Subjects were administered BIIB067 100 mg as specified in the treatment arm.

Number of subjects in period 1	Part A-SAD: Combined Placebo	Part A-SAD: Cohort 1: BIIB067 10 mg	Part A-SAD: Cohort 2: BIIB067 20 mg	Part A-SAD: Cohort 3: BIIB067 40 mg	Part A-SAD: Cohort 4: BIIB067 60 mg	Part B-MAD: Combined Placebo	Part B-MAD: Cohort 5: BIIB067 20 mg	Part B-MAD: Cohort 6: BIIB067 40 mg	Part B-MAD: Cohort 7: BIIB067 60 mg	Part B-MAD: Cohort 8: BIIB067 100 mg	Part C-Pivotal: Placebo	Part C-Pivotal: BIIB067 100 mg
Started	5	3	3	3	6	12	10	9	9	10	36	72
Completed	5	2	3	3	6	10	8	9	8	10	33	64
Not completed	0	1	0	0	0	2	2	0	1	0	3	8
Disease progression	-	-	-	-	-	-	-	-	-	-	2	3
Death	-	-	-	-	-	1	1	-	1	-	-	1
Adverse event	-	-	-	-	-	-	-	-	-	-	-	2
Lost to follow-up	-	-	-	-	-	-	1	-	-	-	-	-
Consent Withdrawn	-	1	-	-	-	1	-	-	-	-	1	2

Baseline characteristics

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Reporting group title

Part A-SAD: Combined Placebo

Reporting group description

Subjects were administered BIIB067-matching placebo once by intrathecal bolus injection on Day 1 of Cohorts 1, 2, 3, and 4 respectively.

Reporting group title

Part A-SAD: Cohort 1: BIIB067 10 mg

Reporting group description

Subjects were administered BIIB067 10 mg once by intrathecal bolus injection on Day 1.

Reporting group title

Part A-SAD: Cohort 2: BIIB067 20 mg

Reporting group description

Subjects were administered BIIB067 20 mg once by intrathecal bolus injection on Day 1 of Cohort 2 after the safety review of Cohort 1.

Reporting group title

Part A-SAD: Cohort 3: BIIB067 40 mg

Reporting group description

Subjects were administered BIIB067 40 mg once by intrathecal bolus injection on Day 1 of Cohort 3 after the safety review of Cohort 2.

Reporting group title

Part A-SAD: Cohort 4: BIIB067 60 mg

Reporting group description

Subjects were administered BIIB067 60 mg once by intrathecal bolus injection on Day 1 of Cohort 4 after the safety review of Cohort 3.

Reporting group title

Part B-MAD: Combined Placebo

Reporting group description

Subjects were administered BIIB067-matching placebo, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection.

Reporting group title

Part B-MAD: Cohort 5: BIIB067 20 mg

Reporting group description

Subjects were administered BIIB067 20 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection.

Reporting group title

Part B-MAD: Cohort 6: BIIB067 40 mg

Reporting group description

Reporting group title

Part B-MAD: Cohort 7: BIIB067 60 mg

Reporting group description

Reporting group title

Part B-MAD: Cohort 8: BIIB067 100 mg

Reporting group description

Reporting group title

Part C-Pivotal: Placebo

Reporting group description

Reporting group title

Part C-Pivotal: BIIB067 100 mg

Reporting group description

Reporting group values	Part A-SAD: Combined Placebo	Part A-SAD: Cohort 1: BIIB067 10 mg	Part A-SAD: Cohort 2: BIIB067 20 mg	Part A-SAD: Cohort 3: BIIB067 40 mg	Part A-SAD: Cohort 4: BIIB067 60 mg	Part B-MAD: Combined Placebo	Part B-MAD: Cohort 5: BIIB067 20 mg	Part B-MAD: Cohort 6: BIIB067 40 mg	Part B-MAD: Cohort 7: BIIB067 60 mg	Part B-MAD: Cohort 8: BIIB067 100 mg	Part C-Pivotal: Placebo	Part C-Pivotal: BIIB067 100 mg	Total
Number of subjects	5	3	3	3	6	12	10	9	9	10	36	72
Age Categorical
Units: Subjects
Age Continuous
Units: years
arithmetic mean (standard deviation)	58.4 ( 9.29 )	50.3 ( 7.64 )	55.3 ( 17.62 )	49.0 ( 3.61 )	45.0 ( 12.82 )	49.2 ( 11.04 )	41.5 ( 10.72 )	58.0 ( 11.09 )	45.6 ( 10.71 )	48.9 ( 10.80 )	51.2 ( 11.57 )	48.1 ( 12.64 )	-
Gender Categorical
Units: Subjects
Female	2	3	0	1	4	5	3	5	3	6	17	29	78
Male	3	0	3	2	2	7	7	4	6	4	19	43	100
Ethnicity
Not reported indicates that ethnicity data was not reported due to confidentiality regulations.
Units: Subjects
Hispanic or Latino	0	0	0	0	0	0	0	0	0	0	1	4	5
Not Hispanic or Latino	4	3	3	1	5	9	5	6	4	7	28	47	122
Not reported	1	0	0	2	1	3	5	3	5	3	7	21	51
Race
Units: Subjects
Asian	0	0	0	0	0	0	0	1	0	0	4	5	10
Black or African American	0	0	0	0	0	0	0	0	0	0	0	1	1
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	1	0	0	0	0	0	0	1
White	4	3	3	1	5	7	5	5	4	7	25	44	113
Not reported	1	0	0	2	1	3	5	3	5	3	7	21	51
Other	0	0	0	0	0	1	0	0	0	0	0	1	2
Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R)
ALSFRS-R measures respiratory, bulbar function, gross, and fine motor skills. 12 questions, each scored from 0-4 (no-full function), for a total score of 48. Scores decline with disease progression. Higher scores represent better function. Modified ITT (mITT) population included all subjects who met the prognostic enrichment criteria for rapid disease progression in Part C who were randomized and received at least 1 dose of study treatment. N=0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 21, and 39 for the arms mentioned respectively. 99999=this study specific measure was only analyzed for Part C arms groups.
Units: score on a scale
arithmetic mean (standard deviation)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	35.4 ( 5.66 )	36.0 ( 6.40 )	-
CSF Levels of Total SOD1 Protein Concentration
PD population is the subset of the ITT population with at least 1 post-dose PD measurement in Part B. mITT population included all subjects who met the prognostic enrichment criteria for rapid disease progression in Part C who were randomized and received at least 1 dose of study treatment. N= 0, 0, 0, 0, 0, 4, 1, 1, 1, 4, 21, and 38 for the arms mentioned respectively. 99999=this study specific measure was only analyzed for Part B and C arms groups.
Units: nanograms per milliliter (ng/mL)
geometric mean (full range (min-max))	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	70.40 (57.2 to 87.9)	102.00 (102.00 to 102.00)	125.00 (125.00 to 125.00)	82.80 (82.8 to 82.8)	135.86 (92.5 to 199.0)	107.07 (60.0 to 322.0)	103.32 (38.8 to 282.0)	-
Percentage (%) Predicted Slow Vital Capacity (SVC)
mITT population included all subjects who met the prognostic enrichment criteria for rapid disease progression in Part C who were randomized and received at least 1 dose of study treatment. N=0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 21, and 39 for the arms mentioned respectively. 99999=this study specific measure was only analyzed for Part C arms groups.
Units: percent predicted
arithmetic mean (standard deviation)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	83.7 ( 17.87 )	80.3 ( 14.22 )	-
Handheld Dynamometry (HHD) Megascore as Measured by the HHD Device
16 muscle groups were evaluated in upper, lower extremities. Strength determinations were converted to Z scores, averaged for an HHD megascore. Muscle strength values normalized to Z scores as (post-baseline measurements – mean)/SD, averaged to provide HHD overall megascore.mITT population=all subjects who met prognostic enrichment criteria for rapid disease progression in Part C who were randomized and received at least 1 dose of study treatment. N=0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 21, 39 for arms mentioned respectively. 99999=this study specific measure was only analyzed for Part C arms groups.
Units: score on a scale
arithmetic mean (standard deviation)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	0.0 ( 0.60 )	0.0 ( 0.67 )	-
Neurofilament Light Chain (NfL) Concentration in Plasma
mITT population included all subjects who met the prognostic enrichment criteria for rapid disease progression in Part C who were randomized and received at least 1 dose of study treatment. N=0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 21, and 39 for the arms mentioned respectively. 99999=this study specific measure was only analyzed for Part C arms groups.
Units: picograms per mL (pg/mL)
geometric mean (full range (min-max))	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	92.7 (9 to 370)	121.8 (12 to 329)	-

End points

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Reporting group title

Part A-SAD: Combined Placebo

Reporting group description

Subjects were administered BIIB067-matching placebo once by intrathecal bolus injection on Day 1 of Cohorts 1, 2, 3, and 4 respectively.

Reporting group title

Part A-SAD: Cohort 1: BIIB067 10 mg

Reporting group description

Subjects were administered BIIB067 10 mg once by intrathecal bolus injection on Day 1.

Reporting group title

Part A-SAD: Cohort 2: BIIB067 20 mg

Reporting group description

Subjects were administered BIIB067 20 mg once by intrathecal bolus injection on Day 1 of Cohort 2 after the safety review of Cohort 1.

Reporting group title

Part A-SAD: Cohort 3: BIIB067 40 mg

Reporting group description

Subjects were administered BIIB067 40 mg once by intrathecal bolus injection on Day 1 of Cohort 3 after the safety review of Cohort 2.

Reporting group title

Part A-SAD: Cohort 4: BIIB067 60 mg

Reporting group description

Subjects were administered BIIB067 60 mg once by intrathecal bolus injection on Day 1 of Cohort 4 after the safety review of Cohort 3.

Reporting group title

Part B-MAD: Combined Placebo

Reporting group description

Subjects were administered BIIB067-matching placebo, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection.

Reporting group title

Part B-MAD: Cohort 5: BIIB067 20 mg

Reporting group description

Subjects were administered BIIB067 20 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection.

Reporting group title

Part B-MAD: Cohort 6: BIIB067 40 mg

Reporting group description

Reporting group title

Part B-MAD: Cohort 7: BIIB067 60 mg

Reporting group description

Reporting group title

Part B-MAD: Cohort 8: BIIB067 100 mg

Reporting group description

Reporting group title

Part C-Pivotal: Placebo

Reporting group description

Reporting group title

Part C-Pivotal: BIIB067 100 mg

Reporting group description

Primary: Parts A and B: Number of Subjects Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs)

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End point title

Parts A and B: Number of Subjects Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) ^[1] ^[2]

End point description

An AE is any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A SAE is any untoward medical occurrence that at any dose results in death, life-threatening event, requires inpatient hospitalization, significant disability/incapacity or congenital anomaly. Safety population included all randomized subjects who received at least 1 dose or a part of 1 dose of study treatment (BIIB067 or placebo) in Part A or B.

End point type

Primary

End point timeframe

Part A: First dose up to Day 63; Part B: First dose up to Day 289

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned or performed for this endpoint.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for the Part A and B arms of the study, so data was reported only for the Part A and B arm groups.

End point values	Part A-SAD: Combined Placebo	Part A-SAD: Cohort 1: BIIB067 10 mg	Part A-SAD: Cohort 2: BIIB067 20 mg	Part A-SAD: Cohort 3: BIIB067 40 mg	Part A-SAD: Cohort 4: BIIB067 60 mg	Part B-MAD: Combined Placebo	Part B-MAD: Cohort 5: BIIB067 20 mg	Part B-MAD: Cohort 6: BIIB067 40 mg	Part B-MAD: Cohort 7: BIIB067 60 mg	Part B-MAD: Cohort 8: BIIB067 100 mg
Number of subjects analysed	5	3	3	3	6	12	10	9	9	10
Units: subjects
AEs	2	2	3	3	6	12	10	9	9	10
SAEs	0	0	0	0	0	2	2	1	2	0

No statistical analyses for this end point

Primary: Parts A and B: Number of Subjects With Clinically Significant Laboratory Abnormalities

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End point title

Parts A and B: Number of Subjects With Clinically Significant Laboratory Abnormalities ^[3] ^[4]

End point description

Clinical laboratory assessments included hematology, chemistry, and urinalysis. Safety population included all randomized subjects who received at least 1 dose or a part of 1 dose of study treatment (BIIB067 or placebo) in Part A or B.

End point type

Primary

End point timeframe

Part A: Up to Day 57; Part B: Up to Day 169

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned or performed for this endpoint.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for the Part A and B arms of the study, so data was reported only for the Part A and B arm groups.

End point values	Part A-SAD: Combined Placebo	Part A-SAD: Cohort 1: BIIB067 10 mg	Part A-SAD: Cohort 2: BIIB067 20 mg	Part A-SAD: Cohort 3: BIIB067 40 mg	Part A-SAD: Cohort 4: BIIB067 60 mg	Part B-MAD: Combined Placebo	Part B-MAD: Cohort 5: BIIB067 20 mg	Part B-MAD: Cohort 6: BIIB067 40 mg	Part B-MAD: Cohort 7: BIIB067 60 mg	Part B-MAD: Cohort 8: BIIB067 100 mg
Number of subjects analysed	5	3	3	3	6	12	10	9	9	10
Units: subjects
Pleocytosis	0	0	0	0	0	0	2	1	0	0
Eosinophilia	0	0	0	0	0	0	0	0	0	1
Blood Phosphorus Decreased	0	0	0	0	0	0	0	0	1	0
CSF Protein Increased	0	0	0	0	0	1	0	0	4	1
CSF White Blood Cell Count Increased	0	0	0	0	0	0	0	1	3	0
CSF White Blood Cell Count Positive	0	0	0	0	0	0	0	0	0	1
Gamma-Glutamyltransferase Increased	0	0	0	0	0	0	1	0	0	0
Urine Output Decreased	0	0	0	0	0	1	0	0	0	0

No statistical analyses for this end point

Primary: Parts A and B: Number of Subjects With Clinically Significant Vital Sign Abnormalities

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End point title

Parts A and B: Number of Subjects With Clinically Significant Vital Sign Abnormalities ^[5] ^[6]

End point description

Safety population included all randomized subjects who received at least 1 dose or a part of 1 dose of study treatment (BIIB067 or placebo) in Part A or B.

End point type

Primary

End point timeframe

Part A: Up to Day 57; Part B: Up to Day 169

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned or performed for this endpoint.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for the Part A and B arms of the study, so data was reported only for the Part A and B arm groups.

End point values	Part A-SAD: Combined Placebo	Part A-SAD: Cohort 1: BIIB067 10 mg	Part A-SAD: Cohort 2: BIIB067 20 mg	Part A-SAD: Cohort 3: BIIB067 40 mg	Part A-SAD: Cohort 4: BIIB067 60 mg	Part B-MAD: Combined Placebo	Part B-MAD: Cohort 5: BIIB067 20 mg	Part B-MAD: Cohort 6: BIIB067 40 mg	Part B-MAD: Cohort 7: BIIB067 60 mg	Part B-MAD: Cohort 8: BIIB067 100 mg
Number of subjects analysed	5	3	3	3	6	12	10	9	9	10
Units: subjects	0	0	0	0	0	0	0	0	0	0

No statistical analyses for this end point

Primary: Parts A and B: Number of Subjects With Clinically Significant Physical Examination Abnormalities

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End point title

Parts A and B: Number of Subjects With Clinically Significant Physical Examination Abnormalities ^[7] ^[8]

End point description

Safety population included all randomized subjects who received at least 1 dose or a part of 1 dose of study treatment (BIIB067 or placebo) in Part A or B.

End point type

Primary

End point timeframe

Part A: Up to Day 57; Part B: Up to Day 169

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned or performed for this endpoint.
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for the Part A and B arms of the study, so data was reported only for the Part A and B arm groups.

End point values	Part A-SAD: Combined Placebo	Part A-SAD: Cohort 1: BIIB067 10 mg	Part A-SAD: Cohort 2: BIIB067 20 mg	Part A-SAD: Cohort 3: BIIB067 40 mg	Part A-SAD: Cohort 4: BIIB067 60 mg	Part B-MAD: Combined Placebo	Part B-MAD: Cohort 5: BIIB067 20 mg	Part B-MAD: Cohort 6: BIIB067 40 mg	Part B-MAD: Cohort 7: BIIB067 60 mg	Part B-MAD: Cohort 8: BIIB067 100 mg
Number of subjects analysed	5	3	3	3	6	12	10	9	9	10
Units: subjects
Weight Decreased	0	0	0	0	0	1	0	0	0	1

No statistical analyses for this end point

Primary: Parts A and B: Number of Subjects With Clinically Significant Neurological Examination Abnormalities

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End point title

Parts A and B: Number of Subjects With Clinically Significant Neurological Examination Abnormalities ^[9] ^[10]

End point description

Safety population included all randomized subjects who received at least 1 dose or a part of 1 dose of study treatment (BIIB067 or placebo) in Part A or B.

End point type

Primary

End point timeframe

Part A: Up to Day 57; Part B: Up to Day 169

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned or performed for this endpoint.
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for the Part A and B arms of the study, so data was reported only for the Part A and B arm groups.

End point values	Part A-SAD: Combined Placebo	Part A-SAD: Cohort 1: BIIB067 10 mg	Part A-SAD: Cohort 2: BIIB067 20 mg	Part A-SAD: Cohort 3: BIIB067 40 mg	Part A-SAD: Cohort 4: BIIB067 60 mg	Part B-MAD: Combined Placebo	Part B-MAD: Cohort 5: BIIB067 20 mg	Part B-MAD: Cohort 6: BIIB067 40 mg	Part B-MAD: Cohort 7: BIIB067 60 mg	Part B-MAD: Cohort 8: BIIB067 100 mg
Number of subjects analysed	5	3	3	3	6	12	10	9	9	10
Units: subjects
Hyporeflexia	0	0	0	0	1	0	0	0	0	0

No statistical analyses for this end point

Primary: Parts A and B: Number of Subjects With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities

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End point title

Parts A and B: Number of Subjects With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities ^[11] ^[12]

End point description

Safety population included all randomized subjects who received at least 1 dose or a part of 1 dose of study treatment (BIIB067 or placebo) in Part A or B. ms=milliseconds.

End point type

Primary

End point timeframe

Part A: Up to Day 57; Part B: Up to Day 169

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned or performed for this endpoint.
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for the Part A and B arms of the study, so data was reported only for the Part A and B arm groups.

End point values	Part A-SAD: Combined Placebo	Part A-SAD: Cohort 1: BIIB067 10 mg	Part A-SAD: Cohort 2: BIIB067 20 mg	Part A-SAD: Cohort 3: BIIB067 40 mg	Part A-SAD: Cohort 4: BIIB067 60 mg	Part B-MAD: Combined Placebo	Part B-MAD: Cohort 5: BIIB067 20 mg	Part B-MAD: Cohort 6: BIIB067 40 mg	Part B-MAD: Cohort 7: BIIB067 60 mg	Part B-MAD: Cohort 8: BIIB067 100 mg
Number of subjects analysed	5	3	3	3	6	12	10	9	9	10
Units: subjects
Maximum Increase From Baseline QTcF > 30 to 60 ms	0	0	0	0	0	3	1	2	2	3
Maximum Post-baseline QTcF > 480 to 500 ms	0	0	0	0	0	1	0	0	0	0

No statistical analyses for this end point

Primary: Parts A and B: PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax)

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End point title

Parts A and B: PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax) ^[13] ^[14]

End point description

PK population is the subset of the ITT population (all randomized subjects who received at least 1 dose or a part of 1 dose of study treatment) of subjects with at least 1 post-dose PK measurement in Part A or B. 99999=Data was not collected for subjects on Day 85 for Part A of the study.

End point type

Primary

End point timeframe

Part A: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1; Part B: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1 and 1, 2, 4, 6 hrs post-dose on Day 85

Notes
[13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned or performed for this endpoint.
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for the Part A and B arms of the study, so data was reported only for the Part A and B arm groups.

End point values	Part A-SAD: Cohort 1: BIIB067 10 mg	Part A-SAD: Cohort 2: BIIB067 20 mg	Part A-SAD: Cohort 3: BIIB067 40 mg	Part A-SAD: Cohort 4: BIIB067 60 mg	Part B-MAD: Cohort 5: BIIB067 20 mg	Part B-MAD: Cohort 6: BIIB067 40 mg	Part B-MAD: Cohort 7: BIIB067 60 mg	Part B-MAD: Cohort 8: BIIB067 100 mg
Number of subjects analysed	3	3	3	6	10	9	9	10
Units: ng/mL
geometric mean (full range (min-max))
Day 1	64.94 (38.8 to 159.0)	75.06 (43.0 to 144.0)	202.09 (174.0 to 236.0)	529.63 (148.0 to 1450.0)	80.75 (20.1 to 393.0)	229.41 (26.3 to 948.0)	437.28 (128.0 to 1930.0)	1031.74 (285.0 to 3530.0)
Day 85 (n=0, 0, 0, 0, 10, 9, 9, 10)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	112.74 (29.7 to 203.0)	199.69 (93.6 to 537.0)	411.00 (74.1 to 1450.0)	1181.83 (170.0 to 3990.0)

No statistical analyses for this end point

Primary: Parts A and B: PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax)

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End point title

Parts A and B: PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax) ^[15] ^[16]

End point description

PK population is the subset of the ITT population with at least 1 post-dose PK measurement in Part A or B. 99999=Data was not collected for subjects on Day 85 for Part A of the study.

End point type

Primary

End point timeframe

Part A: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1; Part B: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1 and 1, 2, 4, 6 hrs post-dose on Day 85

Notes
[15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned or performed for this endpoint.
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for the Part A and B arms of the study, so data was reported only for the Part A and B arm groups.

End point values	Part A-SAD: Cohort 1: BIIB067 10 mg	Part A-SAD: Cohort 2: BIIB067 20 mg	Part A-SAD: Cohort 3: BIIB067 40 mg	Part A-SAD: Cohort 4: BIIB067 60 mg	Part B-MAD: Cohort 5: BIIB067 20 mg	Part B-MAD: Cohort 6: BIIB067 40 mg	Part B-MAD: Cohort 7: BIIB067 60 mg	Part B-MAD: Cohort 8: BIIB067 100 mg
Number of subjects analysed	3	3	3	6	10	9	9	10
Units: hours
geometric mean (full range (min-max))
Day 1	4.58 (4.0 to 6.0)	4.16 (2.0 to 6.0)	6.00 (6.0 to 6.0)	2.70 (2.0 to 6.0)	7.01 (2.0 to 24.0)	3.68 (1.0 to 6.0)	2.44 (1.0 to 6.0)	3.67 (1.0 to 24.0)
Day 85 (n=0, 0, 0, 0, 10, 9, 9, 10)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	3.93 (2.0 to 6.0)	3.97 (1.0 to 6.0)	3.12 (1.0 to 6.0)	3.82 (1.0 to 6.0)

No statistical analyses for this end point

Primary: Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-Time Curve From Time Zero to 24 hours (AUC0-24h)

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End point title

Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-Time Curve From Time Zero to 24 hours (AUC0-24h) ^[17] ^[18]

End point description

PK population is the subset of the ITT population with at least 1 post-dose PK measurement in Part A or B.

End point type

Primary

End point timeframe

Parts A and B: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1

Notes
[17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned or performed for this endpoint.
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for the Part A and B arms of the study, so data was reported only for the Part A and B arm groups.

End point values	Part A-SAD: Cohort 1: BIIB067 10 mg	Part A-SAD: Cohort 2: BIIB067 20 mg	Part A-SAD: Cohort 3: BIIB067 40 mg	Part A-SAD: Cohort 4: BIIB067 60 mg	Part B-MAD: Cohort 5: BIIB067 20 mg	Part B-MAD: Cohort 6: BIIB067 40 mg	Part B-MAD: Cohort 7: BIIB067 60 mg	Part B-MAD: Cohort 8: BIIB067 100 mg
Number of subjects analysed	3	3	3	6	10	9	9	10
Units: hour*ng/mL
geometric mean (full range (min-max))
Day 1	879.86 (550.8 to 1989.5)	1027.18 (879.2 to 1263.2)	2873.77 (2347.2 to 3543.4)	5196.11 (2410.2 to 10977.3)	1009.85 (372.8 to 2192.3)	2875.13 (541.1 to 6984.8)	4289.16 (1347.6 to 10637.1)	11344.47 (4025.5 to 26143.0)

No statistical analyses for this end point

Primary: Part A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf)

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End point title

Part A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) ^[19] ^[20]

End point description

PK population is the subset of the ITT population with at least 1 post-dose PK measurement in Part A or B. 99999=Data is not available as the concentration values were below the level of quantification and could not be quantified to estimate the AUC0-infinity values.

End point type

Primary

End point timeframe

Part A: Pre-dose Day 1, Days 29 and 57; Part B: Pre-dose Days 1, 15, 29, 57 and 85; Day 106 and 169

Notes
[19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned or performed for this endpoint.
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for the Part A and B arms of the study, so data was reported only for the Part A and B arm groups.

End point values	Part A-SAD: Cohort 1: BIIB067 10 mg	Part A-SAD: Cohort 2: BIIB067 20 mg	Part A-SAD: Cohort 3: BIIB067 40 mg	Part A-SAD: Cohort 4: BIIB067 60 mg	Part B-MAD: Cohort 5: BIIB067 20 mg	Part B-MAD: Cohort 6: BIIB067 40 mg	Part B-MAD: Cohort 7: BIIB067 60 mg	Part B-MAD: Cohort 8: BIIB067 100 mg
Number of subjects analysed	3	3	3	6	10	9	9	10
Units: hour*ng/mL
arithmetic mean (standard deviation)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )

No statistical analyses for this end point

Primary: Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast)

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End point title

Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast) ^[21] ^[22]

End point description

PK population is the subset of the ITT population with at least 1 post-dose PK measurement in Part A or B. 99999=due to the large number of BLQ values at various times the last measurable concentration would have varied across individuals which makes this parameter not useful.

End point type

Primary

End point timeframe

Part A: Pre-dose Day 1, Days 29 and 57; Part B: Pre-dose Days 1, 15, 29, 57 and 85; Day 106 and 169

Notes
[21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned or performed for this endpoint.
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for the Part A and B arms of the study, so data was reported only for the Part A and B arm groups.

End point values	Part A-SAD: Cohort 1: BIIB067 10 mg	Part A-SAD: Cohort 2: BIIB067 20 mg	Part A-SAD: Cohort 3: BIIB067 40 mg	Part A-SAD: Cohort 4: BIIB067 60 mg	Part B-MAD: Cohort 5: BIIB067 20 mg	Part B-MAD: Cohort 6: BIIB067 40 mg	Part B-MAD: Cohort 7: BIIB067 60 mg	Part B-MAD: Cohort 8: BIIB067 100 mg
Number of subjects analysed	3	3	3	6	10	9	9	10
Units: hour*ng/mL
arithmetic mean (standard deviation)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )

No statistical analyses for this end point

Primary: Parts A and B: PK Parameter of BIIB067 in Plasma: Apparent Terminal Elimination Half-life (t1/2)

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End point title

Parts A and B: PK Parameter of BIIB067 in Plasma: Apparent Terminal Elimination Half-life (t1/2) ^[23] ^[24]

End point description

End point type

Primary

End point timeframe

Part A: Pre-dose Day 1, Days 29 and 57; Part B: Pre-dose Days 1, 15, 29, 57 and 85; Day 106 and 169

Notes
[23] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned or performed for this endpoint.
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for the Part A and B arms of the study, so data was reported only for the Part A and B arm groups.

End point values	Part A-SAD: Cohort 1: BIIB067 10 mg	Part A-SAD: Cohort 2: BIIB067 20 mg	Part A-SAD: Cohort 3: BIIB067 40 mg	Part A-SAD: Cohort 4: BIIB067 60 mg	Part B-MAD: Cohort 5: BIIB067 20 mg	Part B-MAD: Cohort 6: BIIB067 40 mg	Part B-MAD: Cohort 7: BIIB067 60 mg	Part B-MAD: Cohort 8: BIIB067 100 mg
Number of subjects analysed	3	3	3	6	10	9	9	10
Units: hours
median (inter-quartile range (Q1-Q3))	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Primary: Parts A and B: PK Parameters of BIIB067 in CSF Levels: Terminal Elimination Half-life (t1/2)

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End point title

Parts A and B: PK Parameters of BIIB067 in CSF Levels: Terminal Elimination Half-life (t1/2) ^[25] ^[26]

End point description

PK population is the subset of the ITT population with at least 1 post-dose PK measurement in Part A or B. 99999= Data is not available as the concentration values were below the level of quantification and could not be quantified to estimate the terminal t1/2 values.

End point type

Primary

End point timeframe

Part A: Pre-dose Day 1, Days 29 and 57; Part B: Pre-dose Days 1, 15, 29, 57 and 85; Day 106 and 169

Notes
[25] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned or performed for this endpoint.
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for the Part A and B arms of the study, so data was reported only for the Part A and B arm groups.

End point values	Part A-SAD: Cohort 1: BIIB067 10 mg	Part A-SAD: Cohort 2: BIIB067 20 mg	Part A-SAD: Cohort 3: BIIB067 40 mg	Part A-SAD: Cohort 4: BIIB067 60 mg	Part B-MAD: Cohort 5: BIIB067 20 mg	Part B-MAD: Cohort 6: BIIB067 40 mg	Part B-MAD: Cohort 7: BIIB067 60 mg	Part B-MAD: Cohort 8: BIIB067 100 mg
Number of subjects analysed	3	3	3	6	10	9	9	10
Units: hours
median (inter-quartile range (Q1-Q3))	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Primary: Part C: Change From Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Total Score at Week 28

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End point title

Part C: Change From Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Total Score at Week 28 ^[27]

End point description

The ALSFRS-R measures 4 functional domains, including respiratory, bulbar function, gross motor skills, and fine motor skills. There are 12 questions, each scored from 0 (no function) to 4 (full function), for a total possible score of 48. Scores decline with disease progression. ALSFRS-R scores calculated at diagnosis can be compared to scores throughout time to determine the speed of progression. Higher scores represent better function, negative change from baseline indicates disease progression. mITT population included all subjects who met the prognostic enrichment criteria for rapid disease progression in Part C who were randomized and received at least 1 dose of study treatment.

End point type

Primary

End point timeframe

Baseline, Week 28 (Day 197)

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for the Part C arms of the study, so data was reported only for the Part C arm groups.

End point values	Part C-Pivotal: Placebo	Part C-Pivotal: BIIB067 100 mg
Number of subjects analysed	21	39
Units: score on scale
least squares mean (standard error)	-8.1 ( 1.79 )	-7.0 ( 1.42 )

Part C-Pivotal: Placebo vs BIIB07 100 mg

Statistical analysis description

ANCOVA model included treatment as a fixed effect, adjusts for the covariates: Baseline disease duration since symptom onset, baseline ALSFRS-R total score, and use of riluzole or edaravone. Multiple imputation was used to handle missing data for withdrawals. Joint rank test combining function and mortality were used for statistical inference and the estimates were from the ANCOVA model for change from baseline.

Comparison groups

Part C-Pivotal: BIIB067 100 mg v Part C-Pivotal: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9689 ^[28]

Method

Joint rank

Parameter type

least square (LS) mean difference

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-3.19

upper limit

5.53

Variability estimate

Standard error of the mean

Dispersion value

2.22

Notes
[28] - p-value was calculated from joint rank test.

Secondary: Part B: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline

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End point title

Part B: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline ^[29]

End point description

Total CSF SOD1 protein ratio to baseline was calculated. PD population is the subset of the ITT population with at least 1 post-dose PD measurement in Part B. 99999=Data is not estimable due to small sample size.

End point type

Secondary

End point timeframe

Day 85

Notes
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for the Part B arms of the study, so data was reported only for the Part B arm groups.

End point values	Part B-MAD: Combined Placebo	Part B-MAD: Cohort 5: BIIB067 20 mg	Part B-MAD: Cohort 6: BIIB067 40 mg	Part B-MAD: Cohort 7: BIIB067 60 mg	Part B-MAD: Cohort 8: BIIB067 100 mg
Number of subjects analysed	12	10	9	8	10
Units: ratio
geometric mean (confidence interval 95%)
Day 85	0.97 (0.83 to 1.13)	0.99 (0.83 to 1.18)	0.73 (0.61 to 0.87)	0.79 (0.66 to 0.94)	0.64 (0.55 to 0.76)

Part B-MAD: Placebo vs Cohort 5 (BIIB067 20 mg)

Statistical analysis description

Day 85

Comparison groups

Part B-MAD: Combined Placebo v Part B-MAD: Cohort 5: BIIB067 20 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Wilcoxon rank sum test

Parameter type

diff in LS geometric mean ratio tof:pbo

Point estimate

0.67

Confidence interval

level

95%

sides

2-sided

lower limit

0.53

upper limit

0.84

Part B-MAD: Placebo vs Cohort 6 (BIIB067 40 mg)

Statistical analysis description

Day 85

Comparison groups

Part B-MAD: Combined Placebo v Part B-MAD: Cohort 6: BIIB067 40 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0002

Method

Wilcoxon rank sum test

Parameter type

diff in LS geometric mean ratio tof:pbo

Point estimate

0.75

Confidence interval

level

95%

sides

2-sided

lower limit

0.6

upper limit

0.95

Part B-MAD: Placebo vs Cohort 7 (BIIB067 60 mg)

Statistical analysis description

Day 85

Comparison groups

Part B-MAD: Combined Placebo v Part B-MAD: Cohort 7: BIIB067 60 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0641

Method

Wilcoxon rank sum test

Parameter type

diff in LS geometric mean ratio tof:pbo

Point estimate

0.81

Confidence interval

level

95%

sides

2-sided

lower limit

0.65

upper limit

1.02

Part B-MAD: Placebo vs Cohort 8 (BIIB067 100 mg)

Statistical analysis description

Day 85

Comparison groups

Part B-MAD: Combined Placebo v Part B-MAD: Cohort 8: BIIB067 100 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Wilcoxon rank sum test

Parameter type

diff in LS geometric mean ratio tof:pbo

Point estimate

0.67

Confidence interval

level

95%

sides

2-sided

lower limit

0.53

upper limit

0.84

Secondary: Part C: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline

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End point title

Part C: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline ^[30]

End point description

Total CSF SOD1 protein ratio to baseline was calculated. mITT population included all subjects who met the prognostic enrichment criteria for rapid disease progression in Part C who were randomized and received at least 1 dose of study treatment. Data reported under LS mean refers to ‘LS Geometric Mean Ratio to Baseline’.

End point type

Secondary

End point timeframe

Week 28 (Day 197)

Notes
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for the Part C arms of the study, so data was reported only for the Part C arm groups.

End point values	Part C-Pivotal: Placebo	Part C-Pivotal: BIIB067 100 mg
Number of subjects analysed	21	39
Units: ratio
least squares mean (confidence interval 95%)	1.16 (0.96 to 1.40)	0.71 (0.62 to 0.83)

Part C-Pivotal: Placebo vs BIIB067 100 mg

Statistical analysis description

The ANCOVA model included covariates for the corresponding baseline value i.e. log value, baseline disease duration since symptom onset, and use of riluzole or edaravone. Multiple imputation was used to handle missing data for withdrawals.

Comparison groups

Part C-Pivotal: Placebo v Part C-Pivotal: BIIB067 100 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[31]

Method

ANCOVA

Parameter type

diff in LS geometric mean ratio tof:pbo

Point estimate

0.62

Confidence interval

level

95%

sides

2-sided

lower limit

0.49

upper limit

0.78

Notes
[31] - The analysis was based on ANCOVA model with natural log transformed data.

Secondary: Part C: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) at Week 28

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End point title

Part C: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) at Week 28 ^[32]

End point description

Vital capacity was measured by means of an SVC test, administered in the upright position. mITT population included all subjects who met the prognostic enrichment criteria for rapid disease progression in Part C who were randomized and received at least 1 dose of study treatment.

End point type

Secondary

End point timeframe

Baseline, Week 28 (Day 197)

Notes
[32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for the Part C arms of the study, so data was reported only for the Part C arm groups.

End point values	Part C-Pivotal: Placebo	Part C-Pivotal: BIIB067 100 mg
Number of subjects analysed	21	39
Units: percent predicted
least squares mean (standard error)	-22.20 ( 4.771 )	-14.31 ( 3.557 )

Part C-Pivotal: Placebo vs BIIB067 100 mg

Statistical analysis description

Multiple imputation was used to handle missing data for withdrawals. Joint rank test combining function and mortality were used for statistical inference and the estimates were from the ANCOVA for change from baseline.

Comparison groups

Part C-Pivotal: Placebo v Part C-Pivotal: BIIB067 100 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3233 ^[33]

Method

Joint rank

Parameter type

LS mean difference

Point estimate

7.9

Confidence interval

level

95%

sides

2-sided

lower limit

-3.528

upper limit

19.322

Variability estimate

Standard error of the mean

Dispersion value

5.829

Notes
[33] - Joint rank p-value was calculated from ANCOVA model which included treatment as fixed effect, adjusts for covariates: Baseline disease duration since symptom onset, baseline ALSFRS-R total score, and use of riluzole or edaravone.

Secondary: Part C: Change From Baseline in Handheld Dynamometry (HHD) Megascore as Measured by the HHD Device at Week 28

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End point title

Part C: Change From Baseline in Handheld Dynamometry (HHD) Megascore as Measured by the HHD Device at Week 28 ^[34]

End point description

Quantitative muscle strength was evaluated using HHD, which tests isometric strength of multiple muscles using standard subject positioning. Sixteen muscle groups were evaluated in both upper and lower extremities. Strength determinations were converted to Z scores and averaged to provide an HHD megascore. The muscle strength values were normalized to Z scores as (post-baseline measurements – mean)/SD and averaged to provide HHD overall megascore. The overall megascore was created by averaging all eight bilateral measurement Z scores, if no more than 10 (≤ 10) measures are missing. A negative change from baseline indicated decreased muscle strength. mITT population included all subjects who met the prognostic enrichment criteria for rapid disease progression in Part C who were randomized and received at least 1 dose of study treatment.

End point type

Secondary

End point timeframe

Baseline, Week 28 (Day 197)

Notes
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for the Part C arms of the study, so data was reported only for the Part C arm groups.

End point values	Part C-Pivotal: Placebo	Part C-Pivotal: BIIB067 100 mg
Number of subjects analysed	21	39
Units: score on a scale
least squares mean (standard error)	-0.37 ( 0.096 )	-0.34 ( 0.073 )

Part C-Pivotal: Placebo vs BIIB067 100 mg

Comparison groups

Part C-Pivotal: Placebo v Part C-Pivotal: BIIB067 100 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.839 ^[35]

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.207

upper limit

0.255

Variability estimate

Standard error of the mean

Dispersion value

0.118

Notes
[35] - The ANCOVA model included treatment as a fixed effect and adjusts for the following covariates: baseline disease duration since symptom onset, baseline HHD overall megascore, and use of riluzole or edaravone.

Secondary: Part C: Time to Death or Permanent Ventilation

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End point title

Part C: Time to Death or Permanent Ventilation ^[36]

End point description

Time to Death or Permanent Ventilation is defined as the time to the earliest occurrence of one of the following events that were adjudicated by an independent committee: Death; Permanent ventilation (≥22 hours of mechanical ventilation [invasive or noninvasive] per day for ≥21 consecutive days). mITT population included all subjects who met the prognostic enrichment criteria for rapid disease progression in Part C who were randomized and received at least 1 dose of study treatment. 99999=not estimated due to insufficient number of participants with events.

End point type

Secondary

End point timeframe

Baseline up to Week 28 (Day 197)

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for the Part C arms of the study, so data was reported only for the Part C arm groups.

End point values	Part C-Pivotal: Placebo	Part C-Pivotal: BIIB067 100 mg
Number of subjects analysed	21	39
Units: days
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Part C: Time to Death

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End point title

Part C: Time to Death ^[37]

End point description

mITT population included all subjects who met the prognostic enrichment criteria for rapid disease progression in Part C who were randomized and received at least 1 dose of study treatment. 99999=not estimated due to insufficient number of participants with events.

End point type

Secondary

End point timeframe

Baseline up to Week 28 (Day 197)

Notes
[37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for the Part C arms of the study, so data was reported only for the Part C arm groups.

End point values	Part C-Pivotal: Placebo	Part C-Pivotal: BIIB067 100 mg
Number of subjects analysed	21	39
Units: days
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Part C: Number of Subjects Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs)

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End point title

Part C: Number of Subjects Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) ^[38]

End point description

An AE is any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A SAE is any untoward medical occurrence that at any dose results in death, life-threatening event, requires inpatient hospitalization, significant disability/incapacity or congenital anomaly. Safety population included all subjects in Part C who were randomized and received at least one dose of study treatment.

End point type

Secondary

End point timeframe

First dose up to Day 236

Notes
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for the Part C arms of the study, so data was reported only for the Part C arm groups.

End point values	Part C-Pivotal: Placebo	Part C-Pivotal: BIIB067 100 mg
Number of subjects analysed	36	72
Units: subjects
AEs	34	69
SAEs	5	13

No statistical analyses for this end point

Secondary: Part C: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline

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End point title

Part C: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline ^[39]

End point description

NfL is a biomarker whose concentration was assessed in plasma. Plasma NfL ratio to baseline was calculated. mITT population included all subjects who met the prognostic enrichment criteria for rapid disease progression in Part C who were randomized and received at least 1 dose of study treatment. Data reported under Geometric Mean refers to ‘LS Geometric Mean’.

End point type

Secondary

End point timeframe

Baseline, Day 197 (Week 28)

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for the Part C arms of the study, so data was reported only for the Part C arm groups.

End point values	Part C-Pivotal: Placebo	Part C-Pivotal: BIIB067 100 mg
Number of subjects analysed	21	39
Units: ratio
geometric mean (confidence interval 95%)
Day 197	1.20 (0.94 to 1.52)	0.40 (0.33 to 0.48)

Part C-Pivotal: Placebo vs BIIB067 100 mg

Statistical analysis description

Day 197 (Week 28)

Comparison groups

Part C-Pivotal: Placebo v Part C-Pivotal: BIIB067 100 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[40]

Method

ANCOVA

Parameter type

diff in LS geometric mean ratio tof:pbo

Point estimate

0.33

Confidence interval

level

95%

sides

2-sided

lower limit

0.25

upper limit

0.45

Notes
[40] - The analysis was based on ANCOVA model with natural log transformed data. The model included covariates for the corresponding baseline value i.e. log value, baseline disease duration since symptom onset, and use of riluzole or edaravone.

Adverse events

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Timeframe for reporting adverse events

Part A: First dose up to Day 63; Part B: First dose up to Day 289; Part C: First dose up to Day 236

Adverse event reporting additional description

Safety population included all randomized subjects who received at least 1 dose or a part of 1 dose of study treatment (BIIB067 or placebo) in Part A or B. Safety population included all subjects in Part C who were randomized and received at least one dose of study treatment. MedDRA version for Parts A and B: 22.0, Part C: 24.0

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

Part A-SAD: Cohort 1: BIIB067 10 mg

Reporting group description

Subjects were administered BIIB067 10 mg once by intrathecal bolus injection on Day 1.

Reporting group title

Part A-SAD: Cohort 2: BIIB067 20 mg

Reporting group description

Subjects were administered BIIB067 20 mg once by intrathecal bolus injection on Day 1 of Cohort 2 after the safety review of Cohort 1.

Reporting group title

Part A-SAD: Cohort 3: BIIB067 40 mg

Reporting group description

Subjects were administered BIIB067 40 mg once by intrathecal bolus injection on Day 1 of Cohort 3 after the safety review of Cohort 2.

Reporting group title

Part A-SAD: Cohort 4: BIIB067 60 mg

Reporting group description

Subjects were administered BIIB067 60 mg once by intrathecal bolus injection on Day 1 of Cohort 4 after the safety review of Cohort 3.

Reporting group title

Part A-SAD: Combined Placebo

Reporting group description

Subjects were administered BIIB067-matching placebo once by intrathecal bolus injection on Day 1 of Cohorts 1, 2, 3, and 4 respectively.

Reporting group title

Part B-MAD: Cohort 5: BIIB067 20 mg

Reporting group description

Subjects were administered BIIB067 20 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection.

Reporting group title

Part B-MAD: Cohort 6: BIIB067 40 mg

Reporting group description

Reporting group title

Part B-MAD: Cohort 7: BIIB067 60 mg

Reporting group description

Reporting group title

Part B-MAD: Cohort 8: BIIB067 100 mg

Reporting group description

Reporting group title

Part B-MAD: Combined Placebo

Reporting group description

Subjects were administered BIIB067-matching placebo, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection.

Reporting group title

Part C-Pivotal: BIIB067 100 mg

Reporting group description

Reporting group title

Part C-Pivotal: Placebo

Reporting group description

Part A-SAD: Cohort 1: BIIB067 10 mg

Part A-SAD: Cohort 2: BIIB067 20 mg

Part A-SAD: Cohort 3: BIIB067 40 mg

Part A-SAD: Cohort 4: BIIB067 60 mg

Part A-SAD: Combined Placebo

Part B-MAD: Cohort 5: BIIB067 20 mg

Part B-MAD: Cohort 6: BIIB067 40 mg

Part B-MAD: Cohort 7: BIIB067 60 mg

Part B-MAD: Cohort 8: BIIB067 100 mg

Part B-MAD: Combined Placebo

Part C-Pivotal: BIIB067 100 mg

Part C-Pivotal: Placebo

Total subjects affected by serious adverse events

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

2 / 10 (20.00%)

1 / 9 (11.11%)

2 / 9 (22.22%)

0 / 10 (0.00%)

2 / 12 (16.67%)

13 / 72 (18.06%)

5 / 36 (13.89%)

number of deaths (all causes)

number of deaths resulting from adverse events

Investigations

Csf protein increased

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 9 (11.11%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 72 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Csf white blood cell count increased

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 9 (11.11%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 72 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

Fibula fracture

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

1 / 72 (1.39%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Meningitis chemical

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

1 / 72 (1.39%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vascular disorders

Deep vein thrombosis

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

1 / 72 (1.39%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac disorders

Cardiac failure congestive

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

1 / 10 (10.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

1 / 72 (1.39%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

Nervous system disorders

Loss of consciousness

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

1 / 72 (1.39%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Lumbar radiculopathy

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

1 / 72 (1.39%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Myelitis transverse

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

1 / 72 (1.39%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

General disorders and administration site conditions

Hypothermia

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

1 / 72 (1.39%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Impaired self-care

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

1 / 72 (1.39%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory complication associated with device

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

1 / 72 (1.39%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Faecaloma

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

1 / 72 (1.39%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory, thoracic and mediastinal disorders

Acute respiratory failure

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

1 / 12 (8.33%)

1 / 72 (1.39%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Aspiration

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

1 / 72 (1.39%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Atelectasis

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 72 (0.00%)

1 / 36 (2.78%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Dyspnoea

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

1 / 10 (10.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 72 (0.00%)

2 / 36 (5.56%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Pneumonia aspiration

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

2 / 72 (2.78%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Pulmonary embolism

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

3 / 72 (4.17%)

1 / 36 (2.78%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 1

deaths causally related to treatment / all

0 / 0

Respiratory failure

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 10 (0.00%)

1 / 9 (11.11%)

0 / 10 (0.00%)

1 / 12 (8.33%)

1 / 72 (1.39%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

Infections and infestations

Myelitis

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

1 / 72 (1.39%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

Dehydration

subjects affected / exposed

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 72 (0.00%)

1 / 36 (2.78%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

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

Non-serious adverse events	Part A-SAD: Cohort 1: BIIB067 10 mg	Part A-SAD: Cohort 2: BIIB067 20 mg	Part A-SAD: Cohort 3: BIIB067 40 mg	Part A-SAD: Cohort 4: BIIB067 60 mg	Part A-SAD: Combined Placebo	Part B-MAD: Cohort 5: BIIB067 20 mg	Part B-MAD: Cohort 6: BIIB067 40 mg	Part B-MAD: Cohort 7: BIIB067 60 mg	Part B-MAD: Cohort 8: BIIB067 100 mg	Part B-MAD: Combined Placebo	Part C-Pivotal: BIIB067 100 mg	Part C-Pivotal: Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	2 / 3 (66.67%)	3 / 3 (100.00%)	3 / 3 (100.00%)	6 / 6 (100.00%)	2 / 5 (40.00%)	10 / 10 (100.00%)	9 / 9 (100.00%)	9 / 9 (100.00%)	10 / 10 (100.00%)	11 / 12 (91.67%)	68 / 72 (94.44%)	34 / 36 (94.44%)
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	2
Flushing
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	0	0
Hypertension
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	1 / 72 (1.39%)	2 / 36 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	2
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2
Chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Fatigue
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)	2 / 9 (22.22%)	2 / 10 (20.00%)	2 / 12 (16.67%)	12 / 72 (16.67%)	2 / 36 (5.56%)
occurrences all number	0	0	0	0	0	1	1	2	2	2	22	2
Feeling abnormal
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Feeling hot
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Influenza like illness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	1 / 72 (1.39%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	1	0
Infusion site bruising
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Infusion site swelling
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0
Oedema peripheral
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	2 / 72 (2.78%)	0 / 36 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	2	0
Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)	7 / 72 (9.72%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	13	0
Peripheral swelling
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	1 / 72 (1.39%)	1 / 36 (2.78%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	1	2
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 10 (10.00%)	0 / 12 (0.00%)	3 / 72 (4.17%)	1 / 36 (2.78%)
occurrences all number	0	0	1	0	0	0	0	1	1	0	5	1
Immune system disorders
Dust allergy
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Choking
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2
Cough
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)	5 / 72 (6.94%)	1 / 36 (2.78%)
occurrences all number	0	0	0	0	0	1	0	0	0	1	5	1
Dyspnoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	0 / 10 (0.00%)	1 / 12 (8.33%)	4 / 72 (5.56%)	5 / 36 (13.89%)
occurrences all number	0	0	0	0	0	0	1	1	0	1	4	5
Oropharyngeal pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 10 (20.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 12 (0.00%)	2 / 72 (2.78%)	2 / 36 (5.56%)
occurrences all number	0	1	0	0	0	4	0	1	0	0	3	2
Respiratory symptom
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Rhinorrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Sleep apnoea syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Sputum discoloured
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Upper respiratory tract congestion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Upper-airway cough syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	2	1	0	0	0	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 10 (10.00%)	0 / 12 (0.00%)	4 / 72 (5.56%)	3 / 36 (8.33%)
occurrences all number	0	0	0	0	0	0	0	2	1	0	5	3
Depression
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	1 / 72 (1.39%)	3 / 36 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	3
Insomnia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 12 (0.00%)	3 / 72 (4.17%)	3 / 36 (8.33%)
occurrences all number	0	0	0	0	0	1	0	2	0	0	3	3
Investigations
Csf protein increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	3 / 9 (33.33%)	1 / 10 (10.00%)	1 / 12 (8.33%)	6 / 72 (8.33%)	1 / 36 (2.78%)
occurrences all number	0	0	0	0	0	0	0	3	1	1	6	1
Blood phosphorus decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Csf white blood cell count increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	2 / 9 (22.22%)	0 / 10 (0.00%)	0 / 12 (0.00%)	7 / 72 (9.72%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	1	2	0	0	8	0
Csf white blood cell count positive
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	2	0	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Urine output decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Weight decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	1 / 12 (8.33%)	0 / 72 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	0	2
Injury, poisoning and procedural complications
Accident
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Arthropod bite
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	1 / 36 (2.78%)
occurrences all number	0	0	0	0	0	1	3	1	0	0	0	1
Contusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 10 (20.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	2 / 10 (20.00%)	1 / 12 (8.33%)	3 / 72 (4.17%)	1 / 36 (2.78%)
occurrences all number	0	0	0	0	0	2	1	0	2	1	3	1
Fall
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	3 / 10 (30.00%)	3 / 9 (33.33%)	2 / 9 (22.22%)	5 / 10 (50.00%)	3 / 12 (25.00%)	17 / 72 (23.61%)	15 / 36 (41.67%)
occurrences all number	0	0	0	0	0	4	3	3	11	7	38	38
Foot fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Head injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	1 / 36 (2.78%)
occurrences all number	0	0	0	0	0	0	0	0	3	0	0	2
Joint injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	1 / 72 (1.39%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	3	0
Ligament sprain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 9 (22.22%)	0 / 10 (0.00%)	0 / 12 (0.00%)	4 / 72 (5.56%)	2 / 36 (5.56%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	4	2
Muscle strain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	1 / 72 (1.39%)	1 / 36 (2.78%)
occurrences all number	0	0	0	0	0	0	0	0	2	0	1	1
Musculoskeletal procedural complication
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	3 / 72 (4.17%)	3 / 36 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	4	5
Nasal injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Post lumbar puncture syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	4 / 10 (40.00%)	3 / 9 (33.33%)	3 / 9 (33.33%)	3 / 10 (30.00%)	3 / 12 (25.00%)	13 / 72 (18.06%)	11 / 36 (30.56%)
occurrences all number	0	0	0	0	1	9	9	5	7	4	34	21
Post procedural complication
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)	3 / 72 (4.17%)	4 / 36 (11.11%)
occurrences all number	0	0	0	0	0	0	1	0	0	1	3	4
Post procedural contusion
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	2 / 10 (20.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	1 / 72 (1.39%)	0 / 36 (0.00%)
occurrences all number	0	1	0	1	0	2	1	0	0	0	1	0
Post procedural discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)	0 / 72 (0.00%)	1 / 36 (2.78%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	1
Post-traumatic pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Procedural anxiety
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Procedural complication
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 12 (0.00%)	2 / 72 (2.78%)	1 / 36 (2.78%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	2	1
Procedural dizziness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	1 / 72 (1.39%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	1	0
Procedural headache
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	3	0	0	0
Procedural nausea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)	2 / 72 (2.78%)	2 / 36 (5.56%)
occurrences all number	0	0	0	0	0	1	1	0	0	1	2	2
Procedural pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	3 / 6 (50.00%)	1 / 5 (20.00%)	4 / 10 (40.00%)	1 / 9 (11.11%)	4 / 9 (44.44%)	7 / 10 (70.00%)	5 / 12 (41.67%)	41 / 72 (56.94%)	21 / 36 (58.33%)
occurrences all number	0	2	0	3	1	5	6	13	20	16	110	32
Skin abrasion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 12 (0.00%)	3 / 72 (4.17%)	3 / 36 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	5	5
Skin laceration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	3 / 36 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	5
Subcutaneous haematoma
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	0	0
Sunburn
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Tibia fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	1 / 72 (1.39%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	1	0
Vaccination complication
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	1 / 72 (1.39%)	2 / 36 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	5	2
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)	1 / 72 (1.39%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	1	1	0
Tachycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)	1 / 72 (1.39%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	1	0
Nervous system disorders
Balance disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Dizziness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	3 / 10 (30.00%)	0 / 12 (0.00%)	4 / 72 (5.56%)	3 / 36 (8.33%)
occurrences all number	0	0	0	1	0	0	0	3	5	0	4	3
Dysaesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	1 / 72 (1.39%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	3	0	2	0
Headache
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	1 / 3 (33.33%)	1 / 6 (16.67%)	0 / 5 (0.00%)	4 / 10 (40.00%)	2 / 9 (22.22%)	4 / 9 (44.44%)	6 / 10 (60.00%)	7 / 12 (58.33%)	33 / 72 (45.83%)	16 / 36 (44.44%)
occurrences all number	0	2	1	1	0	4	3	8	11	12	66	32
Hypoaesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	3 / 72 (4.17%)	1 / 36 (2.78%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	3	1
Hyporeflexia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0
Muscle contractions involuntary
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)	4 / 72 (5.56%)	1 / 36 (2.78%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	4	1
Migraine
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	2 / 72 (2.78%)	1 / 36 (2.78%)
occurrences all number	0	0	0	1	0	0	0	0	3	0	2	1
Muscle spasticity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	1 / 72 (1.39%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	1	0
Nerve compression
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2
Neuralgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	4 / 72 (5.56%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	4	0
Paraesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	6 / 72 (8.33%)	6 / 36 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	6	10
Peroneal nerve palsy
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0
Pleocytosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 10 (20.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	3 / 72 (4.17%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	2	1	0	0	0	3	0
Sinus headache
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	1 / 36 (2.78%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	1
Blood and lymphatic system disorders
Eosinophilia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	2 / 72 (2.78%)	2 / 36 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	2
Abdominal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	2 / 72 (2.78%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	2	0
Abdominal pain lower
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0
Constipation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)	6 / 72 (8.33%)	4 / 36 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	6	4
Diarrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	1 / 72 (1.39%)	5 / 36 (13.89%)
occurrences all number	0	0	0	0	0	1	0	0	1	0	1	6
Dyspepsia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Dysphagia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	1 / 72 (1.39%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	1	0
Faeces discoloured
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	1 / 72 (1.39%)	0 / 36 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	1	0
Gastritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2
Gastrointestinal disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Gingival pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	1	0	0	0
Lip swelling
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Nausea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	2 / 9 (22.22%)	1 / 9 (11.11%)	2 / 10 (20.00%)	0 / 12 (0.00%)	9 / 72 (12.50%)	6 / 36 (16.67%)
occurrences all number	0	0	0	0	0	1	2	1	2	0	24	9
Salivary hypersecretion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 10 (10.00%)	0 / 12 (0.00%)	4 / 72 (5.56%)	1 / 36 (2.78%)
occurrences all number	0	0	0	0	0	1	0	1	1	0	4	1
Toothache
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	2 / 9 (22.22%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)	1 / 72 (1.39%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	1	1	0
Skin and subcutaneous tissue disorders
Cold sweat
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0
Decubitus ulcer
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	0
Dermatitis allergic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 12 (0.00%)	1 / 72 (1.39%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	2	0
Eczema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Erythema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	1 / 36 (2.78%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	1
Miliaria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Night sweats
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Pruritus
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	3 / 72 (4.17%)	1 / 36 (2.78%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	3	1
Rash
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	1 / 12 (8.33%)	2 / 72 (2.78%)	0 / 36 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	1	2	2	0
Rash pruritic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Skin disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Skin plaque
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Urinary incontinence
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Urinary retention
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	0 / 5 (0.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	5 / 10 (50.00%)	0 / 12 (0.00%)	15 / 72 (20.83%)	2 / 36 (5.56%)
occurrences all number	0	0	0	2	0	1	1	1	8	0	25	3
Arthralgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	2 / 10 (20.00%)	1 / 12 (8.33%)	10 / 72 (13.89%)	2 / 36 (5.56%)
occurrences all number	0	0	1	0	0	1	1	1	2	1	12	2
Bursitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	1 / 72 (1.39%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	1	0
Flank pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	2 / 72 (2.78%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	2	0
Joint swelling
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	1 / 72 (1.39%)	2 / 36 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	2	2
Muscle spasms
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	5 / 72 (6.94%)	2 / 36 (5.56%)
occurrences all number	0	0	0	2	0	0	1	0	0	0	5	3
Muscle tightness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	1 / 72 (1.39%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	0	1	0
Muscular weakness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	1 / 10 (10.00%)	1 / 12 (8.33%)	4 / 72 (5.56%)	4 / 36 (11.11%)
occurrences all number	0	0	0	0	0	0	1	0	1	1	6	8
Musculoskeletal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	4 / 72 (5.56%)	2 / 36 (5.56%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	4	2
Musculoskeletal stiffness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	4 / 72 (5.56%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	6	0
Neck pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	3 / 12 (25.00%)	4 / 72 (5.56%)	4 / 36 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1	0	3	7	5
Myalgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 9 (22.22%)	0 / 10 (0.00%)	0 / 12 (0.00%)	10 / 72 (13.89%)	2 / 36 (5.56%)
occurrences all number	0	0	0	1	0	0	0	7	0	0	21	3
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	3 / 10 (30.00%)	2 / 12 (16.67%)	19 / 72 (26.39%)	6 / 36 (16.67%)
occurrences all number	0	0	1	1	0	0	1	0	5	2	37	6
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	1 / 36 (2.78%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	1
Ear infection
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0
Fungal skin infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	2 / 9 (22.22%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	1 / 36 (2.78%)
occurrences all number	0	0	0	0	0	0	2	0	0	0	0	1
Gastroenteritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	1 / 36 (2.78%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	1
Gastric infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Hordeolum
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 12 (0.00%)	1 / 72 (1.39%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	1	0
Influenza
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 12 (0.00%)	1 / 72 (1.39%)	1 / 36 (2.78%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	1	1
Labyrinthitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Lower respiratory tract infection
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0
Nasopharyngitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 10 (20.00%)	1 / 9 (11.11%)	3 / 9 (33.33%)	1 / 10 (10.00%)	1 / 12 (8.33%)	2 / 72 (2.78%)	7 / 36 (19.44%)
occurrences all number	0	1	0	0	0	2	1	3	1	1	2	9
Oral herpes
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	2	0	0	0
Pharyngitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Pneumonia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Sinusitis
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	1 / 72 (1.39%)	1 / 36 (2.78%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	2	2
Systemic viral infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Tooth abscess
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	4 / 10 (40.00%)	0 / 9 (0.00%)	2 / 9 (22.22%)	0 / 10 (0.00%)	0 / 12 (0.00%)	5 / 72 (6.94%)	2 / 36 (5.56%)
occurrences all number	0	0	0	0	0	5	0	2	0	0	5	2
Urinary tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	2 / 10 (20.00%)	1 / 12 (8.33%)	2 / 72 (2.78%)	2 / 36 (5.56%)
occurrences all number	0	0	0	0	0	0	1	0	2	1	2	2
Viral upper respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	0	1	2	0	0	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)	3 / 72 (4.17%)	1 / 36 (2.78%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	3	1
Diabetes mellitus inadequate control
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	0 / 36 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Type 2 diabetes mellitus
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 72 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

10 Oct 2016

Added the review of PK data and clarified the review of safety data prior to each dose escalation in Part B (MAD portion) of the study • Added the MMSE as part of the neurological examination • Other major changes were made to the study eligibility criteria for Part A (SAD) to allow only those subjects with ALS caused by a SOD1 mutation to enter the study.

17 Nov 2016

Corrected to reflect in the protocol that sampling for anti-BIIB067 antibodies was occurred during non-dosing clinical visits (except for predose on Day 1).

29 Nov 2017

Added an 8th treatment cohort to assess the safety and tolerability of up to 5 doses of BIB067 100 mg, and to include the option of an interim analysis during Part B (MAD portion) of the study. • Other major changes were made to the study stopping rules to clarify that SAEs or AEs determined to be unrelated to study treatment would not trigger dose suspension and to further specify situations that could trigger dose termination.

20 Dec 2018

Included a third part (Part C [Pivotal]) of approximately 60 subjects (2:1 randomization ratio of BIIB067:placebo) to assess the efficacy, safety, tolerability, PK, and PD of BIIB067 at 100 mg. Part C was to be conducted over a 4-week screening period, 24-week treatment period and 4-week follow-up period. Because the inclusion of Part C also warranted a change in the phase of development of the study, the title of the protocol was changed to accurately reflect study design and objectives and endpoints.

19 Sep 2019

Described the changes to the primary endpoint and statistical methodology, sample size considerations, and inclusion of an optional interim efficacy analysis for Part C (Pivotal) of the study. • The primary efficacy endpoint was revised from ALSFRS-R slope to total score (change from baseline to Week 28) and was analyzed via a joint-rank analysis that combines the ALSFRS-R score and survival time. This approach minimized the dependency on linearity assumptions (of the ALSFRS-R slope decline) and enabled a robust mechanism for accounting for missing data due to death. • The sample size for Part C of the study was increased to approximately 99 subjects (increased from up to 60 subjects) based on the following changes – Revised primary efficacy endpoint of change in ALSFRS-R total score from baseline to Day 197/Week 28 analyzed via the joint-rank methodology, two-sided alpha of 0.05 for the primary analysis, revised survival assumptions based on further review of natural history data and data from an interim analysis of Part B of this study (82% survival in the placebo control group and 90% survival in the tofersen group), • Under these assumptions, approximately 60 subjects (increased from 36) were needed in the mITT population (fast progressors) to achieve approximately 84% power. The target sample size for the non-fast progressor population was increased to approximately 39 subjects (increased from 24) to enable adequate power to detect a statistically significant reduction in CSF SOD1 concentrations. • Also, the assumptions for the sample size needed for the population outside the mITT were updated based on the current results from Part B of Study 2015-004098-33.

30 Sep 2019

Added a provision to collect subject’s urine sample for future exploratory research, in all regions where not prohibited by regulatory authorities or ethics committee.

15 Jun 2021

Updated the final statistical analysis plan for Part C.

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 Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of BIIB067 Administered to Adult Subjects with Amyotrophic Lateral Sclerosis and Confirmed Superoxide Dismutase 1 Mutation

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Parts A and B: Number of Subjects Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs)

Primary: Parts A and B: Number of Subjects Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs)

Primary: Parts A and B: Number of Subjects With Clinically Significant Laboratory Abnormalities

Primary: Parts A and B: Number of Subjects With Clinically Significant Laboratory Abnormalities

Primary: Parts A and B: Number of Subjects With Clinically Significant Vital Sign Abnormalities

Primary: Parts A and B: Number of Subjects With Clinically Significant Vital Sign Abnormalities

Primary: Parts A and B: Number of Subjects With Clinically Significant Physical Examination Abnormalities

Primary: Parts A and B: Number of Subjects With Clinically Significant Physical Examination Abnormalities

Primary: Parts A and B: Number of Subjects With Clinically Significant Neurological Examination Abnormalities

Primary: Parts A and B: Number of Subjects With Clinically Significant Neurological Examination Abnormalities

Primary: Parts A and B: Number of Subjects With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities

Primary: Parts A and B: Number of Subjects With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities

Primary: Parts A and B: PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax)

Primary: Parts A and B: PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax)

Primary: Parts A and B: PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax)

Primary: Parts A and B: PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax)

Primary: Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-Time Curve From Time Zero to 24 hours (AUC0-24h)

Primary: Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-Time Curve From Time Zero to 24 hours (AUC0-24h)

Primary: Part A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf)

Primary: Part A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf)

Primary: Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast)

Primary: Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast)

Primary: Parts A and B: PK Parameter of BIIB067 in Plasma: Apparent Terminal Elimination Half-life (t1/2)

Primary: Parts A and B: PK Parameter of BIIB067 in Plasma: Apparent Terminal Elimination Half-life (t1/2)

Primary: Parts A and B: PK Parameters of BIIB067 in CSF Levels: Terminal Elimination Half-life (t1/2)

Primary: Parts A and B: PK Parameters of BIIB067 in CSF Levels: Terminal Elimination Half-life (t1/2)

Primary: Part C: Change From Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Total Score at Week 28

Primary: Part C: Change From Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Total Score at Week 28

Secondary: Part B: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline

Secondary: Part B: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline

Secondary: Part C: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline

Secondary: Part C: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline

Secondary: Part C: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) at Week 28

Secondary: Part C: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) at Week 28

Secondary: Part C: Change From Baseline in Handheld Dynamometry (HHD) Megascore as Measured by the HHD Device at Week 28

Secondary: Part C: Change From Baseline in Handheld Dynamometry (HHD) Megascore as Measured by the HHD Device at Week 28

Secondary: Part C: Time to Death or Permanent Ventilation

Secondary: Part C: Time to Death or Permanent Ventilation

Secondary: Part C: Time to Death

Secondary: Part C: Time to Death

Secondary: Part C: Number of Subjects Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary: Part C: Number of Subjects Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary: Part C: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline

Secondary: Part C: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of BIIB067 Administered to Adult Subjects with Amyotrophic Lateral Sclerosis and Confirmed Superoxide Dismutase 1 Mutation