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Clinical Trial Results:
A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 1b/2a Study of WVE-004 Administered Intrathecally to Patients with C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) or Frontotemporal Dementia (FTD)

Summary
EudraCT number	2020-005193-94
Trial protocol	DE NL IE SE BE
Global end of trial date	27 Jun 2023

Results information
Results version number	v1(current)
This version publication date	18 Apr 2025
First version publication date	18 Apr 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

WVE-004-001

ISRCTN number

US NCT number

NCT04931862

WHO universal trial number (UTN)

Sponsor organisation name

Wave Life Sciences UK Limited

Sponsor organisation address

1 Chamberlain Square CS , Birmingham, United Kingdom, B3 3AX

Public contact

Daniel Paulson, Wave Life Sciences, +1 617-949-2900, info@wavelifesci.com

Scientific contact

Daniel Paulson, Wave Life Sciences, +1 617-949-2900, info@wavelifesci.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

27 Jun 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

27 Jun 2023

Was the trial ended prematurely?

Yes

Main objective of the trial

To evaluate the safety and tolerability of WVE-004 in participants with amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD) with a documented mutation in the C9orf72 gene.

Protection of trial subjects

The study was conducted according to the study protocol and standard operating procedures that meet the guidelines provided by the International Conference on Harmonisation for Good Clinical Practice in clinical studies, and any other applicable local regulatory requirements.

Background therapy

Evidence for comparator

Actual start date of recruitment

24 Jun 2021

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 4

Country: Number of subjects enrolled

Belgium: 2

Country: Number of subjects enrolled

Canada: 5

Country: Number of subjects enrolled

Ireland: 3

Country: Number of subjects enrolled

Netherlands: 10

Country: Number of subjects enrolled

New Zealand: 1

Country: Number of subjects enrolled

United Kingdom: 10

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

This Phase 1b/2a randomized, double-blind, placebo-controlled study was conducted in adult participants with C9orf72-associated ALS or FTD at 14 investigational sites in 7 countries between 24 June 2021 and 27 June 2023. A total of 35 unique participants were enrolled in this study.

Screening details

The study included 2 distinct periods: Period 1 (SAD) and Period 2 (MAD). A total of 23 participants were randomized to Period 1 and 21 participants (9 participants from Period 1 and 12 new participants) were randomized to Period 2.

Period 1 title

SAD Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer

Are arms mutually exclusive

Yes

SAD: Pooled Placebo

Arm description

Participants were randomized to receive a single dose of placebo matching with WVE-004 on Day 1.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

Single dose of placebo matching with WVE-004 was administered IT by direct lumbar injection using an atraumatic needle on Day 1.

SAD: WVE-004 10 mg

Arm description

Participants were randomized to receive a single dose of WVE-004 10 milligram (mg) intrathecal (IT) injection on Day 1.

Arm type

Experimental

Investigational medicinal product name

WVE-004

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

Single dose of WVE-004 10 mg was administered IT by direct lumbar injection using an atraumatic needle on Day 1.

SAD: WVE-004 20 mg

Arm description

Participants were randomized to receive a single dose of WVE-004 20 mg IT injection on Day 1.

Arm type

Experimental

Investigational medicinal product name

WVE-004

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

Single dose of WVE-004 20 mg was administered IT by direct lumbar injection using an atraumatic needle on Day 1.

SAD: WVE-004 30 mg

Arm description

Participants were randomized to receive a single dose of WVE-004 30 mg IT injection on Day 1.

Arm type

Experimental

Investigational medicinal product name

WVE-004

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

Single dose of WVE-004 30 mg was administered IT by direct lumbar injection using an atraumatic needle on Day 1.

SAD: WVE-004 60 mg

Arm description

Participants were randomized to receive a single dose of WVE-004 60 mg IT injection on Day 1.

Arm type

Experimental

Investigational medicinal product name

WVE-004

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

Single dose of WVE-004 60 mg was administered IT by direct lumbar injection using an atraumatic needle on Day 1.

Number of subjects in period 1 ^[1]	SAD: Pooled Placebo	SAD: WVE-004 10 mg	SAD: WVE-004 20 mg	SAD: WVE-004 30 mg	SAD: WVE-004 60 mg
Started	5	2	8	5	3
Treated	5	2	8	5	3
Completed	5	2	6	3	2
Not completed	0	0	2	2	1
Study terminated by Sponsor	-	-	1	-	-
Adverse event, non-fatal	-	-	-	1	1
Death	-	-	1	1	-

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: In addition to eligible participants from SAD period, newly enrolled participants were randomized into MAD period.

Period 2 title

MAD Period

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer

Are arms mutually exclusive

Yes

MAD: Pooled Placebo

Arm description

Eligible participants from Period 1 and newly enrolled participants were randomized to receive placebo matching with WVE-004 once Q4W or Q12W for 12 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

Placebo matching with WVE-004 was administered IT by direct lumbar injection using an atraumatic needle Q4W or Q12W for 12 weeks.

MAD: WVE-004 10 mg Q4W

Arm description

Eligible participants from Period 1 and newly enrolled participants were randomized to receive WVE-004 10 mg IT injection once Q4W for 12 weeks.

Arm type

Experimental

Investigational medicinal product name

WVE-004

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

WVE-004 10 mg was administered IT by direct lumbar injection using an atraumatic needle Q4W for 12 weeks.

MAD: WVE-004 10 mg Q12W

Arm description

Eligible participants from Period 1 and newly enrolled participants were randomized to receive WVE-004 10 mg IT injection once Q12W for 12 weeks.

Arm type

Experimental

Investigational medicinal product name

WVE-004

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

WVE-004 10 mg was administered IT by direct lumbar injection using an atraumatic needle Q12W for 12 weeks.

Number of subjects in period 2 ^[2] ^[3]	MAD: Pooled Placebo	MAD: WVE-004 10 mg Q4W	MAD: WVE-004 10 mg Q12W
Started	4	2	6
Treated	7	5	9
Completed	6	2	6
Not completed	1	4	3
Consent withdrawn by subject	1	1	1
Study terminated by Sponsor	-	-	1
Death	-	1	1
Unspecified	-	2	-
Joined	3	4	3
Transferred in from other group/arm	3	4	3

Notes
[2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: In addition to eligible participants from SAD period, newly enrolled participants were randomized into MAD period.
[3] - The number of subjects transferring in and out of the arms in the period are not the same. It is expected the net number of transfers in and out of the arms in a period, will be zero.
Justification: Newly enrolled participants were randomized directly into MAD period.

Baseline characteristics

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Reporting group title

SAD: Pooled Placebo

Reporting group description

Participants were randomized to receive a single dose of placebo matching with WVE-004 on Day 1.

Reporting group title

SAD: WVE-004 10 mg

Reporting group description

Participants were randomized to receive a single dose of WVE-004 10 milligram (mg) intrathecal (IT) injection on Day 1.

Reporting group title

SAD: WVE-004 20 mg

Reporting group description

Participants were randomized to receive a single dose of WVE-004 20 mg IT injection on Day 1.

Reporting group title

SAD: WVE-004 30 mg

Reporting group description

Participants were randomized to receive a single dose of WVE-004 30 mg IT injection on Day 1.

Reporting group title

SAD: WVE-004 60 mg

Reporting group description

Participants were randomized to receive a single dose of WVE-004 60 mg IT injection on Day 1.

Reporting group values	SAD: Pooled Placebo	SAD: WVE-004 10 mg	SAD: WVE-004 20 mg	SAD: WVE-004 30 mg	SAD: WVE-004 60 mg	Total
Number of subjects	5	2	8	5	3	23
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	69.2 ( 6.30 )	60.5 ( 0.71 )	59.0 ( 6.89 )	57.6 ( 7.09 )	58.7 ( 9.07 )	-
Gender categorical
Units: Subjects
Female	3	1	2	4	2	12
Male	2	1	6	1	1	11
Ethnicity
Units: Subjects
Hispanic or Latino	0	0	0	0	0	0
Not Hispanic or Latino	5	2	8	5	3	23
Unknown or Not Reported	0	0	0	0	0	0
Race
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0
Asian	0	0	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	1	0	0	1
Black or African American	0	0	0	0	0	0
White	4	2	7	4	2	19
More than one race	0	0	0	0	0	0
Unknown or Not Reported	1	0	0	1	1	3

End points

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Reporting group title

SAD: Pooled Placebo

Reporting group description

Participants were randomized to receive a single dose of placebo matching with WVE-004 on Day 1.

Reporting group title

SAD: WVE-004 10 mg

Reporting group description

Participants were randomized to receive a single dose of WVE-004 10 milligram (mg) intrathecal (IT) injection on Day 1.

Reporting group title

SAD: WVE-004 20 mg

Reporting group description

Participants were randomized to receive a single dose of WVE-004 20 mg IT injection on Day 1.

Reporting group title

SAD: WVE-004 30 mg

Reporting group description

Participants were randomized to receive a single dose of WVE-004 30 mg IT injection on Day 1.

Reporting group title

SAD: WVE-004 60 mg

Reporting group description

Participants were randomized to receive a single dose of WVE-004 60 mg IT injection on Day 1.

Reporting group title

MAD: Pooled Placebo

Reporting group description

Eligible participants from Period 1 and newly enrolled participants were randomized to receive placebo matching with WVE-004 once Q4W or Q12W for 12 weeks.

Reporting group title

MAD: WVE-004 10 mg Q4W

Reporting group description

Eligible participants from Period 1 and newly enrolled participants were randomized to receive WVE-004 10 mg IT injection once Q4W for 12 weeks.

Reporting group title

MAD: WVE-004 10 mg Q12W

Reporting group description

Eligible participants from Period 1 and newly enrolled participants were randomized to receive WVE-004 10 mg IT injection once Q12W for 12 weeks.

Primary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Treatment-Emergent Adverse Events and Withdrew Due to Adverse Events

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End point title

Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Treatment-Emergent Adverse Events and Withdrew Due to Adverse Events ^[1]

End point description

An adverse event (AE) was defined as any untoward medical occurrence in a participant enrolled into this study regardless of its causal relationship to study treatment. A serious AE was defined as any event that results in death, is immediately life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly. A TEAE was defined as any event not present before exposure to study treatment or any event already present that worsens in either intensity or frequency after exposure to study treatment. The Safety population included all participants who were randomized and received at least 1 dose of study treatment.

End point type

Primary

End point timeframe

From the first dose of study treatment (Day 1) up to 51 weeks (Period 1 = 24 weeks of follow-up and Period 2 = 12 weeks of treatment followed by 15 weeks of follow-up)

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 statistical analysis was performed for the primary end point.

End point values	SAD: Pooled Placebo	SAD: WVE-004 10 mg	SAD: WVE-004 20 mg	SAD: WVE-004 30 mg	SAD: WVE-004 60 mg	MAD: Pooled Placebo	MAD: WVE-004 10 mg Q4W	MAD: WVE-004 10 mg Q12W
Number of subjects analysed	5	2	8	5	3	7	5	9
Units: participants
TEAEs	5	2	8	5	3	7	5	7
Serious TEAEs	1	0	1	3	1	3	2	2
Adverse event leading to study discontinuation	0	0	0	1	1	0	0	0

No statistical analyses for this end point

Secondary: Concentration of WVE-004 in Plasma

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End point title

Concentration of WVE-004 in Plasma

End point description

Blood samples collected to determine the concentration of WVE-004 in plasma. The Safety population included all participants who were randomized and received at least 1 dose of study treatment. Here, n= number of participants analyzed at specific timepoints, 9999= no participants analyzed and 99999= Standard deviation is not applicable when only 1 participant was analyzed.

End point type

Secondary

End point timeframe

Pre-dose on Days 1, 29, 57, and 85; 0.5, 1, 2, 4, and 6 hours post-dose on Days 1 and 85, Days 2, 3, 15, 113, 141, and 169 post-dose

End point values	SAD: Pooled Placebo	SAD: WVE-004 10 mg	SAD: WVE-004 20 mg	SAD: WVE-004 30 mg	SAD: WVE-004 60 mg	MAD: Pooled Placebo	MAD: WVE-004 10 mg Q4W	MAD: WVE-004 10 mg Q12W
Number of subjects analysed	5	2	8	5	3	7	5	9
Units: nanogram per milliliter (ng/mL)
arithmetic mean (standard deviation)
Pre-dose (Day 1) (n=5,2,8,5,3,7,5,9)	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )
0.5 hours post-dose on Day 1 (n=5,2,8,5,3,7,5,8)	0.000 ( 0.0000 )	11.072 ( 7.0407 )	24.015 ( 26.5618 )	110.872 ( 210.0965 )	982.573 ( 1576.5449 )	0.000 ( 0.0000 )	25.595 ( 41.3207 )	12.811 ( 16.1575 )
1 hour post-dose on Day 1 (n=5,2,8,5,3,7,5,9)	0.000 ( 0.0000 )	15.600 ( 0.5798 )	37.983 ( 29.0999 )	232.260 ( 290.6490 )	1566.820 ( 2535.1732 )	0.000 ( 0.0000 )	49.456 ( 79.2287 )	39.632 ( 42.1030 )
2 hours post-dose on Day 1 (n=5,2,8,5,3,7,5,9)	0.000 ( 0.0000 )	15.755 ( 7.2196 )	53.901 ( 36.8846 )	254.616 ( 329.1846 )	1153.337 ( 1810.6330 )	0.000 ( 0.0000 )	54.334 ( 89.6615 )	62.059 ( 61.8641 )
4 hours post-dose on Day 1 (n=5,2,8,5,3,7,5,9)	0.000 ( 0.0000 )	15.915 ( 3.4860 )	58.559 ( 25.9130 )	181.638 ( 212.0959 )	477.957 ( 604.5136 )	0.000 ( 0.0000 )	47.821 ( 68.9649 )	68.896 ( 61.2281 )
6 hours post-dose on Day 1 (n=5,2,8,5,3,7,5,9)	0.000 ( 0.0000 )	12.437 ( 3.5822 )	72.855 ( 37.4893 )	164.356 ( 115.9532 )	181.480 ( 123.6849 )	0.000 ( 0.0000 )	42.810 ( 42.9880 )	50.609 ( 33.8274 )
24 hours post-dose on Day 1 (n=5,2,8,5,3,7,5,9)	0.000 ( 0.0000 )	7.048 ( 3.2690 )	48.229 ( 19.4029 )	67.372 ( 26.1047 )	92.537 ( 66.2866 )	0.000 ( 0.0000 )	12.432 ( 4.4660 )	26.894 ( 23.5717 )
Day 3 (n=2,1,0,2,1,0,0,0)	0.000 ( 0.0000 )	4.657 ( 99999 )	9999 ( 9999 )	19.072 ( 21.7761 )	5.201 ( 99999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )
Day 15 (n=5,2,8,5,2,7,5,9)	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.151 ( 0.2804 )	0.786 ( 0.1557 )	0.693 ( 0.0472 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )
Day 29 (n=5,2,8,5,2,6,5,8)	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.254 ( 0.3509 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )
Day 57 (n=5,2,7,4,3,7,5,9)	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )
Day 85 (n=5,2,7,3,2,7,5,8)	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )
0.5 hours post-dose on Day 85 (n=0,0,0,0,0,6,5,8)	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	0.000 ( 0.0000 )	21.729 ( 35.0917 )	16.487 ( 16.0989 )
1 hour post-dose on Day 85 (n=0,0,0,0,0,6,5,8)	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	0.000 ( 0.0000 )	44.126 ( 69.8988 )	47.824 ( 50.8331 )
2 hours post-dose on Day 85 (n=0,0,0,0,0,6,5,8)	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	0.000 ( 0.0000 )	41.473 ( 50.6066 )	75.401 ( 73.2937 )
4 hours post-dose on Day 85 (n=0,0,0,0,0,6,5,8)	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	0.000 ( 0.0000 )	55.927 ( 66.4905 )	82.305 ( 80.8516 )
6 hours post-dose on Day 85 (n=0,0,0,0,0,6,4,8)	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	0.000 ( 0.0000 )	31.173 ( 21.3997 )	64.645 ( 52.1281 )
Day 113 (n=0,0,0,0,0,6,3,8)	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )
Day 141 (n=0,0,0,0,0,6,2,7)	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )
Day 169 (n=0,0,1,0,0,6,2,6)	9999 ( 9999 )	9999 ( 9999 )	0.000 ( 99999 )	9999 ( 9999 )	9999 ( 9999 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )
Pre-dose (Period 2 Day 1) (n=3,2,3,0,1,0,0,0)	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	9999 ( 9999 )	0.000 ( 0.0000 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )

No statistical analyses for this end point

Secondary: Concentration of WVE-004 in Cerebrospinal Fluid (CSF)

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End point title

Concentration of WVE-004 in Cerebrospinal Fluid (CSF)

End point description

CSF samples collected to determine the concentration of WVE-004 in CSF. The Safety population included all participants who were randomized and received at least 1 dose of study treatment. Here, n= number of participants analyzed at specific timepoints, 9999= no participants analyzed and 99999= Standard deviation is not applicable when only 1 participant was analyzed.

End point type

Secondary

End point timeframe

Period 1: Pre-dose; Days 15, 29, 57, 85, 113, 141 and 169; Period 2: Pre-dose; Days 29, 57, 85, 113, 141 and 169

End point values	SAD: Pooled Placebo	SAD: WVE-004 10 mg	SAD: WVE-004 20 mg	SAD: WVE-004 30 mg	SAD: WVE-004 60 mg	MAD: Pooled Placebo	MAD: WVE-004 10 mg Q4W	MAD: WVE-004 10 mg Q12W
Number of subjects analysed	5	2	8	5	3	7	5	9
Units: ng/mL
arithmetic mean (standard deviation)
Pre-dose (n=5,2,8,5,3,7,5,9)	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.000 ( 0.0000 )	0.355 ( 0.7885 )
Day 15 (n=4,2,5,5,2,0,0,0)	0.000 ( 0.0000 )	5.744 ( 1.1434 )	15.070 ( 9.0216 )	11.232 ( 3.2655 )	11.024 ( 13.4584 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )
Day 29 (n=5,1,8,5,3,5,5,8)	0.000 ( 0.0000 )	4.689 ( 99999 )	7.366 ( 2.3799 )	5.921 ( 2.6947 )	7.234 ( 4.6744 )	0.000 ( 0.0000 )	4.047 ( 1.7556 )	4.113 ( 1.4139 )
Day 57 (n=5,2,8,3,3,6,5,8)	0.000 ( 0.0000 )	1.503 ( 2.1256 )	3.894 ( 1.2476 )	2.751 ( 1.6672 )	3.560 ( 3.1008 )	0.000 ( 0.0000 )	4.986 ( 1.9157 )	2.953 ( 1.5480 )
Day 85 (n=5,2,7,3,2,6,5,8)	0.000 ( 0.0000 )	0.985 ( 1.3923 )	3.120 ( 1.5190 )	1.863 ( 1.1513 )	2.283 ( 3.2286 )	0.000 ( 0.0000 )	5.299 ( 2.2021 )	2.525 ( 1.6642 )
Day 113 (n=1,0,6,0,0,6,3,7)	0.000 ( 99999 )	9999 ( 9999 )	3.243 ( 2.1831 )	9999 ( 9999 )	9999 ( 9999 )	0.000 ( 0.0000 )	7.825 ( 3.2123 )	7.780 ( 3.5932 )
Day 141 (n=1,0,4,0,0,4,2,6)	0.000 ( 99999 )	9999 ( 9999 )	2.198 ( 1.6976 )	9999 ( 9999 )	9999 ( 9999 )	0.000 ( 0.0000 )	4.236 ( 0.5006 )	5.003 ( 2.0149 )
Day 169 (n=1,0,5,0,0,5,2,6)	0.000 ( 99999 )	9999 ( 9999 )	1.810 ( 1.2271 )	9999 ( 9999 )	9999 ( 9999 )	0.000 ( 0.0000 )	3.816 ( 1.7444 )	3.638 ( 1.7227 )
Pre-dose (Period 2 Day 1) (n=3,2,3,0,1,0,0,0)	0.000 ( 0.0000 )	0.000 ( 0.0000 )	1.066 ( 1.1622 )	9999 ( 9999 )	0.000 ( 0.0000 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )

No statistical analyses for this end point

Secondary: Change From Baseline in Concentration of Poly Glycine-Proline (Poly-GP) Levels in the CSF Through Day 169

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End point title

Change From Baseline in Concentration of Poly Glycine-Proline (Poly-GP) Levels in the CSF Through Day 169

End point description

CSF samples collected to determine the concentration of poly-GP levels in CSF. The Safety population included all participants who were randomized and received at least 1 dose of study treatment. Here, n= number of participants analyzed at specific timepoints, 9999= no participants analyzed and 99999= Standard deviation is not applicable when only 1 participant was analyzed.

End point type

Secondary

End point timeframe

Period 1: Baseline (Day 1) and Days 15, 29, 57, 85, 113, 141 and 169; Period 2: Baseline (Day 1) and Days 29, 57, 85, 113, 141, and 169

End point values	SAD: Pooled Placebo	SAD: WVE-004 10 mg	SAD: WVE-004 20 mg	SAD: WVE-004 30 mg	SAD: WVE-004 60 mg	MAD: Pooled Placebo	MAD: WVE-004 10 mg Q4W	MAD: WVE-004 10 mg Q12W
Number of subjects analysed	5	2	8	5	3	7	5	9
Units: picogram/mL
arithmetic mean (standard deviation)
Baseline (Day 1) (n=5,2,8,5,3,7,5,9)	28.03 ( 19.943 )	140.80 ( 158.675 )	15.88 ( 4.165 )	21.23 ( 10.820 )	32.97 ( 9.581 )	21.69 ( 9.896 )	60.84 ( 76.321 )	20.70 ( 19.759 )
Day 15 (n=4,2,5,5,2,0,0,0)	25.74 ( 23.325 )	133.80 ( 137.462 )	12.86 ( 6.504 )	15.67 ( 10.217 )	29.65 ( 14.071 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )
Day 29 (n=5,1,8,5,3,5,5,8)	29.21 ( 20.874 )	238.00 ( 99999 )	13.57 ( 4.759 )	14.23 ( 10.075 )	28.93 ( 6.824 )	20.67 ( 12.253 )	53.50 ( 66.685 )	17.85 ( 12.840 )
Day 57 (n=5,2,8,3,3,6,5,8)	28.99 ( 21.130 )	111.05 ( 124.380 )	10.88 ( 4.111 )	14.27 ( 7.419 )	22.83 ( 5.934 )	19.89 ( 9.813 )	47.99 ( 57.109 )	16.76 ( 12.696 )
Day 85 (n=5,2,7,3,2,6,5,8)	29.49 ( 20.546 )	116.75 ( 109.248 )	11.01 ( 3.117 )	11.92 ( 4.175 )	25.15 ( 7.425 )	19.39 ( 10.713 )	46.51 ( 53.808 )	17.06 ( 12.298 )
Day 113 (n=1,0,6,0,0,6,3,7)	44.70 ( 99999 )	9999 ( 9999 )	10.13 ( 3.524 )	9999 ( 9999 )	9999 ( 9999 )	18.71 ( 9.423 )	17.40 ( 12.025 )	12.35 ( 10.967 )
Day 141 (n=1,0,4,0,0,4,2,6)	40.60 ( 99999 )	9999 ( 9999 )	10.49 ( 3.241 )	9999 ( 9999 )	9999 ( 9999 )	20.21 ( 12.370 )	54.10 ( 38.184 )	13.75 ( 12.458 )
Day 169 (n=1,0,5,0,0,5,2,6)	44.60 ( 99999 )	9999 ( 9999 )	9.06 ( 3.544 )	9999 ( 9999 )	9999 ( 9999 )	21.27 ( 11.246 )	48.35 ( 29.911 )	14.88 ( 15.261 )
Period 2 Day 1 (n=3,2,3,0,1,0,0,0)	15.98 ( 12.452 )	116.15 ( 111.511 )	8.19 ( 3.815 )	9999 ( 9999 )	19.30 ( 99999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

TEAEs were collected from the first dose of study treatment (Day 1) up to 51 weeks (Period 1 = 24 weeks of follow-up and Period 2 = 12 weeks of treatment followed by 15 weeks of follow-up)

Adverse event reporting additional description

The Safety population included all participants who were randomized and received at least 1 dose of study treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

SAD: Pooled Placebo

Reporting group description

Participants were randomized to receive a single dose of placebo matching with WVE-004 on Day 1.

Reporting group title

SAD: WVE-004 10 mg

Reporting group description

Participants were randomized to receive a single dose of WVE-004 10 mg IT injection on Day 1.

Reporting group title

SAD: WVE-004 20 mg

Reporting group description

Participants were randomized to receive a single dose of WVE-004 20 mg IT injection on Day 1.

Reporting group title

SAD: WVE-004 30 mg

Reporting group description

Participants were randomized to receive a single dose of WVE-004 30 mg IT injection on Day 1.

Reporting group title

SAD: WVE-004 60 mg

Reporting group description

Participants were randomized to receive a single dose of WVE-004 60 mg IT injection on Day 1.

Reporting group title

MAD: Pooled Placebo

Reporting group description

Eligible participants from Period 1 and newly enrolled participants were randomized to receive placebo matching with WVE-004 Q4W or Q12W for 12 weeks.

Reporting group title

MAD: WVE-004 10 mg Q4W

Reporting group description

Eligible participants from Period 1 and newly enrolled participants were randomized to receive WVE-004 10 mg IT injection Q4W for 12 weeks.

Reporting group title

MAD: WVE-004 10 mg Q12W

Reporting group description

Eligible participants from Period 1 and newly enrolled participants were randomized to receive WVE-004 10 mg IT injection Q12W for 12 weeks.

Serious adverse events	SAD: Pooled Placebo	SAD: WVE-004 10 mg	SAD: WVE-004 20 mg	SAD: WVE-004 30 mg	SAD: WVE-004 60 mg	MAD: Pooled Placebo	MAD: WVE-004 10 mg Q4W	MAD: WVE-004 10 mg Q12W
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 5 (20.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	3 / 5 (60.00%)	1 / 3 (33.33%)	3 / 7 (42.86%)	2 / 5 (40.00%)	2 / 9 (22.22%)
number of deaths (all causes)	0	0	1	2	1	0	1	1
number of deaths resulting from adverse events	0	0	1	2	1	0	1	1
Investigations
Weight decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Head injury
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	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	0 / 0
Post lumbar puncture syndrome
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Nervous system disorders
Cerebellar syndrome
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
Sensory loss
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Status epilepticus
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0
General disorders and administration site conditions
Disease progression
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Vision blurred
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Gastrointestinal disorders
Constipation
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Dysphagia
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 5 (40.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	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	0 / 0
Respiratory failure
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	2 / 5 (40.00%)	1 / 9 (11.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
Psychiatric disorders
Delirium
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 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	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0
Metabolism and nutrition disorders
Hyponatraemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0

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

Non-serious adverse events	SAD: Pooled Placebo	SAD: WVE-004 10 mg	SAD: WVE-004 20 mg	SAD: WVE-004 30 mg	SAD: WVE-004 60 mg	MAD: Pooled Placebo	MAD: WVE-004 10 mg Q4W	MAD: WVE-004 10 mg Q12W
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 5 (100.00%)	2 / 2 (100.00%)	8 / 8 (100.00%)	5 / 5 (100.00%)	3 / 3 (100.00%)	7 / 7 (100.00%)	5 / 5 (100.00%)	7 / 9 (77.78%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Haemangioma of skin
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Vascular disorders
Haematoma
subjects affected / exposed	0 / 5 (0.00%)	1 / 2 (50.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Hypertension
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Peripheral coldness
subjects affected / exposed	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	1	0	1	0	0
General disorders and administration site conditions
Disease progression
subjects affected / exposed	1 / 5 (20.00%)	1 / 2 (50.00%)	1 / 8 (12.50%)	2 / 5 (40.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	1	1	2	0	0	0	0
Fatigue
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	1 / 5 (20.00%)	0 / 3 (0.00%)	2 / 7 (28.57%)	3 / 5 (60.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	1	0	2	3	0
Feeling cold
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Feeling hot
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1
Gait disturbance
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Injection site discomfort
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	1	0
Medical device site pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Oedema peripheral
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Respiratory, thoracic and mediastinal disorders
Choking
subjects affected / exposed	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Cough
subjects affected / exposed	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0
Lung consolidation
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Lung disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1
Respiratory failure
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	2 / 5 (40.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	1	0	1	2	1
Psychiatric disorders
Delirium
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Insomnia
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	2 / 8 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	2	0	0	0	1	0
Poor quality sleep
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Suicidal ideation
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Product issues
Device physical property issue
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Investigations
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Blood fibrinogen decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Blood urine present
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Body temperature increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
C-reactive protein increased
subjects affected / exposed	1 / 5 (20.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	1	1	0	0	0	0
Coagulation test abnormal
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Glycosylated haemoglobin increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1
Heart rate increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	1	0
Weight decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 5 (40.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	2	1
Injury, poisoning and procedural complications
Administration related reaction
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 5 (40.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0
Bone contusion
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	1	0	0	0	0	1
Concussion
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Contusion
subjects affected / exposed	1 / 5 (20.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	1 / 9 (11.11%)
occurrences all number	1	0	1	1	0	0	1	1
Fall
subjects affected / exposed	1 / 5 (20.00%)	1 / 2 (50.00%)	3 / 8 (37.50%)	1 / 5 (20.00%)	1 / 3 (33.33%)	1 / 7 (14.29%)	4 / 5 (80.00%)	5 / 9 (55.56%)
occurrences all number	1	1	3	1	1	1	4	5
Head injury
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Infusion related reaction
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Muscle strain
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Post lumbar puncture syndrome
subjects affected / exposed	2 / 5 (40.00%)	0 / 2 (0.00%)	2 / 8 (25.00%)	2 / 5 (40.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	2	0	2	2	0	0	1	0
Procedural pain
subjects affected / exposed	2 / 5 (40.00%)	0 / 2 (0.00%)	3 / 8 (37.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	2 / 9 (22.22%)
occurrences all number	2	0	3	0	0	0	0	2
Scratch
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Skin abrasion
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	1 / 5 (20.00%)	1 / 9 (11.11%)
occurrences all number	0	0	1	0	0	1	1	1
Skin laceration
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Soft tissue injury
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Stoma site hypergranulation
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Wound
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1
Cardiac disorders
Tachycardia
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Nervous system disorders
Balance disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Cerebellar syndrome
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Cognitive disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Dizziness
subjects affected / exposed	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0
Headache
subjects affected / exposed	4 / 5 (80.00%)	0 / 2 (0.00%)	5 / 8 (62.50%)	1 / 5 (20.00%)	1 / 3 (33.33%)	3 / 7 (42.86%)	1 / 5 (20.00%)	2 / 9 (22.22%)
occurrences all number	4	0	5	1	1	3	1	2
Hypoaesthesia
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	2 / 7 (28.57%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	2	0	1
IIIrd nerve disorder
subjects affected / exposed	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Loss of consciousness
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Migraine
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Muscle contractions involuntary
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	1	0
Paraesthesia
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	1 / 9 (11.11%)
occurrences all number	0	0	1	0	0	0	1	1
Polyneuropathy
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1
Restless legs syndrome
subjects affected / exposed	0 / 5 (0.00%)	1 / 2 (50.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0
Sciatica
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Sensory loss
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Status epilepticus
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1
Taste disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1
Tremor
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Leukocytosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Ear and labyrinth disorders
Hypoacusis
subjects affected / exposed	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Eye disorders
Eye movement disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Periorbital oedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Vision blurred
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Abdominal pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Constipation
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	1 / 3 (33.33%)	1 / 7 (14.29%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	1	0	1	1	0	1
Diarrhoea
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	1 / 5 (20.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	1	1	1
Dry mouth
subjects affected / exposed	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	1	1	0
Dysphagia
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 5 (40.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0
Frequent bowel movements
subjects affected / exposed	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Nausea
subjects affected / exposed	0 / 5 (0.00%)	1 / 2 (50.00%)	2 / 8 (25.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	1	2	1	0	0	1	0
Oral discomfort
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Oral pain
subjects affected / exposed	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Vomiting
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Skin and subcutaneous tissue disorders
Decubitus ulcer
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Dermatitis exfoliative
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Drug eruption
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Dry skin
subjects affected / exposed	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Eczema
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Erythema
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1
Nail discolouration
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1
Glycosuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Haematuria
subjects affected / exposed	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Hypertonic bladder
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Leukocyturia
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Pollakiuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Proteinuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Urinary incontinence
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	1	0
Back pain
subjects affected / exposed	1 / 5 (20.00%)	0 / 2 (0.00%)	3 / 8 (37.50%)	1 / 5 (20.00%)	1 / 3 (33.33%)	1 / 7 (14.29%)	2 / 5 (40.00%)	1 / 9 (11.11%)
occurrences all number	1	0	3	1	1	1	2	1
Flank pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Muscle spasms
subjects affected / exposed	2 / 5 (40.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	2	0	1	0	0	0	0	1
Muscle twitching
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1
Muscular weakness
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	2 / 5 (40.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	2	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Musculoskeletal pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Musculoskeletal stiffness
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0
Myalgia
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Neck pain
subjects affected / exposed	2 / 5 (40.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	2	0	0	0	0	1	0	0
Pain in extremity
subjects affected / exposed	2 / 5 (40.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	2 / 5 (40.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	2	0	1	2	0	0	0	1
Periarthritis
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Infections and infestations
Asymptomatic bacteriuria
subjects affected / exposed	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	1	1	0
Bacteriuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
COVID-19
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	2 / 8 (25.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	2	0	0	1	1	0
Chlamydial infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1
Herpes simplex
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Hordeolum
subjects affected / exposed	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Laryngitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1
Nasopharyngitis
subjects affected / exposed	1 / 5 (20.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	2 / 9 (22.22%)
occurrences all number	1	0	1	0	0	1	0	2
Pneumonia
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 5 (40.00%)	1 / 9 (11.11%)
occurrences all number	0	0	1	0	0	0	2	1
Upper respiratory tract infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	1	0	1
Urinary tract infection
subjects affected / exposed	0 / 5 (0.00%)	1 / 2 (50.00%)	1 / 8 (12.50%)	1 / 5 (20.00%)	0 / 3 (0.00%)	2 / 7 (28.57%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	1	1	0	2	0	0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	1 / 7 (14.29%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	1	1	0	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Dehydration
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1
Hyponatraemia
subjects affected / exposed	0 / 5 (0.00%)	1 / 2 (50.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	1 / 9 (11.11%)
occurrences all number	0	1	0	0	0	0	1	1
Hypophosphataemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0

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Were there any global substantial amendments to the protocol? Yes

17 Dec 2020

• Removed National Cancer Institute Common Terminology Criteria for Adverse Events for AE categorization. • Removed optionality for pre-lumbar puncture (LP) prothrombin time and platelet testing at the Early Termination Visit in Period 1.

23 Aug 2021

• Updated planned dosing regimen in Period 2 Cycle 1 based on available nonclinical Pharmacokinetic and toxicology data. • Revised randomization of new participants in Period 2 to ensure a balance of treatment and placebo participants within disease type. • Modified Period 2 and individual stopping criteria in accordance with regulatory feedback across multiple regions. • Revised to require all participants (not just FTD and mixed phenotype) perform Clinical Dementia Rating plus National Alzheimer’s Coordinating Center Frontotemporal Lobar Degeneration at Screening. • Clarified data required for dose escalation decision. • Clarified timing and duration of contraception.

02 May 2022

• Revised to allow additional participants from Period 1 to receive Period 2 Cycle 1 dose level based on available clinical data. • Provided further clarification regarding potential bleeding disorders that expose participants to risk of injury or unsuccessful LP. • Added exclusion criterion for antiplatelet or anticoagulant concomitant therapies, in accordance with Regulatory feedback. • Provided further clarity regarding the flexibility of the Dose Escalation Committee (DEC) and Data Safety Monitoring Board (DSMB) to change dose level and frequency. • Added additional visits and assessments to further assess Pharmacokinetic, Pharmacodynamic, safety, and clinical effects. • Aligned highly effective methods of contraception with regional regulatory feedback.

07 Oct 2022

• Updated to indicate that the maximum dose level and frequency in Period 2 would not exceed 20 mg Q12W based on recommendations by the DEC/DSMB. • Added Protocol Section 2.4 to reflect the current status of the adaptive design allowing only participation in Period 1 and Period 2, or Period 2 only. • Added a digital health technology device to gain additional data on potential clinical effects of WVE-004.

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.

Due to lack of clinical benefit, development of WVE-004 was stopped.

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Clinical trials

Clinical Trial Results:
A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 1b/2a Study of WVE-004 Administered Intrathecally to Patients with C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) or Frontotemporal Dementia (FTD)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Treatment-Emergent Adverse Events and Withdrew Due to Adverse Events

Primary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Treatment-Emergent Adverse Events and Withdrew Due to Adverse Events

Secondary: Concentration of WVE-004 in Plasma

Secondary: Concentration of WVE-004 in Plasma

Secondary: Concentration of WVE-004 in Cerebrospinal Fluid (CSF)

Secondary: Concentration of WVE-004 in Cerebrospinal Fluid (CSF)

Secondary: Change From Baseline in Concentration of Poly Glycine-Proline (Poly-GP) Levels in the CSF Through Day 169

Secondary: Change From Baseline in Concentration of Poly Glycine-Proline (Poly-GP) Levels in the CSF Through Day 169

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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

Clinical trials

Clinical Trial Results: A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 1b/2a Study of WVE-004 Administered Intrathecally to Patients with C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) or Frontotemporal Dementia (FTD)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Treatment-Emergent Adverse Events and Withdrew Due to Adverse Events

Primary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Treatment-Emergent Adverse Events and Withdrew Due to Adverse Events

Secondary: Concentration of WVE-004 in Plasma

Secondary: Concentration of WVE-004 in Plasma

Secondary: Concentration of WVE-004 in Cerebrospinal Fluid (CSF)

Secondary: Concentration of WVE-004 in Cerebrospinal Fluid (CSF)

Secondary: Change From Baseline in Concentration of Poly Glycine-Proline (Poly-GP) Levels in the CSF Through Day 169

Secondary: Change From Baseline in Concentration of Poly Glycine-Proline (Poly-GP) Levels in the CSF Through Day 169

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 1b/2a Study of WVE-004 Administered Intrathecally to Patients with C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) or Frontotemporal Dementia (FTD)