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Clinical Trial Results:
A Phase 1/2 Open-label, Multiple-dose, Dose-escalating Clinical Trial of the Safety and Tolerability of GTX-102 in Pediatric Patients With Angelman Syndrome (AS)

Summary
EudraCT number	2021-001793-36
Trial protocol	DE ES FR
Global end of trial date	08 Jan 2025

Results information
Results version number	v2(current)
This version publication date	08 May 2026
First version publication date	23 Jan 2026
Other versions	v1
Version creation reason	New data added to full data set Secondary endpoint data added

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

GTX-102-001

ISRCTN number

US NCT number

NCT04259281

WHO universal trial number (UTN)

Sponsor organisation name

Ultragenyx Pharmaceutical Inc.

Sponsor organisation address

60 Leveroni Court, Novato, United States, 94949

Public contact

Trial Recruitment, Ultragenyx Pharmaceutical Inc., +1 8887568657, trialrecruitment@ultragenyx.com

Scientific contact

Medical Information, Ultragenyx Pharmaceutical Inc., +1 8887568657, medinfo@ultragenyx.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

08 Jan 2025

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

08 Jan 2025

Was the trial ended prematurely?

Main objective of the trial

To evaluate the safety and tolerability of multiple-ascending doses of GTX-102 administered by intrathecal (IT) injection to patients with AS.

Protection of trial subjects

All participants, parents and/or legal guardians of the participant will be provided with an Information Sheet and/or Consent Form describing this study and providing sufficient information to make an informed decision about the participation of their represented participant in this study. Where required, consent will be sought from the parents and/or legal guardian of the participant. The Informed Consent Forms (ICFs) and Patient Informed Consent Forms (PICFs) will include all elements required by ICH, Good Clinical Practice (GCP) and applicable regulatory requirements. The Information Sheet and/or Consent Form will be submitted with the protocol for review and approval by the relevant Ethical Review Board for the study in each country. The formal consent of a participant, using the Informed Consent Form approved by the relevant Ethical Review Board, must be obtained before that participant undergoes any study procedure. The consent form must be signed by the participant’s parent/legal guardian, and the Investigator-designated research professional obtaining the consent. Where required by the relevant Ethical Review Board, a witness may sign the consent form.

Background therapy

Evidence for comparator

Actual start date of recruitment

24 Feb 2020

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 5

Country: Number of subjects enrolled

France: 7

Country: Number of subjects enrolled

Germany: 4

Country: Number of subjects enrolled

Australia: 5

Country: Number of subjects enrolled

Canada: 20

Country: Number of subjects enrolled

United Kingdom: 7

Country: Number of subjects enrolled

Israel: 2

Country: Number of subjects enrolled

United States: 24

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

A total of 74 participants were enrolled sequentially into 13 cohorts. After a dosing pause, the participants enrolled in Cohorts 1 and 2 restarted in a redosing cohort. The single Cohort 3 participant continued to be followed in an expanded access trial.

Screening details

Per the Statistical Analysis Plan (SAP), the analysis treatment groups were defined as Cohorts 1-3, US Redosing Cohorts 1-2, Cohorts 4-7, Cohorts A & B, Cohorts C & D and US 2 mg/Cohort E.

Period 1 title

Original Dosing Period

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

GTX-102 Cohorts 1-3

Arm description

Participants received doses ranging from 3.3 to 20 mg followed by dose escalation up to a maximum of 36 mg.

Arm type

Experimental

Investigational medicinal product name

GTX-102

Investigational medicinal product code

GTX-102

Other name

apazunursen

Pharmaceutical forms

Solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

GTX-102 is given through an intrathecal injection via lumbar puncture.

Number of subjects in period 1	GTX-102 Cohorts 1-3
Started	5
Completed	0
Not completed	5
Adverse event, non-fatal	5

Period 2 title

Amended Dosing Period

Is this the baseline period?

Yes ^[1]

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

GTX-102 US Redosing Cohorts 1-2

Arm description

Participants from Cohorts 1-2 were restarted at doses ranging from 5 to 10 mg followed by dose escalation up to a maximum dose of 14 mg every 3 months (Q3M).

Arm type

Experimental

Investigational medicinal product name

GTX-102

Investigational medicinal product code

GTX-102

Other name

apazunursen

Pharmaceutical forms

Solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

GTX-102 is given through an intrathecal injection via lumbar puncture.

GTX-102 Cohorts 4-7

Arm description

Participants received up to 4 loading doses ranging from 3.3 to 10 mg followed by dose escalation up to a maximum dose of 14 mg Q3M.

Arm type

Experimental

Investigational medicinal product name

GTX-102

Investigational medicinal product code

GTX-102

Other name

apazunursen

Pharmaceutical forms

Solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

GTX-102 is given through an intrathecal injection via lumbar puncture.

GTX-102 Cohorts A&B

Arm description

Participants received up to 4 loading doses of 7.5 mg followed by dose escalation up to a maximum dose of 14 mg Q3M.

Arm type

Experimental

Investigational medicinal product name

GTX-102

Investigational medicinal product code

GTX-102

Other name

apazunursen

Pharmaceutical forms

Solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

GTX-102 is given through an intrathecal injection via lumbar puncture.

GTX-102 Cohorts C&D

Arm description

Participants received up to 4 loading doses ranging from 5 to 7.5 mg followed by dose escalation up to a maximum dose of 10 mg Q3M.

Arm type

Experimental

Investigational medicinal product name

GTX-102

Investigational medicinal product code

GTX-102

Other name

apazunursen

Pharmaceutical forms

Solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

GTX-102 is given through an intrathecal injection via lumbar puncture.

GTX-102 US 2 mg/Cohort E

Arm description

Participants received either no treatment or GTX-102. Participants treated with GTX-102 received 4 monthly loading doses of 2 mg, followed by 2 mg Q3M. Participants who received no treatment during the initial period then received 4 monthly doses of 2 mg, followed by 2 mg Q3M. All participants then transitioned to Cohort E regardless of prior GTX-102 treatment duration and received up to 4 loading doses of 5 to 7.5 mg, followed by 7.5 mg every 2 months (Q2M).

Arm type

Experimental

Investigational medicinal product name

GTX-102

Investigational medicinal product code

GTX-102

Other name

apazunursen

Pharmaceutical forms

Solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

GTX-102 is given through an intrathecal injection via lumbar puncture.

Notes
[1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
Justification: Period 2 (Amended Dosing Period) is the Baseline Period.

Number of subjects in period 2	GTX-102 US Redosing Cohorts 1-2	GTX-102 Cohorts 4-7	GTX-102 Cohorts A&B	GTX-102 Cohorts C&D	GTX-102 US 2 mg/Cohort E
Started	4	15	34	12	8
Completed	4	13	31	12	7
Not completed	0	2	3	0	1
Consent withdrawn by subject	-	1	1	-	1
Adverse event, non-fatal	-	1	1	-	-
Parental Decision	-	-	1	-	-

Baseline characteristics

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Reporting group title

GTX-102 US Redosing Cohorts 1-2

Reporting group description

Participants from Cohorts 1-2 were restarted at doses ranging from 5 to 10 mg followed by dose escalation up to a maximum dose of 14 mg every 3 months (Q3M).

Reporting group title

GTX-102 Cohorts 4-7

Reporting group description

Participants received up to 4 loading doses ranging from 3.3 to 10 mg followed by dose escalation up to a maximum dose of 14 mg Q3M.

Reporting group title

GTX-102 Cohorts A&B

Reporting group description

Participants received up to 4 loading doses of 7.5 mg followed by dose escalation up to a maximum dose of 14 mg Q3M.

Reporting group title

GTX-102 Cohorts C&D

Reporting group description

Participants received up to 4 loading doses ranging from 5 to 7.5 mg followed by dose escalation up to a maximum dose of 10 mg Q3M.

Reporting group title

GTX-102 US 2 mg/Cohort E

Reporting group description

Notes
[1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
Justification: A total of 74 participants were enrolled. The US Redosing Cohort 1-2 participants (in Amended Dosing Period) are a subset of the Cohorts 1-3 participants (Original Dosing Period), in which 4 of the 5 participants were re-enrolled. Baseline characteristics details for Cohorts 1-3 (Original Dosing Period) are presented under the Subject Analysis Sets list. (Empty fields are not applicable for this section, and can be ignored.)

Reporting group values	GTX-102 US Redosing Cohorts 1-2	GTX-102 Cohorts 4-7	GTX-102 Cohorts A&B	GTX-102 Cohorts C&D	GTX-102 US 2 mg/Cohort E	Total
Number of subjects	4	15	34	12	8	73
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	13.98 ( 4.4 )	8.4 ( 3.9 )	7.8 ( 3.8 )	8.8 ( 4.3 )	5.9 ( 1.2 )	-
Gender categorical
Units: Subjects
Female	2	8	21	9	5	45
Male	2	7	13	3	3	28
Race
Units: Subjects
Not Allowed per Local Regulation	0	0	7	0	0	7
American Indian or Alaska Native	0	0	0	0	0	0
Asian	0	2	1	1	1	5
Black or African American	0	0	1	0	0	1
Native Hawaiian or Other Pacific Islander	0	0	1	0	0	1
White	4	7	23	11	7	48
Other	0	6	1	0	0	7

Subject analysis set title

GTX-102 Cohorts 1-3 (Period 1)

Subject analysis set type

Per protocol

Subject analysis set description

Participants received doses of 3.3 mg to 20 mg of GTX-102 which were escalated up to a maximum maintenance dose of 36 mg.

Subject analysis set title

GTX-102 2 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received a first dose of 2 mg of GTX-102.

Subject analysis set title

GTX-102 3.3 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received a first dose of 3.3 mg of GTX-102.

Subject analysis set title

GTX-102 5 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received a first dose of 5 mg of GTX-102.

Subject analysis set title

GTX-102 7.5 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received a first dose of 7.5 mg of GTX-102.

Subject analysis set title

GTX-102 10 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received a first dose of 10 mg of GTX-102.

Subject analysis set title

GTX-102 20 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received a first dose of 20 mg of GTX-102.

Subject analysis sets values	GTX-102 Cohorts 1-3 (Period 1)	GTX-102 2 mg	GTX-102 3.3 mg	GTX-102 5 mg	GTX-102 7.5 mg	GTX-102 10 mg	GTX-102 20 mg
Number of subjects	5	8	8	8	3	4	1
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	9.4 ( 4.4 )	( )	( )	( )	( )	( )	( )
Gender categorical
Units: Subjects
Female	2
Male	3
Race
Units: Subjects
Not Allowed per Local Regulation	0
American Indian or Alaska Native	0
Asian	0
Black or African American	0
Native Hawaiian or Other Pacific Islander	0
White	5
Other	0

End points

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Reporting group title

GTX-102 Cohorts 1-3

Reporting group description

Participants received doses ranging from 3.3 to 20 mg followed by dose escalation up to a maximum of 36 mg.

Reporting group title

GTX-102 US Redosing Cohorts 1-2

Reporting group description

Participants from Cohorts 1-2 were restarted at doses ranging from 5 to 10 mg followed by dose escalation up to a maximum dose of 14 mg every 3 months (Q3M).

Reporting group title

GTX-102 Cohorts 4-7

Reporting group description

Participants received up to 4 loading doses ranging from 3.3 to 10 mg followed by dose escalation up to a maximum dose of 14 mg Q3M.

Reporting group title

GTX-102 Cohorts A&B

Reporting group description

Participants received up to 4 loading doses of 7.5 mg followed by dose escalation up to a maximum dose of 14 mg Q3M.

Reporting group title

GTX-102 Cohorts C&D

Reporting group description

Participants received up to 4 loading doses ranging from 5 to 7.5 mg followed by dose escalation up to a maximum dose of 10 mg Q3M.

Reporting group title

GTX-102 US 2 mg/Cohort E

Reporting group description

Subject analysis set title

GTX-102 Cohorts 1-3 (Period 1)

Subject analysis set type

Per protocol

Subject analysis set description

Participants received doses of 3.3 mg to 20 mg of GTX-102 which were escalated up to a maximum maintenance dose of 36 mg.

Subject analysis set title

GTX-102 2 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received a first dose of 2 mg of GTX-102.

Subject analysis set title

GTX-102 3.3 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received a first dose of 3.3 mg of GTX-102.

Subject analysis set title

GTX-102 5 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received a first dose of 5 mg of GTX-102.

Subject analysis set title

GTX-102 7.5 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received a first dose of 7.5 mg of GTX-102.

Subject analysis set title

GTX-102 10 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received a first dose of 10 mg of GTX-102.

Subject analysis set title

GTX-102 20 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received a first dose of 20 mg of GTX-102.

Primary: Number of Participants with Treatment-emergent Adverse Events (TEAEs), Serious TEAEs (SAEs), Adverse Events of Special Interest (AESIs), TEAEs Leading to Discontinuation and TEAEs by Severity

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End point title

Number of Participants with Treatment-emergent Adverse Events (TEAEs), Serious TEAEs (SAEs), Adverse Events of Special Interest (AESIs), TEAEs Leading to Discontinuation and TEAEs by Severity ^[1]

End point description

An adverse event (AE) is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. A TEAE is defined as any AE not present prior to the initiation of the drug treatment or any AE already present that worsens in either intensity or frequency following exposure to the drug treatment. An SAE is an AE that meets any of the following criteria in the view of either the Investigator or Ultragenyx: death; life-threatening; inpatient hospitalization or prolongation of existing hospitalization; disability/Incapacity; congenital anomaly/birth defect not present at screening; other important medical events. Severity of events were graded as mild (grade1), moderate (grade 2), severe (grade 3), life-threatening (grade 4), or death (grade 5). An AESI is an event of scientific or medical interest specific to the drug treatment requiring further investigation and close monitoring to further characterize them.

End point type

Primary

End point timeframe

From the first dose of study drug through last dose of study drug plus 42 (± 14) days. Overall mean duration was 382.0 days for Cohorts 1-3 and was 586.2 days for all other cohorts.

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: Descriptive statistics are presented per protocol.

End point values	GTX-102 Cohorts 1-3	GTX-102 US Redosing Cohorts 1-2	GTX-102 Cohorts 4-7	GTX-102 Cohorts A&B	GTX-102 Cohorts C&D	GTX-102 US 2 mg/Cohort E
Number of subjects analysed	5	4	15	34	12	8
Units: number of participants
Treatment-Emergent Adverse Event (TEAE)	5	2	15	34	12	8
Related TEAE	5	0	4	17	4	1
Serious TEAE	5	0	6	10	4	5
Serious Related TEAE	5	0	1	2	0	0
Grade 3 or 4 Related TEAE	1	0	1	2	0	0
TEAE with Maximum Severity Grade 5	0	0	0	0	0	0
TEAE with Maximum Severity Grade 4	0	0	0	1	0	0
TEAE with Maximum Severity Grade 3	1	0	3	3	1	1
TEAE with Maximum Severity Grade 2	4	1	9	24	8	6
TEAE with Maximum Severity Grade 1	0	1	3	6	3	1
Adverse Event of Special Interest	5	0	1	2	0	0
TEAE Leading to Dose Reduced	0	0	0	4	0	0
TEAE Leading to Dose Interruption	1	0	3	2	2	1
TEAE Leading to Dose Withdrawn	0	0	1	2	0	0
TEAE Leading to Study Discontinuation	0	0	1	1	0	0
TEAE Leading to Death	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Plasma Pharmacokinetics (PK) of GTX-102: Area Under the Concentration Curve (AUC) From Time 0 to 24 Hours Post-Dose (AUC0-24), AUC From Time 0 Extrapolated to Infinity (AUCinf), and AUC From Time 0 to the Last Quantifiable Concentration (AUClast)

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End point title

Plasma Pharmacokinetics (PK) of GTX-102: Area Under the Concentration Curve (AUC) From Time 0 to 24 Hours Post-Dose (AUC0-24), AUC From Time 0 Extrapolated to Infinity (AUCinf), and AUC From Time 0 to the Last Quantifiable Concentration (AUClast)

End point description

PK Analysis Set: participants in the Safety Analysis Set who had at least 1 post-baseline plasma or cerebrospinal fluid (CSF) concentration data. Data are from a subset of total participants enrolled and are presented according to what participants received as the first dose, and where sufficient participant data allowed for each PK parameter analysis.

End point type

Secondary

End point timeframe

Estimated from PK concentration data collected pre-dose (immediately prior or up to 240 minutes prior to first study drug administration) 1, 2, 4, 8, 12, 24, 48 hours after the first dose.

End point values	GTX-102 2 mg	GTX-102 3.3 mg	GTX-102 5 mg	GTX-102 7.5 mg	GTX-102 10 mg	GTX-102 20 mg
Number of subjects analysed	8 ^[2]	8 ^[3]	8 ^[4]	3 ^[5]	4 ^[6]	1 ^[7]
Units: h*ng/mL
geometric mean (geometric coefficient of variation)
AUC0-24; n=7, 8, 8, 3, 4, 1	379 ( 48.6 )	687 ( 42.6 )	669 ( 61.9 )	1730 ( 11.7 )	1950 ( 42.1 )	4010 ( 000000 )
AUCinf; n=3, 1, 2, 1, 2, 1	409 ( 11.4 )	875 ( 000000 )	972 ( 22.9 )	1690 ( 000000 )	1670 ( 23.6 )	5050 ( 000000 )
AUClast; n=8, 8, 8, 3, 4, 1	335 ( 58.4 )	687 ( 42.5 )	669 ( 61.9 )	1730 ( 12.6 )	1960 ( 41.9 )	4840 ( 000000 )

Notes
[2] - n=participants with data for given measure
[3] - n=participants with data for given measure; 000000=Not applicable (1 participant analyzed)
[4] - n=participants with data for given measure
[5] - n=participants with data for given measure; 000000=Not applicable (1 participant analyzed)
[6] - n=participants with data for given measure
[7] - n=participants with data for given measure; 000000=Not applicable (1 participant analyzed)

No statistical analyses for this end point

Secondary: PK of GTX-102: Clearance (CL/F)

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End point title

PK of GTX-102: Clearance (CL/F)

End point description

End point type

Secondary

End point timeframe

Estimated from PK concentration data collected pre-dose (immediately prior or up to 240 minutes prior to first study drug administration) 1, 2, 4, 8, 12, 24, 48 hours after the first dose.

End point values	GTX-102 2 mg	GTX-102 3.3 mg	GTX-102 5 mg	GTX-102 7.5 mg	GTX-102 10 mg	GTX-102 20 mg
Number of subjects analysed	3	1 ^[8]	2	1 ^[9]	2	1 ^[10]
Units: L/h
geometric mean (geometric coefficient of variation)	4.89 ( 11.4 )	3.77 ( 000000 )	5.14 ( 22.9 )	4.43 ( 000000 )	6.00 ( 23.6 )	3.96 ( 000000 )

Notes
[8] - 000000=not applicable (1 participant analyzed)
[9] - 000000=not applicable (1 participant analyzed)
[10] - 000000=not applicable (1 participant analyzed)

No statistical analyses for this end point

Secondary: PK of GTX-102: Last Observed Concentration (Clast), and Maximum Observed Concentration (Cmax)

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End point title

PK of GTX-102: Last Observed Concentration (Clast), and Maximum Observed Concentration (Cmax)

End point description

End point type

Secondary

End point timeframe

Estimated from PK concentration data collected pre-dose (immediately prior or up to 240 minutes prior to first study drug administration) 1, 2, 4, 8, 12, 24, 48 hours after the first dose.

End point values	GTX-102 2 mg	GTX-102 3.3 mg	GTX-102 5 mg	GTX-102 7.5 mg	GTX-102 10 mg	GTX-102 20 mg
Number of subjects analysed	8	8	8	3	4	1 ^[11]
Units: ng/mL
geometric mean (geometric coefficient of variation)
Clast	6.01 ( 68.8 )	13.1 ( 60.8 )	12.2 ( 85.4 )	19.8 ( 93.0 )	19.6 ( 180.0 )	15.0 ( 000000 )
Cmax	35.9 ( 52.4 )	65.6 ( 56.3 )	64.5 ( 104.2 )	182 ( 45.0 )	201 ( 35.3 )	346 ( 000000 )

Notes
[11] - 000000=not applicable (1 participant analyzed)

No statistical analyses for this end point

Secondary: PK of GTX-102: Terminal Elimination Half-Life (T1/2)

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End point title

PK of GTX-102: Terminal Elimination Half-Life (T1/2)

End point description

End point type

Secondary

End point timeframe

Estimated from PK concentration data collected pre-dose (immediately prior or up to 240 minutes prior to first study drug administration) 1, 2, 4, 8, 12, 24, 48 hours after the first dose.

End point values	GTX-102 2 mg	GTX-102 3.3 mg	GTX-102 5 mg	GTX-102 7.5 mg	GTX-102 10 mg	GTX-102 20 mg
Number of subjects analysed	3	1 ^[12]	2	1 ^[13]	2	1 ^[14]
Units: hours
geometric mean (geometric coefficient of variation)	7.92 ( 15.6 )	5.67 ( 000000 )	5.41 ( 50.7 )	4.44 ( 000000 )	4.66 ( 21.0 )	9.89 ( 000000 )

Notes
[12] - 000000=not applicable (1 participant analyzed)
[13] - 000000=not applicable (1 participant analyzed)
[14] - 000000=not applicable (1 participant analyzed)

No statistical analyses for this end point

Secondary: PK of GTX-102: Time Prior to the First Measurable Concentration (Tlag), and Time Corresponding to Occurrence of Cmax (Tmax)

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End point title

PK of GTX-102: Time Prior to the First Measurable Concentration (Tlag), and Time Corresponding to Occurrence of Cmax (Tmax)

End point description

End point type

Secondary

End point timeframe

Estimated from PK concentration data collected pre-dose (immediately prior or up to 240 minutes prior to first study drug administration) 1, 2, 4, 8, 12, 24, 48 hours after the first dose.

End point values	GTX-102 2 mg	GTX-102 3.3 mg	GTX-102 5 mg	GTX-102 7.5 mg	GTX-102 10 mg	GTX-102 20 mg
Number of subjects analysed	8	8	8	3	4	1 ^[15]
Units: hours
median (full range (min-max))
Tlag	0.00 (0.00 to 0.00)	0.00 (0.00 to 0.00)	0.00 (0.00 to 1.18)	0.00 (0.00 to 0.00)	0.00 (0.00 to 0.00)	0.00 (000000 to 000000)
Tmax	3.09 (0.920 to 6.00)	4.05 (2.00 to 10.2)	4.09 (0.670 to 22.1)	2.00 (1.92 to 4.00)	4.19 (1.97 to 6.58)	4.22 (000000 to 999999)

Notes
[15] - 000000 and 999999=not applicable (1 participant analyzed)

No statistical analyses for this end point

Secondary: PK of GTX-102: Volume of Distribution at Steady-State (Vss/F), and Volume of Distribution (Vz/F)

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End point title

PK of GTX-102: Volume of Distribution at Steady-State (Vss/F), and Volume of Distribution (Vz/F)

End point description

End point type

Secondary

End point timeframe

Estimated from PK concentration data collected pre-dose (immediately prior or up to 240 minutes prior to first study drug administration) 1, 2, 4, 8, 12, 24, 48 hours after the first dose.

End point values	GTX-102 2 mg	GTX-102 3.3 mg	GTX-102 5 mg	GTX-102 7.5 mg	GTX-102 10 mg	GTX-102 20 mg
Number of subjects analysed	3	1 ^[16]	2	1 ^[17]	2	1 ^[18]
Units: L
geometric mean (geometric coefficient of variation)
Vss/F	59.7 ( 27.8 )	35.3 ( 000000 )	40.6 ( 33.9 )	26.9 ( 000000 )	46.0 ( 42.0 )	63.4 ( 000000 )
Vz/F	55.8 ( 27.4 )	30.8 ( 000000 )	40.1 ( 25.6 )	28.3 ( 000000 )	40.4 ( 46.3 )	56.5 ( 000000 )

Notes
[16] - 000000=not applicable (1 participant analyzed)
[17] - 000000=not applicable (1 participant analyzed)
[18] - 000000=not applicable (1 participant analyzed)

No statistical analyses for this end point

Secondary: GTX-102 Concentrations in CSF

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End point title

GTX-102 Concentrations in CSF

End point description

PK Analysis Set: participants in the Safety Analysis Set who had at least 1 post-baseline plasma or CSF concentration data. Optional CSF was collected only in the 2 mg US Cohort. Six out of 8 participants participated in the optional CSF sampling.

End point type

Secondary

End point timeframe

24 hours (+/-4 hours) post dose on Day 58

End point values	GTX-102 2 mg
Number of subjects analysed	6
Units: ng/mL
arithmetic mean (standard deviation)	340.7 ( 242.6 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From signing of informed consent (SAEs) or first dose of study drug (non-serious AEs) through last dose of study drug plus 42 (± 14) days. Overall mean duration was 382.0 days for Cohorts 1-3 and was 586.2 days for all other cohorts.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

27.1

Reporting group title

GTX-102 Cohorts 1 - 3

Reporting group description

Participants received doses ranging from 3.3 to 20 mg followed by dose escalation up to a maximum of 36 mg.

Reporting group title

GTX-102 US Redosing Cohorts 1 - 2

Reporting group description

Participants from Cohorts 1-2 were restarted at doses ranging from 5 to 10 mg followed by dose escalation up to a maximum dose of 14 mg Q3M.

Reporting group title

GTX-102 Cohorts 4 - 7

Reporting group description

Participants received up to 4 loading doses ranging from 3.3 to 10 mg followed by dose escalation up to a maximum dose of 14 mg Q3M.

Reporting group title

GTX-102 Cohorts A & B

Reporting group description

Participants received up to 4 loading doses of 7.5 mg followed by dose escalation up to a maximum dose of 14 mg Q3M.

Reporting group title

GTX-102 Cohorts C & D

Reporting group description

Participants received up to 4 loading doses ranging from 5 to 7.5 mg followed by dose escalation up to a maximum dose of 10 mg Q3M.

Reporting group title

GTX-102 US 2 mg/Cohort E

Reporting group description

Serious adverse events	GTX-102 Cohorts 1 - 3	GTX-102 US Redosing Cohorts 1 - 2	GTX-102 Cohorts 4 - 7	GTX-102 Cohorts A & B	GTX-102 Cohorts C & D	GTX-102 US 2 mg/Cohort E
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 5 (100.00%)	0 / 4 (0.00%)	6 / 15 (40.00%)	10 / 34 (29.41%)	4 / 12 (33.33%)	5 / 8 (62.50%)
number of deaths (all causes)	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0
Injury, poisoning and procedural complications
Humerus Fracture
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	1 / 34 (2.94%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	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
Post Lumbar Puncture Syndrome
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 15 (13.33%)	3 / 34 (8.82%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin Laceration
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	1 / 34 (2.94%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	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
Wound Decomposition
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	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
Nervous system disorders
Epilepsy
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	1 / 34 (2.94%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	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
Febrile Convulsion
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences causally related to treatment / all	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
Radiculopathy
subjects affected / exposed	5 / 5 (100.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	1 / 34 (2.94%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	5 / 5	0 / 0	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	1 / 34 (2.94%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure Cluster
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences causally related to treatment / all	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
Status Epilepticus
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences causally related to treatment / all	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
Gastrointestinal disorders
Vomiting
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis Acute
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	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
Pancreatitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	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
Intestinal Obstruction
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	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
Faecaloma
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	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
Constipation
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences causally related to treatment / all	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
Choking
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	1 / 34 (2.94%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	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
Musculoskeletal and connective tissue disorders
Muscular Weakness
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	1 / 34 (2.94%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	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
Infections and infestations
Streptococcal Infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences causally related to treatment / all	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
Pneumonia
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 15 (13.33%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 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
Medical Device Site Infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	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
Herpes Zoster Meningitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	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
Gastroenteritis Viral
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	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
Metabolism and nutrition disorders
Hypophagia
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	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

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

Non-serious adverse events	GTX-102 Cohorts 1 - 3	GTX-102 US Redosing Cohorts 1 - 2	GTX-102 Cohorts 4 - 7	GTX-102 Cohorts A & B	GTX-102 Cohorts C & D	GTX-102 US 2 mg/Cohort E
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 5 (100.00%)	2 / 4 (50.00%)	15 / 15 (100.00%)	33 / 34 (97.06%)	12 / 12 (100.00%)	8 / 8 (100.00%)
Vascular disorders
Hypotension
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	3 / 34 (8.82%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	2	5	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	4 / 34 (11.76%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	5	2	0
Decreased Activity
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Decreased Gait Velocity
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Fatigue
subjects affected / exposed	2 / 5 (40.00%)	1 / 4 (25.00%)	3 / 15 (20.00%)	5 / 34 (14.71%)	1 / 12 (8.33%)	1 / 8 (12.50%)
occurrences all number	3	1	6	6	1	1
Gait Disturbance
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	1 / 34 (2.94%)	1 / 12 (8.33%)	2 / 8 (25.00%)
occurrences all number	0	0	0	2	1	2
Influenza Like Illness
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	3 / 34 (8.82%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	5	0	0
Pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Pyrexia
subjects affected / exposed	1 / 5 (20.00%)	1 / 4 (25.00%)	4 / 15 (26.67%)	7 / 34 (20.59%)	1 / 12 (8.33%)	3 / 8 (37.50%)
occurrences all number	1	1	6	10	1	3
Malaise
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	2	0	0	0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	2 / 34 (5.88%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	3	0	0
Reproductive system and breast disorders
Bartholin's Cyst
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Dysmenorrhoea
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	1 / 34 (2.94%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	1	0	0
Respiratory, thoracic and mediastinal disorders
Adenoidal Hypertrophy
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Dyspnoea
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	1 / 34 (2.94%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	1	0	0
Epistaxis
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	2	0	0	0
Nasal Congestion
subjects affected / exposed	0 / 5 (0.00%)	1 / 4 (25.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	1	0	0	0
Rhinorrhoea
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	2 / 34 (5.88%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	2	0	0
Tonsillar Hypertrophy
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	1 / 34 (2.94%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	1	0	0
Cough
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	2 / 34 (5.88%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	2	0	0
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	2	0	0	0
Abnormal Behaviour
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 15 (13.33%)	1 / 34 (2.94%)	2 / 12 (16.67%)	0 / 8 (0.00%)
occurrences all number	0	0	3	1	2	0
Aggression
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	1 / 34 (2.94%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	1	0
Insomnia
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	2 / 34 (5.88%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	2	0	1
Irritability
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	1 / 34 (2.94%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	1	0
Investigations
Blood Alkaline Phosphatase Increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Blood Pressure Diastolic Decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Body Temperature Increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	3 / 34 (8.82%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	5	0	0
Csf Immunoglobulin Increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	2 / 34 (5.88%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	3	0	0
Csf Pressure Increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	1
Csf Protein Increased
subjects affected / exposed	3 / 5 (60.00%)	0 / 4 (0.00%)	4 / 15 (26.67%)	6 / 34 (17.65%)	2 / 12 (16.67%)	2 / 8 (25.00%)
occurrences all number	3	0	5	7	2	2
Monocyte Count Increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Csf White Blood Cell Count Increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	1 / 34 (2.94%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	1	0
Culture Urine Positive
subjects affected / exposed	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0
Glucose Urine Present
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	0
International Normalised Ratio Increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Csf Red Blood Cell Count Positive
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	0
Neutrophil Count Decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Vitamin D Decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Weight Decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Weight Increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	2 / 34 (5.88%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	2	0	0
White Blood Cell Count Increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Injury, poisoning and procedural complications
Head Injury
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 15 (13.33%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	2	0	0	0
Accidental Exposure To Product
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	1
Arthropod Bite
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	0 / 12 (0.00%)	2 / 8 (25.00%)
occurrences all number	0	0	0	0	0	2
Contusion
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	2 / 34 (5.88%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	3	1	0
Eye Contusion
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	0
Fall
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	4 / 15 (26.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	6	0	0	1
Foreign Body In Respiratory Tract
subjects affected / exposed	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0
Skin Laceration
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	1 / 34 (2.94%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	1	0
Soft Tissue Injury
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	1 / 34 (2.94%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	1	0	0
Thermal Burn
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Tooth Fracture
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Wrist Fracture
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	0
Joint Injury
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	1 / 34 (2.94%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	2	1	0	0
Ligament Sprain
subjects affected / exposed	1 / 5 (20.00%)	1 / 4 (25.00%)	3 / 15 (20.00%)	1 / 34 (2.94%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	1	3	1	0	0
Limb Injury
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	1	0	0	1
Lip Injury
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	1 / 34 (2.94%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	1	0
Post Lumbar Puncture Syndrome
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 15 (13.33%)	7 / 34 (20.59%)	2 / 12 (16.67%)	0 / 8 (0.00%)
occurrences all number	0	0	3	7	2	0
Procedural Pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	1 / 34 (2.94%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	2	0	0
Cardiac disorders
Tachycardia
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	2 / 34 (5.88%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	4	0	0
Nervous system disorders
Ataxia
subjects affected / exposed	5 / 5 (100.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	4 / 34 (11.76%)	0 / 12 (0.00%)	3 / 8 (37.50%)
occurrences all number	11	0	0	4	0	4
Atonic Seizures
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	6 / 34 (17.65%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	7	0	0
Balance Disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	1 / 34 (2.94%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	1	0
Migraine
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	0
Drooling
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	1 / 34 (2.94%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	1	0	0
Epilepsy
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	4 / 34 (11.76%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	6	0	0
Headache
subjects affected / exposed	2 / 5 (40.00%)	1 / 4 (25.00%)	3 / 15 (20.00%)	8 / 34 (23.53%)	1 / 12 (8.33%)	1 / 8 (12.50%)
occurrences all number	3	1	9	11	1	1
Hyperreflexia
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	2
Hypotonia
subjects affected / exposed	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0
Lethargy
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	0
Disturbance In Attention
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	2 / 34 (5.88%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	2	0	0
Myoclonus
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	3 / 34 (8.82%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	7	0	0
Petit Mal Epilepsy
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	3 / 34 (8.82%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	6	0	0
Post-Traumatic Epilepsy
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Radicular Pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Radiculopathy
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	2 / 34 (5.88%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	2	0	0
Seizure
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 15 (13.33%)	12 / 34 (35.29%)	1 / 12 (8.33%)	2 / 8 (25.00%)
occurrences all number	0	0	5	15	1	2
Sensory Disturbance
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Somnolence
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	3 / 34 (8.82%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	3	1	0
Syncope
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Seizure Like Phenomena
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Lymphocytosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Ear and labyrinth disorders
Ear Discomfort
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Ear Haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Middle Ear Effusion
subjects affected / exposed	0 / 5 (0.00%)	1 / 4 (25.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0
Ear Pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	2	0	0	0
Eye disorders
Eyelid Myoclonus
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	2 / 34 (5.88%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	2	0	0
Ocular Hyperaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Gastrointestinal disorders
Angular Cheilitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Abdominal Pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Aphthous Ulcer
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	2 / 34 (5.88%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	2	0	0
Constipation
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	3 / 15 (20.00%)	4 / 34 (11.76%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	0	0	8	4	1	0
Dental Discomfort
subjects affected / exposed	0 / 5 (0.00%)	1 / 4 (25.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	3	0	0	0	0
Diarrhoea
subjects affected / exposed	1 / 5 (20.00%)	0 / 4 (0.00%)	2 / 15 (13.33%)	4 / 34 (11.76%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences all number	1	0	4	6	0	1
Food Poisoning
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Gastritis
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Vomiting
subjects affected / exposed	1 / 5 (20.00%)	0 / 4 (0.00%)	7 / 15 (46.67%)	15 / 34 (44.12%)	6 / 12 (50.00%)	4 / 8 (50.00%)
occurrences all number	1	0	10	20	9	8
Lower Gastrointestinal Haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Nausea
subjects affected / exposed	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	2 / 34 (5.88%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	1	0	0	4	1	0
Retching
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	1 / 34 (2.94%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	1	0	0
Salivary Hypersecretion
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Stomatitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 15 (13.33%)	2 / 34 (5.88%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	2	4	0	0
Toothache
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Gastrooesophageal Reflux Disease
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	3 / 34 (8.82%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	3	1	0
Hepatobiliary disorders
Hepatic Steatosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Skin and subcutaneous tissue disorders
Dermatitis Atopic
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	1
Dermatitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	1	0
Macule
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Perioral Dermatitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	1
Rash
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	2 / 34 (5.88%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	1	2	0	1
Skin Irritation
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	0
Urticaria
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	1 / 34 (2.94%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	1	0	0
Skin Hyperpigmentation
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Renal and urinary disorders
Glycosuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	0
Musculoskeletal and connective tissue disorders
Mobility Decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	3	0	0	0
Back Pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	3 / 15 (20.00%)	3 / 34 (8.82%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	0	0	5	3	1	0
Jaw Disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Limb Discomfort
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Muscular Weakness
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	2 / 34 (5.88%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	3	0	0
Neck Pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Pain In Extremity
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	2 / 34 (5.88%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	2	0	0
Infections and infestations
Covid-19
subjects affected / exposed	1 / 5 (20.00%)	0 / 4 (0.00%)	5 / 15 (33.33%)	4 / 34 (11.76%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences all number	1	0	5	4	0	1
Bronchitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	2 / 34 (5.88%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	2	0	0
Croup Infectious
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	1 / 34 (2.94%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	1	0	1
Ear Infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	3 / 34 (8.82%)	2 / 12 (16.67%)	2 / 8 (25.00%)
occurrences all number	0	0	1	4	3	2
Enterobiasis
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	2 / 34 (5.88%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	2	0	0
Eye Infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	1 / 34 (2.94%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	1	0	1
Fungal Skin Infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	3	0
Gastroenteritis
subjects affected / exposed	1 / 5 (20.00%)	0 / 4 (0.00%)	4 / 15 (26.67%)	5 / 34 (14.71%)	2 / 12 (16.67%)	0 / 8 (0.00%)
occurrences all number	1	0	4	7	3	0
Lower Respiratory Tract Infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 15 (13.33%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	3	0	0	0
Hand-Foot-And-Mouth Disease
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	2 / 34 (5.88%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	3	0	1
Hepatitis Infectious Mononucleosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	1
Impetigo
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	1 / 34 (2.94%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	2	1	0	0
Influenza
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	5 / 34 (14.71%)	3 / 12 (25.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	8	3	1
Laryngitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	2 / 34 (5.88%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	3	0	0
Lice Infestation
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	2	0	0	0
Gastroenteritis Viral
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 15 (13.33%)	1 / 34 (2.94%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	2	1	0	1
Medical Device Site Infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	2	0	0	0
Myringitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	1
Nasopharyngitis
subjects affected / exposed	0 / 5 (0.00%)	1 / 4 (25.00%)	6 / 15 (40.00%)	8 / 34 (23.53%)	5 / 12 (41.67%)	1 / 8 (12.50%)
occurrences all number	0	1	14	12	6	1
Oral Candidiasis
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	1 / 34 (2.94%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	1	0	0
Otitis Externa
subjects affected / exposed	1 / 5 (20.00%)	1 / 4 (25.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	1	0	0	0	0
Otitis Media
subjects affected / exposed	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	2 / 34 (5.88%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	3	0	0
Pneumonia
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 15 (13.33%)	2 / 34 (5.88%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	0	0	2	2	1	0
Pantoea Agglomerans Infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	0
Parvovirus B19 Infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	2 / 34 (5.88%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	2	0	0
Pertussis
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Pharyngitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	3 / 34 (8.82%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	3	0	0
Pharyngitis Streptococcal
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	1 / 34 (2.94%)	4 / 12 (33.33%)	1 / 8 (12.50%)
occurrences all number	0	0	0	3	6	2
Otitis Media Acute
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	2 / 34 (5.88%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	2	0	1
Rhinitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	2 / 34 (5.88%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	2	0	0
Rhinovirus Infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	0 / 34 (0.00%)	1 / 12 (8.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	0
Sinusitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	1 / 34 (2.94%)	2 / 12 (16.67%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	2	0
Tonsillitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 15 (0.00%)	2 / 34 (5.88%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	3	0	0
Upper Respiratory Tract Infection
subjects affected / exposed	1 / 5 (20.00%)	1 / 4 (25.00%)	5 / 15 (33.33%)	6 / 34 (17.65%)	6 / 12 (50.00%)	4 / 8 (50.00%)
occurrences all number	1	1	15	10	8	5
Urinary Tract Infection
subjects affected / exposed	2 / 5 (40.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	2 / 34 (5.88%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences all number	3	0	4	2	0	1
Viral Infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	10 / 34 (29.41%)	0 / 12 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	1	12	0	1
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Hypoglycaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 15 (6.67%)	0 / 34 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0
Decreased Appetite
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 15 (13.33%)	0 / 34 (0.00%)	2 / 12 (16.67%)	0 / 8 (0.00%)
occurrences all number	0	0	3	0	2	0

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Were there any global substantial amendments to the protocol? Yes

17 Dec 2019

*Changed number of patients treated by cohort *Medical monitor review of safety data prior to dose escalation within dose cohort *Change to DSMB requirements *Updated number of patients per cohort *Added new exclusion criteria *Open label extension will be conducted under a separate protocol, clarification that patients may remain on study without treatment until initiation of OLE *Added details on anesthesia use *Added details related to LP procedure *Eliminated obtaining weights every 2 weeks *Changed inflammatory marker to be analyzed.

01 May 2020

*LPs allowed without anesthesia *Added inclusion criteria *Given COVID-19 pandemic; allow EEG to be obtained outside in-patient hospital setting, allow safety visits via video conference/telemedicine and home visits from visiting nurses or health care provider *Added blood and urine collection for other biomarkers *Changed time of ECG for patient convenience *Changed time of neurological exam *Specified time limit on duration of AEs that require discontinuation from study *Updated management of thrombocytopenia and proteinuria.

29 Jul 2022

*Change of sponsor from GeneTx to Ultragenyx *Removed specificity of UK and Canada *Adjusted efficacy measures

13 Mar 2023

*Removed Dose-selection Cohorts 8-12 *Expansion Cohorts A and B updates to loading and maintenance period *Dose-selection Cohorts 4-7 maintenance dosing modified *Dexamethasone premedication required for loading doses *Radiculopathy defined as AESI *Contraception guidance added.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
20 Jul 2020	The Sponsor suspended dosing and enrollment into the study according to the protocol-defined dose stopping criteria after the first patient experienced the related SAE of radiculopathy. On 03 November 2020, the FDA placed the study on a Full Clinical Hold. The Sponsor engaged with the Agency to review data and discuss changes to the study design.	24 Sep 2021

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

None reported

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Clinical trials

Clinical Trial Results:
A Phase 1/2 Open-label, Multiple-dose, Dose-escalating Clinical Trial of the Safety and Tolerability of GTX-102 in Pediatric Patients With Angelman Syndrome (AS)

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 TEAEs (SAEs), Adverse Events of Special Interest (AESIs), TEAEs Leading to Discontinuation and TEAEs by Severity

Primary: Number of Participants with Treatment-emergent Adverse Events (TEAEs), Serious TEAEs (SAEs), Adverse Events of Special Interest (AESIs), TEAEs Leading to Discontinuation and TEAEs by Severity

Secondary: Plasma Pharmacokinetics (PK) of GTX-102: Area Under the Concentration Curve (AUC) From Time 0 to 24 Hours Post-Dose (AUC0-24), AUC From Time 0 Extrapolated to Infinity (AUCinf), and AUC From Time 0 to the Last Quantifiable Concentration (AUClast)

Secondary: Plasma Pharmacokinetics (PK) of GTX-102: Area Under the Concentration Curve (AUC) From Time 0 to 24 Hours Post-Dose (AUC0-24), AUC From Time 0 Extrapolated to Infinity (AUCinf), and AUC From Time 0 to the Last Quantifiable Concentration (AUClast)

Secondary: PK of GTX-102: Clearance (CL/F)

Secondary: PK of GTX-102: Clearance (CL/F)

Secondary: PK of GTX-102: Last Observed Concentration (Clast), and Maximum Observed Concentration (Cmax)

Secondary: PK of GTX-102: Last Observed Concentration (Clast), and Maximum Observed Concentration (Cmax)

Secondary: PK of GTX-102: Terminal Elimination Half-Life (T1/2)

Secondary: PK of GTX-102: Terminal Elimination Half-Life (T1/2)

Secondary: PK of GTX-102: Time Prior to the First Measurable Concentration (Tlag), and Time Corresponding to Occurrence of Cmax (Tmax)

Secondary: PK of GTX-102: Time Prior to the First Measurable Concentration (Tlag), and Time Corresponding to Occurrence of Cmax (Tmax)

Secondary: PK of GTX-102: Volume of Distribution at Steady-State (Vss/F), and Volume of Distribution (Vz/F)

Secondary: PK of GTX-102: Volume of Distribution at Steady-State (Vss/F), and Volume of Distribution (Vz/F)

Secondary: GTX-102 Concentrations in CSF

Secondary: GTX-102 Concentrations in CSF

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: A Phase 1/2 Open-label, Multiple-dose, Dose-escalating Clinical Trial of the Safety and Tolerability of GTX-102 in Pediatric Patients With Angelman Syndrome (AS)

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 TEAEs (SAEs), Adverse Events of Special Interest (AESIs), TEAEs Leading to Discontinuation and TEAEs by Severity

Primary: Number of Participants with Treatment-emergent Adverse Events (TEAEs), Serious TEAEs (SAEs), Adverse Events of Special Interest (AESIs), TEAEs Leading to Discontinuation and TEAEs by Severity

Secondary: Plasma Pharmacokinetics (PK) of GTX-102: Area Under the Concentration Curve (AUC) From Time 0 to 24 Hours Post-Dose (AUC0-24), AUC From Time 0 Extrapolated to Infinity (AUCinf), and AUC From Time 0 to the Last Quantifiable Concentration (AUClast)

Secondary: Plasma Pharmacokinetics (PK) of GTX-102: Area Under the Concentration Curve (AUC) From Time 0 to 24 Hours Post-Dose (AUC0-24), AUC From Time 0 Extrapolated to Infinity (AUCinf), and AUC From Time 0 to the Last Quantifiable Concentration (AUClast)

Secondary: PK of GTX-102: Clearance (CL/F)

Secondary: PK of GTX-102: Clearance (CL/F)

Secondary: PK of GTX-102: Last Observed Concentration (Clast), and Maximum Observed Concentration (Cmax)

Secondary: PK of GTX-102: Last Observed Concentration (Clast), and Maximum Observed Concentration (Cmax)

Secondary: PK of GTX-102: Terminal Elimination Half-Life (T1/2)

Secondary: PK of GTX-102: Terminal Elimination Half-Life (T1/2)

Secondary: PK of GTX-102: Time Prior to the First Measurable Concentration (Tlag), and Time Corresponding to Occurrence of Cmax (Tmax)

Secondary: PK of GTX-102: Time Prior to the First Measurable Concentration (Tlag), and Time Corresponding to Occurrence of Cmax (Tmax)

Secondary: PK of GTX-102: Volume of Distribution at Steady-State (Vss/F), and Volume of Distribution (Vz/F)

Secondary: PK of GTX-102: Volume of Distribution at Steady-State (Vss/F), and Volume of Distribution (Vz/F)

Secondary: GTX-102 Concentrations in CSF

Secondary: GTX-102 Concentrations in CSF

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 1/2 Open-label, Multiple-dose, Dose-escalating Clinical Trial of the Safety and Tolerability of GTX-102 in Pediatric Patients With Angelman Syndrome (AS)