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Clinical Trial Results:
A Phase 1/2 Multiple-Ascending-Dose Study With a Long-Term Open-Label Extension to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Effect on Disease Progression of BIIB105 Administered Intrathecally to Adults With Amyotrophic Lateral Sclerosis With or Without Poly-CAG Expansion in the Ataxin-2 Gene

Summary
EudraCT number	2020-000207-36
Trial protocol	NL
Global end of trial date	13 Aug 2024

Results information
Results version number	v1(current)
This version publication date	28 Aug 2025
First version publication date	28 Aug 2025
Other versions

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

275AS101

ISRCTN number

US NCT number

NCT04494256

WHO universal trial number (UTN)

Sponsor organisation name

Biogen

Sponsor organisation address

225 Binney Street, Cambridge, Massachusetts, United States, 02142

Public contact

Study Medical Director, Biogen, clinicaltrials@biogen.com

Scientific contact

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

13 Aug 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

13 Aug 2024

Was the trial ended prematurely?

Yes

Main objective of the trial

Part 1: The primary objective was to evaluate the safety and tolerability of BIIB105 in participants with amyotrophic lateral sclerosis (ALS) or poly-CAG expansion (polyQ)-ALS. Part 2: The primary objective was to evaluate the long-term safety and tolerability of BIIB105 in participants with ALS or polyQ-ALS. Integrated Parts 1 and 2: The primary objective was to evaluate the long-term safety and tolerability of BIIB105 in participants with ALS or polyQ-ALS.

Protection of trial subjects

Written informed consent was obtained from each subject prior to evaluations being performed for eligibility. Adequate time to review the information in the informed consent and ask questions concerning all portions of the conduct of the study was provided. Through the informed consent process, awareness of the purpose of the study, the procedures, the benefits and risks of the study, the discomforts and the precautions taken was made. Any side effects or other health issues occurring during the study were followed up by the study doctor. Subjects were able to stop taking part in the study at any time without giving any reason.

Background therapy

Evidence for comparator

Actual start date of recruitment

28 Sep 2020

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 81

Country: Number of subjects enrolled

Netherlands: 10

Country: Number of subjects enrolled

Canada: 7

Country: Number of subjects enrolled

Italy: 1

Worldwide total number of subjects

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants diagnosed with amyotrophic lateral sclerosis (ALS) and ALS associated with ataxin-2 (ATXN2) polyCAG expansion (polyQALS) took part in the study at investigational sites in the United States, Netherlands, Canada and Italy from 28 September 2020 to 13 August 2024.

Screening details

A total of 99 participants were randomised in Part 1 (placebo-controlled) of study to receive BIIB105 or placebo, of which 80 participants completed Part 1. A total of 70 eligible participants who completed Part 1 were enrolled into Part 2 (open-label) of study to receive BIIB105. Part 2 of study was terminated early based on Sponsor's decision.

Period 1 title

Part 1: Double blinded Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Part 1: Pooled Placebo 1+2

Arm description

Participants with ALS and polyQ-ALS from Cohorts A, B, C1 and C2 received 3 loading doses of BIIB105-matched placebo, administered every 2 weeks (on Days 1, 15 and 29), followed by 2 maintenance doses administered once every 4 weeks (on Days 57 and 85), for a total of 5 doses over approximately 13 weeks. Participants with ALS and polyQ-ALS from Cohorts D1 and D2 received 3 loading doses of BIIB105- matched placebo administered every 2 weeks (on Days 1, 15, and 29), followed by 5 maintenance doses administered once every 4 weeks (on Days 57, 85, 113, 141, and 169), for a total of 8 doses over approximately 25 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in vial

Routes of administration

Intrathecal use

Dosage and administration details

Administered as specified in the treatment arm.

Part 1: Cohort A: BIIB105 5 mg

Arm description

Participants with ALS received 3 loading doses of BIIB105 5 mg, IT, administered every 2 weeks (on Days 1, 15, and 29), followed by 2 maintenance doses administered once every 4 weeks (on Days 57 and 85), for a total of 5 doses over approximately 13 weeks.

Arm type

Experimental

Investigational medicinal product name

BIIB105

Investigational medicinal product code

BIIB105

Other name

Pharmaceutical forms

Solution for injection in vial

Routes of administration

Intrathecal use

Dosage and administration details

Administered as specified in the treatment arm.

Part 1: Cohort B: BIIB105 20 mg

Arm description

Participants with ALS received 3 loading doses of BIIB105 20 mg, IT, administered every 2 weeks (on Days 1, 15, and 29), followed by 2 maintenance doses administered once every 4 weeks (on Days 57 and 85), for a total of 5 doses over approximately 13 weeks.

Arm type

Experimental

Investigational medicinal product name

BIIB105

Investigational medicinal product code

BIIB105

Other name

Pharmaceutical forms

Solution for injection in vial

Routes of administration

Intrathecal use

Dosage and administration details

Administered as specified in the treatment arm.

Part 1: Cohorts C1+C2: BIIB105 60 mg

Arm description

Participants from cohorts A-C2, who received 5, 20 and 60 mg doses of BIIB105 and placebo in Part 1 and completed Week 25 (Day 175) visit in Part 1 received BIIB105 60 mg in Part 2.

Arm type

Experimental

Investigational medicinal product name

BIIB105

Investigational medicinal product code

BIIB105

Other name

Pharmaceutical forms

Solution for injection in vial

Routes of administration

Intrathecal use

Dosage and administration details

Administered as specified in the treatment arm.

Part 1: Cohorts D1 + D2: BIIB105 120 mg

Arm description

Participants from Cohorts D1 and D2 who received 120 mg dose of BIIB105 and placebo in Part 1 and completed Week 25 (Day 176) visit in Part 1 received BIIB105 120 mg in Part 2.

Arm type

Experimental

Investigational medicinal product name

BIIB105

Investigational medicinal product code

BIIB105

Other name

Pharmaceutical forms

Solution for injection in vial

Routes of administration

Intrathecal use

Dosage and administration details

Administered as specified in the treatment arm.

Number of subjects in period 1	Part 1: Pooled Placebo 1+2	Part 1: Cohort A: BIIB105 5 mg	Part 1: Cohort B: BIIB105 20 mg	Part 1: Cohorts C1+C2: BIIB105 60 mg	Part 1: Cohorts D1 + D2: BIIB105 120 mg
Started	28	6	6	11	48
Completed	26	6	5	9	34
Not completed	2	0	1	2	14
SubjectWithdrawal-VisitBurden/SchedulingConflict	-	-	-	1	3
Adverse event, non-fatal	1	-	-	-	3
Reason Not Specified	-	-	-	-	1
Withdrawal by Subject - Other	1	-	1	1	1
Disease Progression - As Defined by the Protocol	-	-	-	-	5
Protocol deviation	-	-	-	-	1

Period 2 title

Part 2: Open Label Period

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Part 2: BIIB105 60 mg

Arm description

Participants from cohorts A-C2, who received 5, 20 and 60 mg doses of BIIB105 and placebo in Part 1 and completed Week 25 (Day 175) visit in Part 1 received BIIB105 60 mg in Part 2.

Arm type

Experimental

Investigational medicinal product name

BIIB105

Investigational medicinal product code

BIIB105

Other name

Pharmaceutical forms

Solution for injection in vial

Routes of administration

Intrathecal use

Dosage and administration details

Administered as specified in the treatment arm.

Part 2: BIIB105 120 mg

Arm description

Participants from Cohorts D1 and D2 who received 120 mg dose of BIIB105 and placebo in Part 1 and completed Week 25 (Day 176) visit in Part 1 received BIIB105 120 mg in Part 2.

Arm type

Experimental

Investigational medicinal product name

BIIB105

Investigational medicinal product code

BIIB105

Other name

Pharmaceutical forms

Solution for injection in vial

Routes of administration

Intrathecal use

Dosage and administration details

Administered as specified in the treatment arm.

Number of subjects in period 2	Part 2: BIIB105 60 mg	Part 2: BIIB105 120 mg
Started	19	51
Completed	0	0
Not completed	19	51
Adverse event, serious fatal	4	2
SubjectWithdrawal-VisitBurden/SchedulingConflict	5	4
Lack of Efficacy - Based on Subject Perception	-	1
Adverse event, non-fatal	-	2
Study Terminated by Sponsor	4	35
Withdrawal by Subject - Other	1	1
Disease Progression - As Defined by the Protocol	5	6

Baseline characteristics

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Reporting group title

Part 1: Pooled Placebo 1+2

Reporting group description

Reporting group title

Part 1: Cohort A: BIIB105 5 mg

Reporting group description

Reporting group title

Part 1: Cohort B: BIIB105 20 mg

Reporting group description

Reporting group title

Part 1: Cohorts C1+C2: BIIB105 60 mg

Reporting group description

Participants from cohorts A-C2, who received 5, 20 and 60 mg doses of BIIB105 and placebo in Part 1 and completed Week 25 (Day 175) visit in Part 1 received BIIB105 60 mg in Part 2.

Reporting group title

Part 1: Cohorts D1 + D2: BIIB105 120 mg

Reporting group description

Participants from Cohorts D1 and D2 who received 120 mg dose of BIIB105 and placebo in Part 1 and completed Week 25 (Day 176) visit in Part 1 received BIIB105 120 mg in Part 2.

Reporting group values	Part 1: Pooled Placebo 1+2	Part 1: Cohort A: BIIB105 5 mg	Part 1: Cohort B: BIIB105 20 mg	Part 1: Cohorts C1+C2: BIIB105 60 mg	Part 1: Cohorts D1 + D2: BIIB105 120 mg	Total
Number of subjects	28	6	6	11	48
Age Categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	59.9 ( 11.15 )	60.5 ( 5.72 )	49.3 ( 17.84 )	53.3 ( 12.77 )	57.7 ( 11.45 )	-
Gender categorical
Units: Subjects
Female	9	2	3	3	14	31
Male	19	4	3	8	34	68
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	4	0	2	1	3	10
Not Hispanic or Latino	23	6	4	10	45	88
Unknown or Not Reported	1	0	0	0	0	1
Race/Ethnicity, Customized
Units: Subjects
American Indian or Alaska Native	0	0	0	0	1	1
Asian	3	0	0	0	1	4
Black or African American	0	0	0	0	1	1
Native Hawaiian or Other Pacific Islander	0	0	0	0	1	1
White	22	6	5	10	40	83
Multiple	0	0	0	0	1	1
Not reported due to confidentiality regulations	1	0	0	0	0	1
Other	2	0	1	1	3	7

End points

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Reporting group title

Part 1: Pooled Placebo 1+2

Reporting group description

Reporting group title

Part 1: Cohort A: BIIB105 5 mg

Reporting group description

Reporting group title

Part 1: Cohort B: BIIB105 20 mg

Reporting group description

Reporting group title

Part 1: Cohorts C1+C2: BIIB105 60 mg

Reporting group description

Participants from cohorts A-C2, who received 5, 20 and 60 mg doses of BIIB105 and placebo in Part 1 and completed Week 25 (Day 175) visit in Part 1 received BIIB105 60 mg in Part 2.

Reporting group title

Part 1: Cohorts D1 + D2: BIIB105 120 mg

Reporting group description

Participants from Cohorts D1 and D2 who received 120 mg dose of BIIB105 and placebo in Part 1 and completed Week 25 (Day 176) visit in Part 1 received BIIB105 120 mg in Part 2.

Reporting group title

Part 2: BIIB105 60 mg

Reporting group description

Participants from cohorts A-C2, who received 5, 20 and 60 mg doses of BIIB105 and placebo in Part 1 and completed Week 25 (Day 175) visit in Part 1 received BIIB105 60 mg in Part 2.

Reporting group title

Part 2: BIIB105 120 mg

Reporting group description

Participants from Cohorts D1 and D2 who received 120 mg dose of BIIB105 and placebo in Part 1 and completed Week 25 (Day 176) visit in Part 1 received BIIB105 120 mg in Part 2.

Subject analysis set title

Early-start BIIB105 120 mg

Subject analysis set type

Full analysis

Subject analysis set description

Participants from Cohorts D1 and D2 from the Part 1 FAS population who received BIIB105 120 mg in Part 1, who may or may not have continued their study treatment in Part 2 were included in this group.

Subject analysis set title

Placebo/Delayed-start BIIB105 120 mg

Subject analysis set type

Full analysis

Subject analysis set description

Participants from Cohorts D1 and D2 from the Part 1 FAS population who received placebo in Part 1, who may or may not have rolled over to Part 2 and started active treatment with BIIB105 were included in this group.

Primary: Part 1: Number of Participants with Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

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End point title

Part 1: Number of Participants with Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) ^[1]

End point description

An AE was any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An SAE was any untoward medical occurrence that at any dose results in death, places the participant at immediate risk of death, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, or is a medically important event. A TEAE/TESAE was defined as any AE/SAE with an onset date that is on or after the first dose of study drug or any pre-existing condition that has worsened in severity after the first dose of study drug. Part 1 safety analysis population included all randomised participants who received at least 1 dose of study treatment in Part 1.

End point type

Primary

End point timeframe

From first dose of the study drug in Part 1 up to end of follow up period in Part 1 (up to Day 260)

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: Only descriptive statistics were planned for this endpoint.

End point values	Part 1: Pooled Placebo 1+2	Part 1: Cohort A: BIIB105 5 mg	Part 1: Cohort B: BIIB105 20 mg	Part 1: Cohorts C1+C2: BIIB105 60 mg	Part 1: Cohorts D1 + D2: BIIB105 120 mg
Number of subjects analysed	28	6	6	11	48
Units: participants
TEAEs	28	6	6	11	48
TESAEs	5	0	0	1	7

No statistical analyses for this end point

Primary: Part 2: Number of Participants with TEAEs and TESAEs

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End point title

Part 2: Number of Participants with TEAEs and TESAEs ^[2]

End point description

End point type

Primary

End point timeframe

From first dose of the study in Part 2 up to end of follow up period in Part 2 (up to Day 1184)

Notes
[2] - 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: Only descriptive statistics were planned for this endpoint.

End point values	Part 2: BIIB105 60 mg	Part 2: BIIB105 120 mg
Number of subjects analysed	19	51
Units: participants
TEAEs	19	49
TESAEs	7	14

No statistical analyses for this end point

Secondary: Part 1: Serum Concentrations of BIIB105

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End point title

Part 1: Serum Concentrations of BIIB105 ^[3]

End point description

The Part 1 pharmacokinetic (PK) analysis population included all randomised participants who received at least 1 dose of study treatment and had at least 1 postdose serum and/or cerebrospinal fluid (CSF) BIIB105 measurement in Part 1. '99999' signifies that since no participant was evaluable, geometric mean and coefficient of variation were not estimated. ‘Number analysed (n)’ signifies number of participants evaluable for this outcome measure at the specified timepoint.

End point type

Secondary

End point timeframe

Pre-dose and 1, 2, 4, 6 hours post-dose on days 1, 15, 29, 57, 85,113, 141, 169 and on days 2, 8, 92, and 176

Notes
[3] - 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: Part 1 arms were planned to be analysed for this end point.

End point values	Part 1: Cohort A: BIIB105 5 mg	Part 1: Cohort B: BIIB105 20 mg	Part 1: Cohorts C1+C2: BIIB105 60 mg	Part 1: Cohorts D1 + D2: BIIB105 120 mg
Number of subjects analysed	6	6	11	48
Units: nanograms per milliliter (ng/mL)
geometric mean (geometric coefficient of variation)
Day 1: Pre-dose (n=6,6,11,47)	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )
Day 1: 1 HR post (n=6,6,11,47)	7.21 ( 500.18 )	57.70 ( 285.30 )	34.98 ( 465.78 )	187.14 ( 351.05 )
Day 1: 2 HR post-dose (n=6,6,11,47)	32.20 ( 177.01 )	135.71 ( 109.27 )	250.28 ( 101.57 )	620.38 ( 132.37 )
Day 1: 4 HR post-dose (n=6,6,11,47)	41.38 ( 125.95 )	211.34 ( 68.29 )	488.11 ( 51.22 )	798.21 ( 86.03 )
Day 1: 6 HR post-dose (n=6,6,11,47)	39.27 ( 102.97 )	165.05 ( 60.63 )	528.45 ( 61.49 )	774.73 ( 60.51 )
Day 2 (n=6,6,11,48)	6.76 ( 65.90 )	29.07 ( 76.82 )	118.70 ( 103.89 )	260.03 ( 67.59 )
Day 8 (n=6,6,11,44)	0.46 ( 18.74 )	0.47 ( 36.02 )	1.38 ( 74.15 )	2.97 ( 43.60 )
Day 15: Pre-dose (n=6,6,11,44)	0.00 ( 0.00 )	0.50 ( 20.12 )	0.78 ( 52.94 )	1.90 ( 43.15 )
Day 15: 1 HR post-dose (n=6,6,11,41)	3.85 ( 172.70 )	22.24 ( 226.26 )	56.01 ( 489.04 )	257.73 ( 290.21 )
Day 15: 2 HR post-dose (n=6,6,11,41)	16.89 ( 111.49 )	94.51 ( 140.45 )	246.73 ( 142.61 )	972.44 ( 110.25 )
Day 15: 4 HR post-dose (n=6,6,11,41)	30.07 ( 74.48 )	139.75 ( 137.49 )	363.86 ( 77.37 )	996.20 ( 83.48 )
Day 15: 6 HR post-dose (n=6,6,11,41)	27.28 ( 106.96 )	139.00 ( 98.33 )	411.61 ( 49.33 )	897.25 ( 78.56 )
Day 29: Pre-dose (n=6,6,11,43)	0.45 ( 24.48 )	0.48 ( 28.47 )	1.23 ( 64.84 )	2.59 ( 59.99 )
Day 29: 1 HR post-dose (n=6,6,11,42)	5.80 ( 117.90 )	16.45 ( 557.48 )	114.69 ( 226.87 )	248.00 ( 152.63 )
Day 29: 2 HR post-dose (n=6,6,11,42)	16.53 ( 121.68 )	51.58 ( 602.03 )	420.39 ( 116.92 )	773.11 ( 95.92 )
Day 29: 4 HR post-dose (n=6,6,11,42)	31.29 ( 120.91 )	102.80 ( 200.28 )	566.43 ( 71.83 )	953.50 ( 80.75 )
Day 29: 6 HR post-dose (n=6,6,11,40)	33.28 ( 127.43 )	151.47 ( 87.99 )	555.65 ( 52.83 )	942.06 ( 69.00 )
Day 57: Pre-dose (n=6,6,11,41)	0.00 ( 0.00 )	0.41 ( 21.53 )	0.79 ( 80.26 )	1.83 ( 69.80 )
Day 57: 1 HR post-dose (n=6,6,11,41)	7.45 ( 275.61 )	7.98 ( 159.54 )	44.33 ( 615.14 )	227.06 ( 214.59 )
Day 57: 2 HR post-dose (n=6,6,11,40)	22.05 ( 153.51 )	26.59 ( 107.62 )	274.02 ( 128.39 )	713.36 ( 122.48 )
Day 57: 4 HR post-dose (n=6,6,11,41)	27.72 ( 123.67 )	74.60 ( 85.53 )	471.12 ( 95.76 )	887.82 ( 105.32 )
Day 57: 6 HR post-dose (n=6,6,11,40)	27.33 ( 105.30 )	89.38 ( 74.82 )	416.91 ( 94.12 )	889.54 ( 89.20 )
Day 85: Pre-dose (n=6,5,10,41)	0.50 ( 0.00 )	0.40 ( 33.26 )	0.74 ( 64.453 )	1.91 ( 113.18 )
Day 85: 1 HR post-dose (n=6,5,10,40)	7.02 ( 111.81 )	18.91 ( 240.40 )	77.63 ( 142.75 )	231.31 ( 236.91 )
Day 85: 2 HR post-dose (n=6,5,10,40)	20.60 ( 95.33 )	69.04 ( 265.82 )	248.33 ( 84.14 )	651.00 ( 127.92 )
Day 85: 4 HR post-dose (n=6,5,10,40)	27.69 ( 111.28 )	140.04 ( 91.00 )	416.74 ( 80.90 )	799.70 ( 89.26 )
Day 85: 6 HR post-dose (n=6,5,10,40)	29.83 ( 119.17 )	140.74 ( 50.95 )	453.58 ( 74.39 )	837.50 ( 73.65 )
Day 92 (n=6,5,10,6)	0.43 ( 23.54 )	0.56 ( 47.98 )	2.05 ( 92.02 )	4.47 ( 64.10 )
Day 113: Pre-dose (n=0,0,0,39)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	1.95 ( 59.79 )
Day 113: 1 HR post-dose (n=0,0,0,39)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	193.04 ( 198.68 )
Day 113: 2 HR post-dose (n=0,0,0,39)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	632.28 ( 91.07 )
Day 113: 4 HR post-dose (n=0,0,0,39)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	802.46 ( 91.76 )
Day 113: 6 HR post-dose (n=0,0,0,39)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	858.58 ( 86.76 )
Day 141: Pre-dose (n=0,0,0,38)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	2.07 ( 80.82 )
Day 141: 1 HR post-dose (n=0,0,0,37)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	457.25 ( 162.57 )
Day 141: 2 HR post-dose (n=0,0,0,37)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	949.31 ( 120.40 )
Day 141: 4 HR post-dose (n=0,0,0,37)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	1044.80 ( 101.09 )
Day 141: 6 HR post-dose (n=0,0,0,36)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	996.44 ( 85.54 )
Day 169: Pre-dose (n=0,0,0,36)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	2.95 ( 153.02 )
Day 169: 1 HR post-dose (n=0,0,0,35)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	288.75 ( 217.19 )
Day 169: 2 HR post-dose (n=0,0,0,35)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	702.24 ( 107.10 )
Day 169: 4 HR post-dose (n=0,0,0,36)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	816.90 ( 86.61 )
Day 169: 6 HR post-dose (n=0,0,0,37)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	683.89 ( 158.85 )
Day 176 (n=0,0,0,33)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	6.97 ( 132.41 )

No statistical analyses for this end point

Secondary: Part 1: CSF Concentrations of BIIB105

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End point title

Part 1: CSF Concentrations of BIIB105 ^[4]

End point description

The Part 1 PK analysis population included all randomised participants who received at least 1 dose of study treatment and had at least 1 postdose serum and/or CSF BIIB105 measurement in Part 1. '99999' signifies that since no participant was evaluable, geometric mean and coefficient of variation were not estimated. ‘Number analysed (n)’ signifies number of participants evaluable for this outcome measure at the specified time point.

End point type

Secondary

End point timeframe

Pre-dose on Days 1, 15, 29, 57, 85, 113, 141, 169, and on days 92, 130, 175, and 176

Notes
[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: Part 1 arms were planned to be analysed for this end point.

End point values	Part 1: Cohort A: BIIB105 5 mg	Part 1: Cohort B: BIIB105 20 mg	Part 1: Cohorts C1+C2: BIIB105 60 mg	Part 1: Cohorts D1 + D2: BIIB105 120 mg
Number of subjects analysed	6	6	11	48
Units: ng/mL
geometric mean (geometric coefficient of variation)
Day 1 : Pre-dose (n=6,6,11,47)	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )
Day 15 : Pre-dose (n=6,6,11,44)	1.93 ( 41.54 )	2.71 ( 55.21 )	5.75 ( 62.33 )	14.54 ( 82.48 )
Day 29 : Pre-dose (n=6,6,11,43)	3.53 ( 33.52 )	4.32 ( 52.42 )	11.53 ( 49.38 )	17.53 ( 95.18 )
Day 57 : Pre-dose (n=6,6,11,42)	2.32 ( 28.96 )	2.65 ( 46.23 )	4.82 ( 59.33 )	10.29 ( 79.90 )
Day 85 : Pre-dose (n=6,5,10,40)	2.37 ( 30.35 )	3.18 ( 72.73 )	6.50 ( 36.23 )	14.06 ( 77.42 )
Day 92 (n=6,5,10,0)	5.01 ( 30.62 )	6.28 ( 74.45 )	25.51 ( 66.26 )	99999 ( 99999 )
Day 113 (n=0,0,0,40)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	17.08 ( 86.41 )
Day 130 (n=6,5,10,0)	2.09 ( 32.22 )	2.45 ( 57.06 )	5.42 ( 40.72 )	99999 ( 99999 )
Day 141 (n=0,0,0,38)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	17.91 ( 84.83 )
Day 169 (n=0,0,0,37)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	18.88 ( 74.23 )
Day 175 (n=6,6,11,0)	1.16 ( 54.77 )	1.16 ( 36.06 )	2.68 ( 46.05 )	99999 ( 99999 )
Day 176 (n=0,0,0,2)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	17.35 ( 0.04 )

No statistical analyses for this end point

Secondary: Part 1: Area Under the Serum Concentration-Time Curve From Time Zero to Infinity (AUCinf)

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End point title

Part 1: Area Under the Serum Concentration-Time Curve From Time Zero to Infinity (AUCinf) ^[5]

End point description

AUCinf is the area under the serum concentration-time profile from time 0 extrapolated to infinite time. AUCinf was reported following dose 1 as planned. Part 1 PK analysis population included all randomised participants who received at least 1 dose of study treatment and had at least 1 postdose serum and/or CSF BIIB105 measurement in Part 1. ‘Overall number of participants analysed’ signifies number of participants with data available for outcome measure analysis.

End point type

Secondary

End point timeframe

Day 1

Notes
[5] - 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: Part 1 arms were planned to be analysed for this end point.

End point values	Part 1: Cohort A: BIIB105 5 mg	Part 1: Cohort B: BIIB105 20 mg	Part 1: Cohorts C1+C2: BIIB105 60 mg	Part 1: Cohorts D1 + D2: BIIB105 120 mg
Number of subjects analysed	2	5	10	42
Units: Hournanogram per milliliter (hng/mL)
geometric mean (geometric coefficient of variation)	934.22 ( 52.89 )	3546.89 ( 53.50 )	11258.45 ( 14.57 )	24466.44 ( 30.24 )

No statistical analyses for this end point

Secondary: Part 1: Area Under the Serum Concentration-Time Curve From Time Zero to Time of the Last Measurable Concentration (AUClast)

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End point title

Part 1: Area Under the Serum Concentration-Time Curve From Time Zero to Time of the Last Measurable Concentration (AUClast) ^[6]

End point description

AUClast was reported following dose 1 as planned. Part 1 PK analysis population included all randomised participants who received at least 1 dose of study treatment and had at least 1 postdose serum and/or CSF BIIB105 measurement in Part 1. ‘Overall number of participants analysed’ signifies number of participants with data available for outcome measure analysis.

End point type

Secondary

End point timeframe

Day 1

Notes
[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: Part 1 arms were planned to be analysed for this end point.

End point values	Part 1: Cohort A: BIIB105 5 mg	Part 1: Cohort B: BIIB105 20 mg	Part 1: Cohorts C1+C2: BIIB105 60 mg	Part 1: Cohorts D1 + D2: BIIB105 120 mg
Number of subjects analysed	6	6	11	44
Units: h*ng/mL
geometric mean (geometric coefficient of variation)	574.59 ( 79.16 )	3239.40 ( 52.73 )	11758.68 ( 21.12 )	24289.70 ( 30.50 )

No statistical analyses for this end point

Secondary: Part 1: Maximum Observed Serum Concentration (Cmax)

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End point title

Part 1: Maximum Observed Serum Concentration (Cmax) ^[7]

End point description

Part 1 PK analysis population included all randomised participants who received at least 1 dose of study treatment and had at least 1 postdose serum and/or CSF BIIB105 measurement in Part 1. '99999' signifies that since no participant was evaluable, geometric mean and coefficient of variation were not estimated. ‘Number analysed (n)’ signifies number of participants evaluable for this outcome measure at the specified timepoint.

End point type

Secondary

End point timeframe

Days 1, 15, 29, 57, 85, 113, 141 and 169

Notes
[7] - 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: Part 1 arms were planned to be analysed for this end point.

End point values	Part 1: Cohort A: BIIB105 5 mg	Part 1: Cohort B: BIIB105 20 mg	Part 1: Cohorts C1+C2: BIIB105 60 mg	Part 1: Cohorts D1 + D2: BIIB105 120 mg
Number of subjects analysed	6	6	11	48
Units: ng/mL
geometric mean (geometric coefficient of variation)
Day 1 (n=6,6,11,47)	52.18 ( 123.13 )	227.80 ( 73.20 )	644.10 ( 55.31 )	1019.11 ( 76.61 )
Day 15 (n=6,6,11,41)	31.03 ( 78.23 )	165.37 ( 118.45 )	495.03 ( 76.73 )	1312.42 ( 93.96 )
Day 29 (n=6,6,11,40)	34.11 ( 119.62 )	164.15 ( 101.46 )	616.02 ( 61.54 )	1173.71 ( 75.74 )
Day 57 (n=6,6,11,40)	31.92 ( 136.57 )	94.60 ( 75.30 )	513.84 ( 98.01 )	1052.70 ( 99.57 )
Day 85 (n=6,5,10,40)	31.43 ( 117.43 )	168.38 ( 59.96 )	476.91 ( 75.87 )	1009.44 ( 84.68 )
Day 113 (n=0,0,0,39)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	949.58 ( 83.69 )
Day 141 (n=0,0,0,36)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	1243.75 ( 91.13 )
Day 169 (n=0,0,0,36)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	957.24 ( 86.51 )

No statistical analyses for this end point

Secondary: Part 1: Time to Reach Maximum Observed Serum Concentration (Tmax)

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End point title

Part 1: Time to Reach Maximum Observed Serum Concentration (Tmax) ^[8]

End point description

Part 1 PK analysis population included all randomised participants who received at least 1 dose of study treatment and had at least 1 postdose serum and/or CSF BIIB105 measurement in Part 1. '99999' signifies that since no participant was evaluable, median and full range were not estimated. ‘Number analysed (n)’ signifies number of participants evaluable for this outcome measure at the specified timepoint.

End point type

Secondary

End point timeframe

Days 1, 15, 29, 57, 85, 113, 141 and 169

Notes
[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: Part 1 arms were planned to be analysed for this end point.

End point values	Part 1: Cohort A: BIIB105 5 mg	Part 1: Cohort B: BIIB105 20 mg	Part 1: Cohorts C1+C2: BIIB105 60 mg	Part 1: Cohorts D1 + D2: BIIB105 120 mg
Number of subjects analysed	6	6	11	48
Units: hour
median (full range (min-max))
Day 1 (n=6,6,11,47)	4.2 (2 to 6)	4.2 (2 to 6)	5.8 (2 to 23)	4.3 (1 to 24)
Day 15 (n=6,6,11,41)	5.0 (4 to 6)	5.0 (2 to 6)	5.9 (2 to 6)	4.1 (1 to 6)
Day 29 (n=6,6,11,40)	5.8 (4 to 6)	5.8 (2 to 6)	4.2 (2 to 6)	4.1 (2 to 6)
Day 57 (n=6,6,11,40)	5.8 (2 to 6)	5.0 (4 to 6)	4.2 (1 to 6)	4.5 (1 to 6)
Day 85 (n=6,5,10,40)	5.1 (4 to 6)	4.3 (4 to 6)	5.8 (4 to 6)	5.8 (2 to 6)
Day 113 (n=0,0,0,39)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	5.3 (1 to 6)
Day 141 (n=0,0,0,36)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	4.0 (1 to 6)
Day 169 (n=0,0,0,36)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	4.1 (1 to 6)

No statistical analyses for this end point

Secondary: Part 1: Elimination Half-Life (t1/2) in Serum

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End point title

Part 1: Elimination Half-Life (t1/2) in Serum ^[9]

End point description

Elimination half-life (t1/2) was reported following dose 1 as planned. Part 1 PK analysis population included all randomised participants who received at least 1 dose of study treatment and had at least 1 postdose serum and/or CSF BIIB105 measurement in Part 1. ‘Overall number of participants’ signifies number of participants evaluable for this outcome measure.

End point type

Secondary

End point timeframe

Day 1

Notes
[9] - 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: Part 1 arms were planned to be analysed for this end point.

End point values	Part 1: Cohort A: BIIB105 5 mg	Part 1: Cohort B: BIIB105 20 mg	Part 1: Cohorts C1+C2: BIIB105 60 mg	Part 1: Cohorts D1 + D2: BIIB105 120 mg
Number of subjects analysed	2	5	10	42
Units: hour
median (full range (min-max))	14.0 (5 to 23)	26.6 (17 to 62)	41.7 (33 to 62)	39.8 (22 to 82)

No statistical analyses for this end point

Secondary: Part 1: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline

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End point title

Part 1: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline

End point description

Plasma NfL ratio to baseline was reported in terms of geometric mean ratio. The Part 1 pharmacodynamic (PD) population included participants who received at least 1 dose of study treatment and have at least 1 available postdose evaluation of the respective PD endpoint in the study in Part 1. '99999' signifies that since one or no participant was evaluable, geometric mean and coefficient of variation were not estimated. 'Number analysed (n)' indicates the number of participants evaluable for the outcome measure at the specified timepoint.

End point type

Secondary

End point timeframe

Days 29, 57, 85, 113, 130 (For cohorts A, B, C1 and C2)/141 (For cohorts D1 and D2), 169 (For cohorts A, B, C1 and C2)/175 (For cohorts D1 and D2) and 241

End point values	Part 1: Pooled Placebo 1+2	Part 1: Cohort A: BIIB105 5 mg	Part 1: Cohort B: BIIB105 20 mg	Part 1: Cohorts C1+C2: BIIB105 60 mg	Part 1: Cohorts D1 + D2: BIIB105 120 mg
Number of subjects analysed	28	6	6	11	47
Units: ratio
geometric mean (geometric coefficient of variation)
Day 29 (n=28,6,6,11,45)	1.04 ( 20.32 )	1.05 ( 8.47 )	0.83 ( 47.1 )	1.06 ( 11.23 )	1.15 ( 72.72 )
Day 57 (n=28,6,6,11,44)	1.08 ( 19.91 )	0.95 ( 14.63 )	0.97 ( 15.95 )	1.08 ( 20.43 )	1.03 ( 21.7 )
Day 85 (n=27,6,5,10,41)	0.99 ( 17.27 )	0.99 ( 15.7 )	0.98 ( 26.4 )	1.11 ( 19.85 )	0.99 ( 19.62 )
Day 113 (n=17,0,0,0,40)	1.06 ( 19.95 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	1.01 ( 21.77 )
Day130(A,B,C1,C2)/Day141(D1,D2)n=25,6,5,10,39	1.09 ( 20.46 )	1.10 ( 8.58 )	0.92 ( 40.79 )	0.99 ( 30.8 )	1.03 ( 41.35 )
Day 169 (A,B,C1,C2)/Day 175 (D1,D2)n=24,6,5,9,39	1.10 ( 23.67 )	1.02 ( 22.58 )	1.10 ( 24.55 )	1.08 ( 29.73 )	1.06 ( 24.92 )
Day 214 (n=0,0,0,0,1)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	1.07 ( 99999 )

No statistical analyses for this end point

Secondary: Integrated Part 1 and Part 2: CSF PK Concentration of BIIB105

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End point title

Integrated Part 1 and Part 2: CSF PK Concentration of BIIB105

End point description

Integrated data for Part 1 and Part 2 was analysed based on the PK population defined for Part 1. Part 1 PK analysis population included all randomised participants who received at least 1 dose of study treatment and had at least 1 postdose serum and/or CSF BIIB105 measurement in Part 1. '99999' signifies that since one or no participant was evaluable, geometric mean and coefficient of variation were not estimated. ‘Overall number of participants analysed’ signifies number of participants with data available for outcome measure analysis. ‘Number analysed (n)’: number of participants evaluable at the specified timepoint.

End point type

Secondary

End point timeframe

Predose on Days 1,15,29,57,85 and on Days 1,15,29,57,85,113,141,169.176,197,210,225,253,281,309,337,365,393,420,448,476,504,532,560,588,616,644,672,700,726,728

End point values	Early-start BIIB105 120 mg	Placebo/Delayed-start BIIB105 120 mg
Number of subjects analysed	48	17
Units: ng/mL
geometric mean (geometric coefficient of variation)
Day 1 : Pre-dose (n=48,0)	0.13 ( 0.00 )	99999 ( 99999 )
Day 1 (n=0,17)	99999 ( 99999 )	0.15 ( 37.88 )
Day 15 : Pre-dose (n=44,0)	14.54 ( 82.48 )	99999 ( 99999 )
Day 15 (n=1,17)	31.04 ( 99999 )	12.93 ( 70.31 )
Day 29: Pre-dose (n=43,0)	17.53 ( 95.18 )	99999 ( 99999 )
Day 29: (n=0,17)	99999 ( 99999 )	18.62 ( 93.41 )
Day 57 : Pre-dose (n=42,0)	10.29 ( 79.90 )	99999 ( 99999 )
Day 57 (n=0,14)	99999 ( 99999 )	9.72 ( 49.08 )
Day 85 : Pre-dose (n=40,0)	14.06 ( 77.42 )	99999 ( 99999 )
Day 85 (n=0,13)	99999 ( 99999 )	14.54 ( 63.76 )
Day 113 (n=40,11)	17.08 ( 86.41 )	20.70 ( 56.82 )
Day 141 (n=38,8)	17.91 ( 84.83 )	24.50 ( 30.13 )
Day 169 (n=37,7)	18.88 ( 74.23 )	19.32 ( 36.08 )
Day 176 (n=2,0)	17.35 ( 0.04 )	99999 ( 99999 )
Day 197 (n=32,5)	24.88 ( 57.69 )	24.99 ( 71.18 )
Day 210 (n=31,0)	49.04 ( 67.88 )	99999 ( 99999 )
Day 225 (n=33,5)	24.14 ( 63.21 )	30.52 ( 13.97 )
Day 253 (n=33,5)	23.54 ( 62.86 )	21.68 ( 70.34 )
Day 281 (n=27,2)	26.51 ( 73.96 )	23.79 ( 8.69 )
Day 309 (n=25,2)	27.14 ( 63.54 )	30.47 ( 13.01 )
Day 337 (n=20,2)	31.34 ( 71.84 )	22.11 ( 16.80 )
Day 365 (n=16,0)	30.16 ( 62.35 )	99999 ( 99999 )
Day 393 (n=11,2)	23.56 ( 31.29 )	15.36 ( 13.95 )
Day 420 (n=11,1)	25.84 ( 42.82 )	21.91 ( 99999 )
Day 448 (n=9,1)	23.53 ( 40.75 )	28.43 ( 99999 )
Day 476 (n=7,1)	30.87 ( 28.29 )	25.95 ( 99999 )
Day 504 (n=6,0)	28.24 ( 38.06 )	99999 ( 99999 )
Day 532 (n=5,0)	26.73 ( 44.19 )	99999 ( 99999 )
Day 560 (n=4,0)	26.42 ( 36.82 )	99999 ( 99999 )
Day 588 (n=3,0)	40.26 ( 68.00 )	99999 ( 99999 )
Day 616 (n=3,0)	24.69 ( 109.22 )	99999 ( 99999 )
Day 644 (n=4,0)	21.15 ( 39.95 )	99999 ( 99999 )
Day 672 (n=3,0)	30.75 ( 48.18 )	99999 ( 99999 )
Day 700 (n=2,0)	23.85 ( 1.63 )	99999 ( 99999 )
Day 726 (n=1,0)	28.22 ( 99999 )	99999 ( 99999 )
Day 728 (n=1,0)	26.28 ( 99999 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Integrated Part 1 and Part 2: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline

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End point title

Integrated Part 1 and Part 2: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline

End point description

Plasma NfL ratio to baseline was reported in terms of geometric mean ratio. '99999' signifies that since one or no participant was evaluable, geometric mean and coefficient of variation were not estimated. 'Number analysed (n)' indicates the number of participants evaluable for the outcome measure at the specified timepoint.

End point type

Secondary

End point timeframe

Days 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, 365, 393, 421, 449, 477, 505, 533, 561, 589, 617, 645, 673, 701

End point values	Early-start BIIB105 120 mg	Placebo/Delayed-start BIIB105 120 mg
Number of subjects analysed	47	19
Units: ratio
geometric mean (geometric coefficient of variation)
Day 29 (n=45,19)	1.15 ( 72.72 )	1.03 ( 22.35 )
Day 57 (n=44,19)	1.03 ( 21.7 )	1.11 ( 18.9 )
Day 85 (n=41,18)	0.99 ( 19.62 )	1.00 ( 18.00 )
Day 113 (n=40,17)	1.01 ( 21.77 )	1.06 ( 19.95 )
Day 141 (n=39,16)	1.03 ( 41.35 )	1.10 ( 20.84 )
Day 169 (n=39,16)	1.06 ( 24.92 )	1.06 ( 20.33 )
Day 197 (n=31,13)	1.08 ( 28.28 )	1.08 ( 23.6 )
Day 225 (n=31,13)	1.12 ( 38.42 )	1.12 ( 31.12 )
Day 253 (n=26,12)	1.15 ( 28.4 )	1.06 ( 27.71 )
Day 281 (n=22,10)	1.14 ( 26.57 )	1.18 ( 21.26 )
Day 309 (n=17,9)	1.07 ( 31.81 )	1.09 ( 24.46 )
Day 337 (n=12,6)	1.05 ( 38.67 )	1.18 ( 23.3 )
Day 365 (n=11,4)	0.99 ( 32.42 )	1.20 ( 29.59 )
Day 393 (n=9,4)	0.95 ( 48.05 )	1.26 ( 24.88 )
Day 421 (n=9,3)	0.92 ( 36.61 )	1.21 ( 58.82 )
Day 449 (n=7,3)	0.82 ( 28.9 )	1.06 ( 32.94 )
Day 477 (n=5,2)	0.85 ( 23.15 )	0.92 ( 32.52 )
Day 505 (n=3,2)	0.77 ( 25.18 )	0.88 ( 46.94 )
Day 533 (n=4,2)	0.78 ( 14.58 )	1.15 ( 32.24 )
Day 561 (n=3,0)	0.65 ( 14.63 )	99999 ( 99999 )
Day 589 (n=3,2)	0.77 ( 39.28 )	0.90 ( 23.38 )
Day 617 (n=3,1)	0.80 ( 38.48 )	0.70 ( 99999 )
Day 645 (n=2,0)	0.76 ( 52.68 )	99999 ( 99999 )
Day 673 (n=2,0)	0.66 ( 30.22 )	99999 ( 99999 )
Day 701 (n=1,0)	0.54 ( 99999 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Integrated Part 1 and Part 2: Serum Concentration of BIIB105

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End point title

Integrated Part 1 and Part 2: Serum Concentration of BIIB105

End point description

Serum concentration of BIIB105 was not analysed for Integrated Parts 1 and 2 as serum samples for BIIB105 concentration were not collected and analysed after completion of Part 1. Serum PK concentration for Part 1 is reported in another outcome measure.

End point type

Secondary

End point timeframe

Days 1, 2, 8, 15, 29, 57,85, 92, 113, 142, 169, 176, 337, 505, 673, 841 and 1009

End point values	Early-start BIIB105 120 mg	Placebo/Delayed-start BIIB105 120 mg
Number of subjects analysed	48	17
Units: ng/mL
geometric mean (geometric coefficient of variation)	99999 ( 99999 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Integrated Part 1 and Part 2: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC)

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End point title

Integrated Part 1 and Part 2: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC)

End point description

Vital capacity was measured by means of the slow vital capacity (SVC) test using a facemask with the participant sitting upright. SVC was determined by performing at least 3 trials. If the difference between the two highest values of the three trials was ≥10%, then up to 5 trials were performed. The highest percent predicted SVC value at each visit was used for the analysis. Here, baseline is defined as Part 1 day 1 value prior to the study drug. As specified in SAP, change from baseline at Week 40 (Day 281) in least square means and corresponding standard errors was summarized using the analysis of covariance (ANCOVA) model. Negative change from baseline indicates decrease in lung function. Integrated data for Part 1 and Part 2 was analysed based on the clinical function population defined for Part 1. The Part 1 clinical function population included participants from the FAS population who have at least 1 postdose measurement in Part 1.

End point type

Secondary

End point timeframe

Baseline, Day 281

End point values	Early-start BIIB105 120 mg	Placebo/Delayed-start BIIB105 120 mg
Number of subjects analysed	48	19
Units: percent predicted
least squares mean (standard error)	-14.49 ( 4.093 )	-14.41 ( 7.133 )

Early-start vs Placebo/Delayed-start BIIB105 120mg

Comparison groups

Placebo/Delayed-start BIIB105 120 mg v Early-start BIIB105 120 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9924 ^[10]

Method

ANCOVA

Parameter type

Least square (LS) mean difference

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-15.47

upper limit

15.32

Variability estimate

Standard error of the mean

Dispersion value

7.84

Notes
[10] - ANCOVA model included: treatment as a fixed effect and adjusted for the following covariates: baseline disease duration since symptom onset, baseline percent predicted SVC, baseline plasma NfL, and use of riluzole or edaravone.

Secondary: Integrated Part 1 and Part 2: Change From Baseline in Muscle Strength as Measured by Handheld Dynamometry (HHD) Megascore

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End point title

Integrated Part 1 and Part 2: Change From Baseline in Muscle Strength as Measured by Handheld Dynamometry (HHD) Megascore

End point description

Quantitative muscle strength was evaluated using HHD, which tested isometric strength of multiple muscles using standard participant positioning. Approximately 8 muscle groups were examined (per each side) in both upper and lower extremities. 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 Z scores, if no more than 14 (≤ 14) measures are missing. Higher scores indicate greater strength. A negative change from baseline indicated decreased muscle strength. As specified in SAP, for the integrated analyses of Part 1 and 2, change from baseline at Week 40 (Day 281) in LS means and corresponding SE is reported at Week 40. Integrated data for Part 1 and 2 was analysed based on clinical function population defined for Part 1. Part 1 clinical function population: participants from FAS population who have at least 1 postdose measurement in Part 1.

End point type

Secondary

End point timeframe

Baseline, Day 281

End point values	Early-start BIIB105 120 mg	Placebo/Delayed-start BIIB105 120 mg
Number of subjects analysed	48	19
Units: score on a scale
least squares mean (standard error)	-0.46 ( 0.066 )	-0.28 ( 0.105 )

Early-start vs Placebo/Delayed-start BIIB105 120mg

Comparison groups

Early-start BIIB105 120 mg v Placebo/Delayed-start BIIB105 120 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1069 ^[11]

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.41

upper limit

0.04

Variability estimate

Standard error of the mean

Dispersion value

0.12

Notes
[11] - ANCOVA model included: treatment as a fixed effect and adjusted for the following covariates: baseline disease duration since symptom onset, baseline percent predicted SVC, baseline plasma NfL, and use of riluzole or edaravone.

Secondary: Integrated Part 1 and Part 2: Change From Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) Score

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End point title

Integrated Part 1 and Part 2: Change From Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) Score

End point description

The ALSFRS-R is a questionnaire that measured degree of impairment in 4 functional domains: respiratory function, bulbar function, gross motor skills, and fine motor skills. Each domain consists of 3 items, each scored from 0 to 4, with higher scores representing better function. Each domain score can have maximum score of 12 calculated as the sum of scores of 3 items for that domain and the total possible score for ALSFRS-R is 48. The total score is the sum of the 4 functional domain scores or all individual item scores if no missing item scores are present. Here, baseline is defined as Part 1 day 1 value prior to the study drug. Negative change from baseline indicates disease progression. As specified in SAP change from baseline at Week 40 (Day 281) in least square means and corresponding standard errors was summarized using the ANCOVA model. Integrated data for Part 1 and 2 was analysed based on clinical function population defined for Part 1.

End point type

Secondary

End point timeframe

Baseline, Day 281

End point values	Early-start BIIB105 120 mg	Placebo/Delayed-start BIIB105 120 mg
Number of subjects analysed	48	19
Units: score on a scale
least squares mean (standard error)	-8.46 ( 1.105 )	-8.26 ( 1.819 )

Early-start vs Placebo/Delayed-start BIIB105 120mg

Comparison groups

Early-start BIIB105 120 mg v Placebo/Delayed-start BIIB105 120 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9203 ^[12]

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-4.14

upper limit

3.74

Variability estimate

Standard error of the mean

Dispersion value

2.01

Notes
[12] - ANCOVA model included: treatment as a fixed effect and adjusted for the following covariates: baseline disease duration since symptom onset, baseline percent predicted SVC, baseline plasma NfL, and use of riluzole or edaravone.

Secondary: Integrated Part 1 and Part 2: Time to Death or Permanent Ventilation

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End point title

Integrated Part 1 and Part 2: Time to Death or Permanent Ventilation

End point description

Time to death or permanent ventilation is defined as the time from first dose to death or permanent ventilation ( ≥ 22 hours of mechanical ventilation [invasive or noninvasive] per day for ≥ 21 consecutive days), whichever comes first. Participants who did not meet the endpoint definition were censored on the date of participant's last contact in Part 1 or Part 2. Time to death or permanent ventilation data was summarized using Kaplan-Meier curves based on randomisation in Part 1. '99999' signifies median and 95% confidence interval (CI) were not estimable due to low number events of permanent ventilation or death. Integrated data for Part 1 and Part 2 was analysed based on the FAS population defined for Part 1. Part 1 FAS population included all randomised participants who received at least 1 dose of study treatment in Part 1 and 2.

End point type

Secondary

End point timeframe

Baseline up to Day 1184

End point values	Early-start BIIB105 120 mg	Placebo/Delayed-start BIIB105 120 mg
Number of subjects analysed	48	19
Units: weeks
median (confidence interval 95%)	99999 (72.7 to 99999)	99999 (99999 to 99999)

Early-start vs Placebo/Delayed-start BIIB105 120mg

Comparison groups

Early-start BIIB105 120 mg v Placebo/Delayed-start BIIB105 120 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1003

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

4.29

Confidence interval

level

95%

sides

2-sided

lower limit

0.433

upper limit

42.587

Secondary: Integrated Parts 1 and 2: Time to Death

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End point title

Integrated Parts 1 and 2: Time to Death

End point description

Time to death was defined as the time from first dose to death. Integrated data for Part 1 and Part 2 was analysed based on the FAS population defined for Part 1. Part 1 FAS population included all randomised participants who received at least 1 dose of study treatment in Part 1 and 2. '99999' signifies median and 95% confidence interval (CI) were not estimable due to low number events of death. Integrated data for Part 1 and Part 2 was analysed based on the FAS population defined for Part 1. Part 1 FAS population included all randomised participants who received at least 1 dose of study treatment in Part 1 and 2.

End point type

Secondary

End point timeframe

Baseline up to Day 1184

End point values	Early-start BIIB105 120 mg	Placebo/Delayed-start BIIB105 120 mg
Number of subjects analysed	48	19
Units: weeks
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)

Early-start vs Placebo/Delayed-start BIIB105 120mg

Comparison groups

Early-start BIIB105 120 mg v Placebo/Delayed-start BIIB105 120 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1143

Method

Kaplan-Meier product limit method

Parameter type

Hazard ratio (HR)

Point estimate

99999

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

99999

Secondary: Integrated Part 1 and Part 2: Time to Death, Incorporating Post-Study Withdrawal or Study Completion Vital Status Data

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End point title

Integrated Part 1 and Part 2: Time to Death, Incorporating Post-Study Withdrawal or Study Completion Vital Status Data

End point description

End point type

Secondary

End point timeframe

Up to Day 1184

End point values	Early-start BIIB105 120 mg	Placebo/Delayed-start BIIB105 120 mg
Number of subjects analysed	0 ^[13]	0 ^[14]
Units: hour
median (full range (min-max))	( to )	( to )

Notes
[13] - Time to death analysis with post-study vital status was not done as data were unavailable.
[14] - Time to death analysis with post-study vital status was not done as data were unavailable.

No statistical analyses for this end point

Post-hoc: Part 2: Serum Concentration of BIIB105

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End point title

Part 2: Serum Concentration of BIIB105

End point description

The PK analysis population is defined as all randomised participants who received at least 1 dose of study treatment and have at least 1 postdose serum and/or CSF BIIB105 measurement. '99999’ signiﬁes that since no participant was evaluable, geometric mean and coefficient of variation were not estimated. 'Number analysed' indicates the number of participants evaluable at the specified time point.

End point type

Post-hoc

End point timeframe

Days 1, 169, 337, 505 and 673

End point values	Part 2: BIIB105 60 mg	Part 2: BIIB105 120 mg
Number of subjects analysed	19	51
Units: ng/ml
geometric mean (geometric coefficient of variation)
Day 1 (n=19,50)	0.50 ( 0.00 )	1.47 ( 139.00 )
Day 169 (n=11,18)	1.25 ( 186.75 )	3.50 ( 151.48 )
Day 337 (n=9,7)	2.46 ( 333.20 )	2.50 ( 95.95 )
Day 505(n=7,1)	3.53 ( 340.11 )	8.54 ( 0.00 )
Day 673 (n=3,0)	18.89 ( 164.41 )	99999 ( 99999 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose of study drug up to end of study (up to 1416 days)

Adverse event reporting additional description

The Part 1 safety analysis population included all randomised participants who received at least 1 dose of study treatment in Part 1. The Part 2 safety analysis population included all participants who received at least 1 dose of study treatment in Part 2.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

27.0

Reporting group title

Part 1: Pooled Placebo 1+2

Reporting group description

Reporting group title

Part 1: Cohort A: BIIB105 5 mg

Reporting group description

Participants with ALS received 3 loading doses of BIIB105 5mg, IT, administered every 2 weeks (on Days 1, 15, and 29), followed by 2 maintenance doses administered once every 4 weeks (on Days 57 and 85), for a total of 5 doses over approximately 13 weeks.

Reporting group title

Part 1: Cohort B: BIIB105 20 mg

Reporting group description

Reporting group title

Part 2: BIIB105 120 mg

Reporting group description

Participants from Cohorts D1 and D2 who received 120 mg dose of BIIB105 and placebo in Part 1 and completed Week 25 (Day 176) visit in Part 1 received BIIB105 120 mg in Part 2.

Reporting group title

Part 1: Cohorts D1 + D2: BIIB105 120 mg

Reporting group description

Participants with ALS (Cohort D1) and polyQ-ALS (Cohort D2) received BIIB105 120 mg, IT, as 3 loading doses administered every 2 weeks (on Days 1, 15, and 29), followed by 5 maintenance doses administered once every 4 weeks (on Days 57, 85, 113, 141, and 169), for a total of 8 doses over approximately 25 weeks.

Reporting group title

Part 2: BIIB105 60 mg

Reporting group description

Participants from cohorts A-C2, who received 5, 20 and 60 mg doses of BIIB105 and placebo in Part 1 and completed Week 25 (Day 175) visit in Part 1 received BIIB105 60 mg in Part 2.

Reporting group title

Part 1: Cohorts C1+C2: BIIB105 60 mg

Reporting group description

Participants with ALS (Cohort C1) and polyQ-ALS (Cohort C2) received 3 loading doses of BIIB105 60 mg, IT, administered every 2 weeks (on Days 1, 15, and 29), followed by 2 maintenance doses administered once every 4 weeks (on Days 57 and 85), for a total of 5 doses over approximately 13 weeks.

Serious adverse events	Part 1: Pooled Placebo 1+2	Part 1: Cohort A: BIIB105 5 mg	Part 1: Cohort B: BIIB105 20 mg	Part 2: BIIB105 120 mg	Part 1: Cohorts D1 + D2: BIIB105 120 mg	Part 2: BIIB105 60 mg	Part 1: Cohorts C1+C2: BIIB105 60 mg
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 28 (17.86%)	0 / 6 (0.00%)	0 / 6 (0.00%)	14 / 51 (27.45%)	7 / 48 (14.58%)	7 / 19 (36.84%)	1 / 11 (9.09%)
number of deaths (all causes)	0	0	0	6	0	4	0
number of deaths resulting from adverse events	0	0	0	4	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Plasma cell myeloma
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 48 (2.08%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Craniofacial fracture
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	2 / 28 (7.14%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 51 (3.92%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	0 / 19 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Jaw fracture
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Amyotrophic lateral sclerosis
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Balance disorder
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral venous sinus thrombosis
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 48 (2.08%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Radiculopathy
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Toxic encephalopathy
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Ileus
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Food poisoning
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	0 / 19 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic respiratory failure
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspiration
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 48 (2.08%)	2 / 19 (10.53%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	1 / 48 (2.08%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	3 / 51 (5.88%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 51 (3.92%)	1 / 48 (2.08%)	2 / 19 (10.53%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 48 (2.08%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seronegative arthritis
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Covid-19
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 48 (2.08%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 48 (2.08%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary sepsis
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 48 (2.08%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	1 / 48 (2.08%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	1 / 48 (2.08%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Part 1: Pooled Placebo 1+2	Part 1: Cohort A: BIIB105 5 mg	Part 1: Cohort B: BIIB105 20 mg	Part 2: BIIB105 120 mg	Part 1: Cohorts D1 + D2: BIIB105 120 mg	Part 2: BIIB105 60 mg	Part 1: Cohorts C1+C2: BIIB105 60 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	27 / 28 (96.43%)	6 / 6 (100.00%)	6 / 6 (100.00%)	45 / 51 (88.24%)	47 / 48 (97.92%)	19 / 19 (100.00%)	11 / 11 (100.00%)
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	1	0
Flushing
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 51 (1.96%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Hypertension
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	0	1	0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 51 (3.92%)	1 / 48 (2.08%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	3	1	0	0
Asthenia
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	4 / 51 (7.84%)	5 / 48 (10.42%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	7	7	0	0
Chills
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	4 / 48 (8.33%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	2	6	0	0
Fatigue
subjects affected / exposed	3 / 28 (10.71%)	0 / 6 (0.00%)	0 / 6 (0.00%)	7 / 51 (13.73%)	8 / 48 (16.67%)	3 / 19 (15.79%)	5 / 11 (45.45%)
occurrences all number	3	0	0	10	9	5	8
Medical device site burn
subjects affected / exposed	0 / 28 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Pyrexia
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	5 / 51 (9.80%)	2 / 48 (4.17%)	1 / 19 (5.26%)	1 / 11 (9.09%)
occurrences all number	0	0	0	6	2	1	1
Oedema peripheral
subjects affected / exposed	2 / 28 (7.14%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	2 / 48 (4.17%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	0	0	1	2	0	0
Pain
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 51 (3.92%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	3	0	1	0
Peripheral swelling
subjects affected / exposed	0 / 28 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	2 / 51 (3.92%)	3 / 48 (6.25%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	2	3	0	0
Oedema
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 48 (2.08%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	1	0
Swelling face
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	1 / 48 (2.08%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	1	0	0
Vaccination site pain
subjects affected / exposed	0 / 28 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	0 / 19 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	1	0	0	0	0	3
Immune system disorders
Seasonal allergy
subjects affected / exposed	0 / 28 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	1	0	0	0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 51 (1.96%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Breast pain
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	0 / 19 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	4 / 28 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	4 / 51 (7.84%)	2 / 48 (4.17%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	5	0	0	4	3	1	0
Dyspnoea
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	3 / 51 (5.88%)	2 / 48 (4.17%)	0 / 19 (0.00%)	1 / 11 (9.09%)
occurrences all number	2	0	0	4	2	0	1
Dyspnoea at rest
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Laryngospasm
subjects affected / exposed	0 / 28 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Nasal congestion
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 48 (2.08%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	1	0
Nasal polyps
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Respiratory failure
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	1	0
Respiratory tract congestion
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Psychiatric disorders
Suicidal ideation
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 51 (3.92%)	2 / 48 (4.17%)	0 / 19 (0.00%)	1 / 11 (9.09%)
occurrences all number	1	0	0	2	2	0	1
Affect lability
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 51 (1.96%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	1	1	0	0	0
Insomnia
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	1 / 48 (2.08%)	2 / 19 (10.53%)	0 / 11 (0.00%)
occurrences all number	1	0	0	1	1	2	0
Depression
subjects affected / exposed	0 / 28 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 51 (1.96%)	1 / 48 (2.08%)	1 / 19 (5.26%)	1 / 11 (9.09%)
occurrences all number	0	1	0	1	1	1	1
Confusional state
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Anxiety
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	4 / 48 (8.33%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	4	1	0
Sleep disorder
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	0 / 19 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	1	0	0	1
Product issues
Device dislocation
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 48 (2.08%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	2	1	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	2 / 19 (10.53%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	2 / 19 (10.53%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	0	2	0
Blood uric acid increased
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Breath sounds abnormal
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	1	0
Csf protein increased
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	7 / 51 (13.73%)	11 / 48 (22.92%)	4 / 19 (21.05%)	0 / 11 (0.00%)
occurrences all number	0	0	0	7	11	4	0
Csf white blood cell count increased
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	7 / 51 (13.73%)	6 / 48 (12.50%)	3 / 19 (15.79%)	0 / 11 (0.00%)
occurrences all number	0	0	0	7	7	4	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	2 / 19 (10.53%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Hepatic enzyme increased
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	2 / 48 (4.17%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	2	1	0
Weight decreased
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	6 / 51 (11.76%)	1 / 48 (2.08%)	4 / 19 (21.05%)	0 / 11 (0.00%)
occurrences all number	0	0	0	6	1	4	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	2 / 28 (7.14%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 51 (3.92%)	5 / 48 (10.42%)	2 / 19 (10.53%)	1 / 11 (9.09%)
occurrences all number	2	0	0	4	7	4	2
Bone contusion
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	3 / 48 (6.25%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	3	0	0
Concussion
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 51 (3.92%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	3	0	0	0
Fall
subjects affected / exposed	14 / 28 (50.00%)	1 / 6 (16.67%)	4 / 6 (66.67%)	19 / 51 (37.25%)	18 / 48 (37.50%)	9 / 19 (47.37%)	4 / 11 (36.36%)
occurrences all number	32	1	9	62	56	25	14
Femur fracture
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Head injury
subjects affected / exposed	2 / 28 (7.14%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	2 / 48 (4.17%)	2 / 19 (10.53%)	1 / 11 (9.09%)
occurrences all number	2	0	0	0	2	3	1
Immunisation reaction
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	0 / 19 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	1
Post procedural inflammation
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	0 / 19 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	1
Neurological procedural complication
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	0	1	0
Post lumbar puncture syndrome
subjects affected / exposed	7 / 28 (25.00%)	3 / 6 (50.00%)	1 / 6 (16.67%)	7 / 51 (13.73%)	15 / 48 (31.25%)	7 / 19 (36.84%)	6 / 11 (54.55%)
occurrences all number	15	4	1	18	23	20	18
Post procedural contusion
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 48 (2.08%)	0 / 19 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	1	0	1
Post procedural discomfort
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	1 / 48 (2.08%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	3	0	1	0	1	0	0
Musculoskeletal procedural complication
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	0 / 19 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	2
Post procedural swelling
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 48 (2.08%)	0 / 19 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	1	0	2
Procedural complication
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	2 / 19 (10.53%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Procedural dizziness
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Procedural nausea
subjects affected / exposed	2 / 28 (7.14%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	2 / 11 (18.18%)
occurrences all number	2	0	0	0	0	1	2
Procedural pain
subjects affected / exposed	15 / 28 (53.57%)	5 / 6 (83.33%)	4 / 6 (66.67%)	20 / 51 (39.22%)	25 / 48 (52.08%)	13 / 19 (68.42%)	7 / 11 (63.64%)
occurrences all number	34	19	10	46	50	45	21
Skin laceration
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	3 / 51 (5.88%)	1 / 48 (2.08%)	1 / 19 (5.26%)	2 / 11 (18.18%)
occurrences all number	0	0	1	3	1	1	3
Rib fracture
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	0 / 19 (0.00%)	1 / 11 (9.09%)
occurrences all number	1	0	0	1	0	0	1
Road traffic accident
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Shoulder fracture
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 51 (1.96%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Skin abrasion
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	3 / 51 (5.88%)	2 / 48 (4.17%)	0 / 19 (0.00%)	3 / 11 (27.27%)
occurrences all number	0	0	0	5	2	0	3
Procedural vomiting
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	1 / 11 (9.09%)
occurrences all number	1	0	0	0	0	1	1
Stoma site discharge
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Stoma site pain
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	2 / 48 (4.17%)	2 / 19 (10.53%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	2	2	0
Cardiac disorders
Tachycardia
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 48 (2.08%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	1	0
Nervous system disorders
Cluster headache
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Clonus
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 51 (1.96%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Brain fog
subjects affected / exposed	0 / 28 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	1	0
Balance disorder
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	3 / 51 (5.88%)	6 / 48 (12.50%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	4	10	0	0
Cognitive disorder
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Dizziness
subjects affected / exposed	3 / 28 (10.71%)	0 / 6 (0.00%)	0 / 6 (0.00%)	5 / 51 (9.80%)	8 / 48 (16.67%)	0 / 19 (0.00%)	2 / 11 (18.18%)
occurrences all number	4	0	0	6	11	0	3
Dysgeusia
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	0 / 19 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	1
Head discomfort
subjects affected / exposed	2 / 28 (7.14%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	0	0	0	0	0	0
Muscle contractions involuntary
subjects affected / exposed	2 / 28 (7.14%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	2 / 48 (4.17%)	0 / 19 (0.00%)	1 / 11 (9.09%)
occurrences all number	3	0	0	0	2	0	1
Loss of consciousness
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Hypoaesthesia
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	1	0
Hemihypoaesthesia
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	0 / 19 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	1
Headache
subjects affected / exposed	12 / 28 (42.86%)	3 / 6 (50.00%)	4 / 6 (66.67%)	19 / 51 (37.25%)	28 / 48 (58.33%)	5 / 19 (26.32%)	5 / 11 (45.45%)
occurrences all number	19	4	15	26	45	6	11
Menstrual headache
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Neuropathy peripheral
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Syncope
subjects affected / exposed	2 / 28 (7.14%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	3	0	0	1	0	0	0
Speech disorder
subjects affected / exposed	0 / 28 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 48 (2.08%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	1	0	0
Sciatica
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	3	0
Radicular pain
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Presyncope
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 51 (1.96%)	2 / 48 (4.17%)	1 / 19 (5.26%)	1 / 11 (9.09%)
occurrences all number	0	0	1	1	2	1	1
Post-traumatic headache
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 51 (1.96%)	1 / 48 (2.08%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	1	2	1	0	0
Pleocytosis
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	4 / 51 (7.84%)	6 / 48 (12.50%)	3 / 19 (15.79%)	0 / 11 (0.00%)
occurrences all number	0	0	0	6	7	3	0
Parosmia
subjects affected / exposed	0 / 28 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Paraesthesia
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	4 / 48 (8.33%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	8	0	0
Blood and lymphatic system disorders
Iron deficiency anaemia
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 48 (2.08%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	1	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 28 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 51 (1.96%)	1 / 48 (2.08%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	1	1	0	0
Hypoacusis
subjects affected / exposed	0 / 28 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Tinnitus
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	1	0	0	1	0	1	0
Vertigo positional
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 48 (2.08%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	1	0
Eye disorders
Conjunctival haemorrhage
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	0	1	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	1 / 6 (16.67%)	4 / 51 (7.84%)	7 / 48 (14.58%)	4 / 19 (21.05%)	1 / 11 (9.09%)
occurrences all number	1	0	1	5	9	5	1
Abdominal distension
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	0 / 19 (0.00%)	1 / 11 (9.09%)
occurrences all number	1	0	0	0	0	0	1
Constipation
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	7 / 51 (13.73%)	2 / 48 (4.17%)	6 / 19 (31.58%)	1 / 11 (9.09%)
occurrences all number	1	0	0	8	2	11	2
Dysphagia
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	0 / 19 (0.00%)	1 / 11 (9.09%)
occurrences all number	1	0	0	1	0	0	1
Food poisoning
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	0	2	0
Gastritis
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	2 / 19 (10.53%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Mouth ulceration
subjects affected / exposed	0 / 28 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Haematemesis
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Hiatus hernia
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 51 (3.92%)	0 / 48 (0.00%)	0 / 19 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	1	2	0	0	1
Nausea
subjects affected / exposed	3 / 28 (10.71%)	0 / 6 (0.00%)	2 / 6 (33.33%)	2 / 51 (3.92%)	5 / 48 (10.42%)	4 / 19 (21.05%)	3 / 11 (27.27%)
occurrences all number	3	0	2	2	7	4	3
Oesophagitis
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Oral dysaesthesia
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Vomiting
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	3 / 48 (6.25%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	5	1	0
Salivary hypersecretion
subjects affected / exposed	2 / 28 (7.14%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	2 / 48 (4.17%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	0	0	1	2	0	0
Skin and subcutaneous tissue disorders
Dermatitis allergic
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	0 / 19 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	1
Decubitus ulcer
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	3 / 51 (5.88%)	1 / 48 (2.08%)	2 / 19 (10.53%)	0 / 11 (0.00%)
occurrences all number	0	0	0	3	1	2	0
Erythema
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	1	0	0	1	0	1	0
Hyperhidrosis
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	1	0
Nodular rash
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Pruritus
subjects affected / exposed	2 / 28 (7.14%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	2 / 48 (4.17%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	4	0	0	0	2	0	0
Rash
subjects affected / exposed	1 / 28 (3.57%)	1 / 6 (16.67%)	1 / 6 (16.67%)	6 / 51 (11.76%)	1 / 48 (2.08%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	5	1	7	1	0	0
Skin lesion
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	1	1
Ecchymosis
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	0 / 19 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	1
Renal and urinary disorders
Urinary retention
subjects affected / exposed	2 / 28 (7.14%)	0 / 6 (0.00%)	0 / 6 (0.00%)	5 / 51 (9.80%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	2	0	0	6	0	1	0
Pollakiuria
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	1 / 48 (2.08%)	3 / 19 (15.79%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	1	4	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 28 (7.14%)	2 / 6 (33.33%)	3 / 6 (50.00%)	11 / 51 (21.57%)	6 / 48 (12.50%)	3 / 19 (15.79%)	4 / 11 (36.36%)
occurrences all number	4	3	6	16	9	7	7
Muscle tightness
subjects affected / exposed	2 / 28 (7.14%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 48 (2.08%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	0	0	0	1	0	0
Back pain
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	2 / 6 (33.33%)	2 / 51 (3.92%)	12 / 48 (25.00%)	1 / 19 (5.26%)	3 / 11 (27.27%)
occurrences all number	1	0	3	3	15	1	5
Joint swelling
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 51 (3.92%)	1 / 48 (2.08%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	2	1	1	0
Mobility decreased
subjects affected / exposed	2 / 28 (7.14%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	4	0	0	0	0	1	0
Muscle spasms
subjects affected / exposed	6 / 28 (21.43%)	1 / 6 (16.67%)	2 / 6 (33.33%)	2 / 51 (3.92%)	3 / 48 (6.25%)	2 / 19 (10.53%)	4 / 11 (36.36%)
occurrences all number	9	3	2	3	3	2	5
Myalgia
subjects affected / exposed	2 / 28 (7.14%)	1 / 6 (16.67%)	0 / 6 (0.00%)	7 / 51 (13.73%)	7 / 48 (14.58%)	2 / 19 (10.53%)	2 / 11 (18.18%)
occurrences all number	2	1	0	12	21	3	5
Musculoskeletal stiffness
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	5 / 51 (9.80%)	2 / 48 (4.17%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	5	3	0	0
Musculoskeletal pain
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 51 (3.92%)	2 / 48 (4.17%)	1 / 19 (5.26%)	2 / 11 (18.18%)
occurrences all number	0	0	0	2	4	1	3
Musculoskeletal chest pain
subjects affected / exposed	1 / 28 (3.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 51 (3.92%)	0 / 48 (0.00%)	0 / 19 (0.00%)	1 / 11 (9.09%)
occurrences all number	1	0	0	2	0	0	1
Muscular weakness
subjects affected / exposed	3 / 28 (10.71%)	0 / 6 (0.00%)	0 / 6 (0.00%)	7 / 51 (13.73%)	9 / 48 (18.75%)	3 / 19 (15.79%)	1 / 11 (9.09%)
occurrences all number	3	0	0	10	10	6	1
Neck pain
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 51 (1.96%)	2 / 48 (4.17%)	3 / 19 (15.79%)	2 / 11 (18.18%)
occurrences all number	0	0	1	1	2	3	2
Pain in extremity
subjects affected / exposed	7 / 28 (25.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	7 / 51 (13.73%)	11 / 48 (22.92%)	4 / 19 (21.05%)	2 / 11 (18.18%)
occurrences all number	9	1	0	12	25	8	2
Infections and infestations
Hordeolum
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	0	1	0
Device related infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Gastroenteritis viral
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Covid-19
subjects affected / exposed	2 / 28 (7.14%)	0 / 6 (0.00%)	0 / 6 (0.00%)	6 / 51 (11.76%)	4 / 48 (8.33%)	4 / 19 (21.05%)	0 / 11 (0.00%)
occurrences all number	2	0	0	6	4	6	0
Influenza
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	4 / 51 (7.84%)	1 / 48 (2.08%)	2 / 19 (10.53%)	0 / 11 (0.00%)
occurrences all number	0	0	0	4	1	4	0
Nasopharyngitis
subjects affected / exposed	2 / 28 (7.14%)	0 / 6 (0.00%)	0 / 6 (0.00%)	6 / 51 (11.76%)	3 / 48 (6.25%)	2 / 19 (10.53%)	0 / 11 (0.00%)
occurrences all number	3	0	0	9	4	3	0
Pneumonia
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	2 / 48 (4.17%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	2	4	0
Sinusitis
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	0	2	0
Upper respiratory tract infection
subjects affected / exposed	2 / 28 (7.14%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 48 (0.00%)	0 / 19 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	1	0	1	0	0	0
Urinary tract infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	3 / 51 (5.88%)	2 / 48 (4.17%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	5	5	2	0
Stoma site infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Metabolism and nutrition disorders
Hypocalcaemia
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Hyperuricaemia
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Hyperglycaemia
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 48 (0.00%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Dehydration
subjects affected / exposed	0 / 28 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	2 / 48 (4.17%)	1 / 19 (5.26%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	3	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

01 Mar 2021

- Clarified the dosing of the sentinel pair in cohort C2 to avoid the possible unblinding of study participants’ treatment assignment. - Note associated with the Columbia Suicide Severity Rating Scale (C-SSRS) Questionnaire was corrected to indicate that the “since last visit” version of the C-SSRS should be used from Day 8 forward, as indicated in the corresponding row in the Schedule of Activities. - The definition of the ALSFRS-R slope calculation was corrected.

17 Nov 2021

- Extended the treatment period for cohorts D1 and D2 from approximately 13 weeks to approximately 25 weeks, and added a second part to the study (Part 2, open-label long-term extension). - New nonclinical study information was added. - The natural history run-in period for Cohort D2 was removed from the protocol. - Language was added allowing follow-up of health status after withdrawal from or end of study, if a participant consents to data collection after withdrawal or study completion. - Safety surveillance team review criteria for Cohorts D1 and D2 was separated from the criteria for Cohorts A, B, C1, and C2. - Cohort study stopping rules were updated to include additional information on the role of the SST. - Study termination criteria were clarified. - Part 1 inclusion criteria were updated. - A rescreening option was added for screen failures. - Text was updated to state that indwelling injection ports/catheters are prohibited only during Part 1 of the study. - Information was updated to clearly reflect Part 1 and Part 2 assessment requirements. - Text was added defining the analysis populations. - Details were added to clarify the planned statistical analyses of AEs. - Details for planned laboratory analyses were added. - A section was added to account for the digital data collected by participants.

09 Sep 2022

- Increased the sample size in Cohort D1 from n = 20 to n = 48. - Details about the study structure, objectives, and phase was added. - Information on a newly approved ALS therapy was added. - Newly available data from fertility and fetal toxicity studies were summarized. - References to new nonclinical reproductive and developmental toxicity data and emerging clinical data from the ongoing study were added to the Benefit-Risk Assessment, and a Sponsor position on the benefit-risk profile was added. - CSF PK and plasma NfL were elevated from exploratory to secondary endpoints. PD and biomarker objectives and endpoints were separated out by study part (Part 1, Part 2) and prospectively defined for the integrated analyses (Integrated Part 1 and Part 2). - Safety surveillance team review criteria for Cohorts D1 and D2 were updated. - ICF requirements were updated in the inclusion criteria. - The minimum prescreening ALFRS-R slope requirement was removed for Cohort D1 in the exclusion criteria (Part 1). - A new exclusion criterion (for Part 1) was added to restrict allowable ALS treatment for study participants. - Exclusion criterion of Part 2 was updated to permit participants who contracted HIV, HBV, or HCV during Part 1 to continue into Part 2 if appropriate in the exclusion criteria. - Screen failure section was updated to allow re-use of screening assessments that will not change over time. - Optional collection of vital status was permitted. - Clarified that separate analyses will be performed for separate Parts of the study and on integrated data study populations were defined - Method of analysis section was updated that included handling of data from different parts of the study. - Described early-termination scenarios and permit additional interim analyses.

07 Sep 2023

- Updated to reflect changes in the BIIB105 manufacturing process. The manufacturing changes affected the study drug product presentation (concentration and volume) but did not have any impact on the final formulation of BIIB105 administered to study participants - Extended the maintenance dosing portion of the treatment period of Part 2 by up to approximately 52 weeks. - Amended dose termination rules, including lifting them if SST review of Cohort D1 data supports continued dosing at the highest dose level. - Updated how data will be analysed and presented for safety, PK, clinical function and quality of life measures, time to death or permanent ventilation, and time to death.

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.

Study terminated because of sponsor's decision.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part 1: Number of Participants with Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

Primary: Part 1: Number of Participants with Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

Primary: Part 2: Number of Participants with TEAEs and TESAEs

Primary: Part 2: Number of Participants with TEAEs and TESAEs

Secondary: Part 1: Serum Concentrations of BIIB105

Secondary: Part 1: Serum Concentrations of BIIB105

Secondary: Part 1: CSF Concentrations of BIIB105

Secondary: Part 1: CSF Concentrations of BIIB105

Secondary: Part 1: Area Under the Serum Concentration-Time Curve From Time Zero to Infinity (AUCinf)

Secondary: Part 1: Area Under the Serum Concentration-Time Curve From Time Zero to Infinity (AUCinf)

Secondary: Part 1: Area Under the Serum Concentration-Time Curve From Time Zero to Time of the Last Measurable Concentration (AUClast)

Secondary: Part 1: Area Under the Serum Concentration-Time Curve From Time Zero to Time of the Last Measurable Concentration (AUClast)

Secondary: Part 1: Maximum Observed Serum Concentration (Cmax)

Secondary: Part 1: Maximum Observed Serum Concentration (Cmax)

Secondary: Part 1: Time to Reach Maximum Observed Serum Concentration (Tmax)

Secondary: Part 1: Time to Reach Maximum Observed Serum Concentration (Tmax)

Secondary: Part 1: Elimination Half-Life (t1/2) in Serum

Secondary: Part 1: Elimination Half-Life (t1/2) in Serum

Secondary: Part 1: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline

Secondary: Part 1: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline

Secondary: Integrated Part 1 and Part 2: CSF PK Concentration of BIIB105

Secondary: Integrated Part 1 and Part 2: CSF PK Concentration of BIIB105

Secondary: Integrated Part 1 and Part 2: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline

Secondary: Integrated Part 1 and Part 2: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline

Secondary: Integrated Part 1 and Part 2: Serum Concentration of BIIB105

Secondary: Integrated Part 1 and Part 2: Serum Concentration of BIIB105

Secondary: Integrated Part 1 and Part 2: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC)

Secondary: Integrated Part 1 and Part 2: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC)

Secondary: Integrated Part 1 and Part 2: Change From Baseline in Muscle Strength as Measured by Handheld Dynamometry (HHD) Megascore

Secondary: Integrated Part 1 and Part 2: Change From Baseline in Muscle Strength as Measured by Handheld Dynamometry (HHD) Megascore

Secondary: Integrated Part 1 and Part 2: Change From Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) Score

Secondary: Integrated Part 1 and Part 2: Change From Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) Score

Secondary: Integrated Part 1 and Part 2: Time to Death or Permanent Ventilation

Secondary: Integrated Part 1 and Part 2: Time to Death or Permanent Ventilation

Secondary: Integrated Parts 1 and 2: Time to Death

Secondary: Integrated Parts 1 and 2: Time to Death

Secondary: Integrated Part 1 and Part 2: Time to Death, Incorporating Post-Study Withdrawal or Study Completion Vital Status Data

Secondary: Integrated Part 1 and Part 2: Time to Death, Incorporating Post-Study Withdrawal or Study Completion Vital Status Data

Post-hoc: Part 2: Serum Concentration of BIIB105

Post-hoc: Part 2: Serum Concentration of BIIB105

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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