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Clinical Trial Results:
A phase I/II, open label, escalating dose, pilot study to assess the effect, safety, tolerability and pharmacokinetics of multiple subcutaneous doses of drisapersen in patients with Duchenne muscular dystrophy and to assess the potential for intravenous dosing as an alternative route of administration

Summary
EudraCT number	2007-004819-54
Trial protocol	BE NL SE
Global end of trial date	25 Jun 2013

Results information
Results version number	v2(current)
This version publication date	07 May 2020
First version publication date	23 Mar 2017
Other versions	v1
Version creation reason	Correction of full data set This study is split in 2 parts and for te first part the CSR summary was uploaded. Now for the second part, the dataset will be uploaded.

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

PRO051-02 & DMD114673

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline

Sponsor organisation address

980 Great West Road, Brentford, Middlesex, United Kingdom,

Public contact

GSK Response Centre, GlaxoSmithKline., 1 8664357343, GSKClinicalSupportHD@GSK.com

Scientific contact

GSK Response Centre, GlaxoSmithKline., 1 8664357343, GSKClinicalSupportHD@GSK.com

Sponsor organisation name

Prosensa Therapeutics B.V.

Sponsor organisation address

Wassenaarseweg 72, 2333 AL Leiden, Netherlands,

Public contact

Clinical Trails Information, Prosensa Therapeutics B.V., +31(0) 71 3322100, info@prosensa.nl

Scientific contact

Clinical Trails Information, Prosensa Therapeutics B.V., +31(0) 71 3322100, info@prosensa.nl

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?

Yes

Analysis stage

Final

Date of interim/final analysis

16 Jul 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

25 Jun 2013

Was the trial ended prematurely?

Main objective of the trial

Core study: To preliminarily assess the effect of PRO051 at different dose levels in patients with DMD. To assess the safety and tolerability of PRO051 at different dose levels in patients with DMD. To determine the pharmacokinetics of PRO051 at different dose levels after SC administration in patients with DMD. Administration of PRO051 beyond the core study period (SC administration): To assess the effect of PRO051 after SC administration at 6 mg/kg or capped at 300 mg in patients with DMD. To assess the safety and tolerability of PRO051 after SC at 6 mg/kg or capped at 300 mg in patients with DMD. To determine the pharmacokinetics of PRO051 after SC administration at 6 mg/kg in patients with DMD. Administration of PRO051 beyond the core study period (IV administration): IV dosing will be investigated as an alternative route of administration.

Protection of trial subjects

This study was performed in compliance with Good Clinical Practices and GlaxoSmithKline Standard Operating Procedures for all processes involved, including the archiving of essential documents. This study complies with US 21 CFR 312.120, as described in the Ethics and Good Clinical Practice section.

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Mar 2008

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 7

Country: Number of subjects enrolled

Sweden: 5

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

Study was conducted at 2 study centers in 2 countries.

Screening details

Total of 14 subjects screened, 12 subjects started the PRO051 treatment period. All 12 subjects who participated in the initial Study Period were subsequently enrolled into the Continued Treatment phase.

Period 1 title

Initial Study Period - PRO051-02

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Group I - 0.5 mg/kg

Arm description

PRO051 at 0.5 mg/kg subcutaneous administration per week, for five weeks.

Arm type

Experimental

Investigational medicinal product name

Drisapersen

Investigational medicinal product code

BMN051

Other name

PRO051, GSK2402968

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

PRO051 at 0.5 mg/kg solution for subcutaneous injection per week, for five weeks.

Group II - 2 mg/kg

Arm description

PRO051 at 2 mg/kg solution for subcutaneous injection per week, for five weeks.

Arm type

Experimental

Investigational medicinal product name

Drisapersen

Investigational medicinal product code

BMN051

Other name

PRO051, GSK2402968

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

PRO051 at 2 mg/kg solution for subcutaneous injection per week, for five weeks.

Group III - 4 mg/kg

Arm description

PRO051 at 4 mg/kg solution for subcutaneous injection per week, for five weeks.

Arm type

Experimental

Investigational medicinal product name

Drisapersen

Investigational medicinal product code

BMN051

Other name

PRO051, GSK2402968

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

PRO051 at 4 mg/kg solution for subcutaneous injection per week, for five weeks.

Group IV - 6 mg/kg

Arm description

PRO051 at 6 mg/kg solution for subcutaneous injection per week, for five weeks.

Arm type

Experimental

Investigational medicinal product name

Drisapersen

Investigational medicinal product code

BMN051

Other name

PRO051, GSK2402968

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

PRO051 at 6 mg/kg solution for subcutaneous injection per week, for five weeks.

Number of subjects in period 1	Group I - 0.5 mg/kg	Group II - 2 mg/kg	Group III - 4 mg/kg	Group IV - 6 mg/kg
Started	3	3	3	3
Completed	3	3	3	3

Period 2 title

Continued Treatment phase - DMD114673

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Continued Treatment phase - 6 mg/kg

Arm description

PRO051 at 6 mg/kg solution for subcutaneous injection per week, for five weeks.

Arm type

Experimental

Investigational medicinal product name

Drisapersen

Investigational medicinal product code

BMN051

Other name

PRO051, GSK2402968

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

PRO051 at 6 mg/kg solution for subcutaneous injection per week, for five weeks.

IV sub-study - 0.5 mg/kg over 4 hours

Arm description

0.5 mg/kg over 4 hours intravenous infusion at Visit 202.

Arm type

Experimental

Investigational medicinal product name

Drisapersen

Investigational medicinal product code

BMN051

Other name

PRO051, GSK2402968

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

0.5 mg/kg over 4 hours intravenous infusion at Visit 202.

IV sub-study - 1.4 mg/kg over 4 hours

Arm description

1.4 mg/kg over 4 hours intravenous infusion at Visit 205.

Arm type

Experimental

Investigational medicinal product name

Drisapersen

Investigational medicinal product code

BMN051

Other name

PRO051, GSK2402968

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

1.4 mg/kg over 4 hours intravenous infusion at Visit 205.

IV sub-study - 2.7 mg/kg over 4 hours

Arm description

2.7 mg/kg over 4 hours intravenous infusion at Visit 208.

Arm type

Experimental

Investigational medicinal product name

Drisapersen

Investigational medicinal product code

BMN051

Other name

PRO051, GSK2402968

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

2.7 mg/kg over 4 hours intravenous infusion at Visit 208.

IV sub-study - 2.7 mg/kg over 2 hours

Arm description

2.7 mg/kg over 2 hours intravenous infusion at Visit 211.

Arm type

Experimental

Investigational medicinal product name

Drisapersen

Investigational medicinal product code

BMN051

Other name

PRO051, GSK2402968

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

2.7 mg/kg over 2 hours intravenous infusion at Visit 211.

IV sub-study - 2.7 mg/kg over 1 hour

Arm description

2.7 mg/kg over 1 hour intravenous infusion at Visit 214.

Arm type

Experimental

Investigational medicinal product name

Drisapersen

Investigational medicinal product code

BMN051

Other name

PRO051, GSK2402968

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

2.7 mg/kg over 1 hour intravenous infusion at Visit 214.

Number of subjects in period 2	Continued Treatment phase - 6 mg/kg	IV sub-study - 0.5 mg/kg over 4 hours	IV sub-study - 1.4 mg/kg over 4 hours	IV sub-study - 2.7 mg/kg over 4 hours	IV sub-study - 2.7 mg/kg over 2 hours	IV sub-study - 2.7 mg/kg over 1 hour
Started	12	7	7	7	7	7
Completed	12	7	7	7	7	7

Baseline characteristics

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Reporting group title

Group I - 0.5 mg/kg

Reporting group description

PRO051 at 0.5 mg/kg subcutaneous administration per week, for five weeks.

Reporting group title

Group II - 2 mg/kg

Reporting group description

PRO051 at 2 mg/kg solution for subcutaneous injection per week, for five weeks.

Reporting group title

Group III - 4 mg/kg

Reporting group description

PRO051 at 4 mg/kg solution for subcutaneous injection per week, for five weeks.

Reporting group title

Group IV - 6 mg/kg

Reporting group description

PRO051 at 6 mg/kg solution for subcutaneous injection per week, for five weeks.

Reporting group values	Group I - 0.5 mg/kg	Group II - 2 mg/kg	Group III - 4 mg/kg	Group IV - 6 mg/kg	Total
Number of subjects	3	3	3	3	12
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	9.8 ± 3.15	9.09 ± 1.55	8.2 ± 3.01	9.71 ± 1.02	-
Gender categorical
Units: Subjects
Female	0	0	0	0	0
Male	3	3	3	3	12
Weight
Units: kg
arithmetic mean (standard deviation)	27.87 ± 5.88	32.2 ± 16.47	21.2 ± 6.49	30.07 ± 4.41	-
Height
Units: cm
arithmetic mean (standard deviation)	125 ± 9.85	122.33 ± 13.32	111.67 ± 14.98	126.67 ± 11.37	-
Body Mass Index
Units: kg/m^2
arithmetic mean (standard deviation)	17.67 ± 0.9	20.57 ± 5.87	16.63 ± 0.99	18.77 ± 1.7	-

End points

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Reporting group title

Group I - 0.5 mg/kg

Reporting group description

PRO051 at 0.5 mg/kg subcutaneous administration per week, for five weeks.

Reporting group title

Group II - 2 mg/kg

Reporting group description

PRO051 at 2 mg/kg solution for subcutaneous injection per week, for five weeks.

Reporting group title

Group III - 4 mg/kg

Reporting group description

PRO051 at 4 mg/kg solution for subcutaneous injection per week, for five weeks.

Reporting group title

Group IV - 6 mg/kg

Reporting group description

PRO051 at 6 mg/kg solution for subcutaneous injection per week, for five weeks.

Reporting group title

Continued Treatment phase - 6 mg/kg

Reporting group description

PRO051 at 6 mg/kg solution for subcutaneous injection per week, for five weeks.

Reporting group title

IV sub-study - 0.5 mg/kg over 4 hours

Reporting group description

0.5 mg/kg over 4 hours intravenous infusion at Visit 202.

Reporting group title

IV sub-study - 1.4 mg/kg over 4 hours

Reporting group description

1.4 mg/kg over 4 hours intravenous infusion at Visit 205.

Reporting group title

IV sub-study - 2.7 mg/kg over 4 hours

Reporting group description

2.7 mg/kg over 4 hours intravenous infusion at Visit 208.

Reporting group title

IV sub-study - 2.7 mg/kg over 2 hours

Reporting group description

2.7 mg/kg over 2 hours intravenous infusion at Visit 211.

Reporting group title

IV sub-study - 2.7 mg/kg over 1 hour

Reporting group description

2.7 mg/kg over 1 hour intravenous infusion at Visit 214.

Subject analysis set title

IV Sub-Set - All Doses

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who received at least one dose of study medication. This is the primary population for evaluation of safety variables.

Primary: Production of exon 51 skip mRNA in muscle biopsy during Initial study period by dose group per visit - 0.5 mg/kg

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End point title

Production of exon 51 skip mRNA in muscle biopsy during Initial study period by dose group per visit - 0.5 mg/kg ^[1] ^[2]

End point description

Intention-to-Treat (ITT) sample. A muscle biopsy from the tibialis anterior muscle was taken according to a sparse sampling schedule in order to limit the number of biopsies taken per participant. Endogenous production of the expected mRNA in the muscle biopsy was assessed. Y/N is a non-conclusive result due to either technical limitations, poor sample quality or non-reproducible or conflicting results.

End point type

Primary

End point timeframe

At Visit 1 nd Visit 8

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were conducted.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No formal statistical analyses were conducted.

End point values	Group I - 0.5 mg/kg
Number of subjects analysed	3
Units: Number of observations
Visit 1 - No	3
Visit 1 - Yes	0
Visit 1 - Y/N	0
Visit 8 - No	3
Visit 8 - Yes	0
Visit 8 - Y/N	0

No statistical analyses for this end point

Primary: Production of exon 51 skip mRNA in muscle biopsy during Initial study period by dose group per visit - 2, 4 and 6mg/kg

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End point title

Production of exon 51 skip mRNA in muscle biopsy during Initial study period by dose group per visit - 2, 4 and 6mg/kg ^[3] ^[4]

End point description

End point type

Primary

End point timeframe

At Visit 8 and Visit 10

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were conducted.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No formal statistical analyses were conducted.

End point values	Group II - 2 mg/kg	Group III - 4 mg/kg	Group IV - 6 mg/kg
Number of subjects analysed	3	3	3
Units: Number of observations
Visit 8 - No	2	0	1
Visit 8 - Yes	1	3	1
Visit 8 - Y/N	0	0	1
Visit 10 - No	2	0	0
Visit 10 - Yes	1	3	1
Visit 10 - Y/N	0	0	2

No statistical analyses for this end point

Primary: Presence of dystrophin in cross sections of muscle biopsy during Initial study period, by dose group per visit - 0.5 mg/kg

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End point title

Presence of dystrophin in cross sections of muscle biopsy during Initial study period, by dose group per visit - 0.5 mg/kg ^[5] ^[6]

End point description

Intention-to-Treat (ITT) sample. A muscle biopsy from the tibialis anterior muscle was taken according to a sparse sampling schedule in order to limit the number of biopsies taken per participant. Dystrophin expression in the muscle biopsy was assessed Y/N is a non-conclusive result due to either technical limitations, poor sample quality or non-reproducible or conflicting results.

End point type

Primary

End point timeframe

At Visit 1 and Visit 8

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were conducted.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No formal statistical analyses were conducted.

End point values	Group I - 0.5 mg/kg
Number of subjects analysed	3
Units: Number of observations
Visit 1 - No	1
Visit 1 - Yes	0
Visit 1 - Y/N	2
Visit 8 - No	0
Visit 8 - Yes	2
Visit 8 - Y/N	1

No statistical analyses for this end point

Primary: Presence of dystrophin in cross sections of muscle biopsy during Initial study period, by dose group per visit - 2, 4 and 6 mg/kg

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End point title

Presence of dystrophin in cross sections of muscle biopsy during Initial study period, by dose group per visit - 2, 4 and 6 mg/kg ^[7] ^[8]

End point description

Intention-to-Treat (ITT) sample. A muscle biopsy from the tibialis anterior muscle was taken according to a sparse sampling schedule in order to limit the number of biopsies taken per participant. Dystrophin expression in the muscle biopsy was assessed. Y/N is a non-conclusive result due to either technical limitations, poor sample quality or non-reproducible or conflicting results.

End point type

Primary

End point timeframe

At Visit 8 and Visit 10

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were conducted.
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No formal statistical analyses were conducted.

End point values	Group II - 2 mg/kg	Group III - 4 mg/kg	Group IV - 6 mg/kg
Number of subjects analysed	3	3	3
Units: Number of observations
Visit 8 - No	0	0	0
Visit 8 - Yes	3	1	2
Visit 8 - Y/N	0	2	1
Visit 10 - No	0	0	0
Visit 10 - Yes	2	3	3
Visit 10 - Y/N	1	0	0

No statistical analyses for this end point

Primary: Presence of dystrophin in total protein extract during Initial study period, by dose group per visit - 0.5 mg/kg

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End point title

Presence of dystrophin in total protein extract during Initial study period, by dose group per visit - 0.5 mg/kg ^[9] ^[10]

End point description

Intention-to-Treat (ITT) sample. A muscle biopsy from the tibialis anterior muscle was taken according to a sparse sampling schedule in order to limit the number of biopsies taken per participant. Presence of dystrophin in total protein extract was assessed in the muscle biopsy. Y/N is a non-conclusive result due to either technical limitations, poor sample quality or non-reproducible or conflicting results.

End point type

Primary

End point timeframe

At Visit 1 and Visit 8

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were conducted.
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No formal statistical analyses were conducted.

End point values	Group I - 0.5 mg/kg
Number of subjects analysed	3
Units: Number of observations
Visit 1 - No	1
Visit 1 - Yes	0
Visit 1 - Y/N	2
Visit 8 - No	1
Visit 8 - Yes	1
Visit 8 - Y/N	1

No statistical analyses for this end point

Primary: Presence of dystrophin in total protein extract during Initial study period, by dose group per visit - 2, 4 and 6 mg/kg

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End point title

Presence of dystrophin in total protein extract during Initial study period, by dose group per visit - 2, 4 and 6 mg/kg ^[11] ^[12]

End point description

Intention-to-Treat (ITT) sample. A muscle biopsy from the tibialis anterior muscle was taken according to a sparse sampling schedule in order to limit the number of biopsies taken per participant. Presence of dystrophin in total protein extract was assessed in the muscle biopsy. Y/N is a non-conclusive result due to either technical limitations, poor sample quality or non-reproducible or conflicting results.

End point type

Primary

End point timeframe

At Visit 8 and Visit 10

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were conducted.
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No formal statistical analyses were conducted.

End point values	Group II - 2 mg/kg	Group III - 4 mg/kg	Group IV - 6 mg/kg
Number of subjects analysed	3	3	3
Units: Number of observations
Visit 8 - No	0	0	0
Visit 8 - yes	1	2	3
Visit 8 - Y/N	2	1	0
Visit 10 - No	0	0	0
Visit 10 - Yes	2	2	3
Visit 10 - Y/N	1	1	0

No statistical analyses for this end point

Primary: Production of exon 51 skip mRNA in peripheral blood mononuclear cells, during Initial Study Period, by dose group per visit

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End point title

Production of exon 51 skip mRNA in peripheral blood mononuclear cells, during Initial Study Period, by dose group per visit ^[13]

End point description

Intention-to-Treat (ITT) sample. Whole blood samples were collected to assess exon skipping in mononuclear blood cells. Y/N is a non-conclusive result due to either technical limitations, poor sample quality or non-reproducible or conflicting results.

End point type

Primary

End point timeframe

At Visit 1, Visit 3, Visit 5, Visit 6 and Visit 8

Notes
[13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were conducted.

End point values	Group I - 0.5 mg/kg	Group II - 2 mg/kg	Group III - 4 mg/kg	Group IV - 6 mg/kg
Number of subjects analysed	3	3	3	3
Units: Number of observations
Visit 1 -No	3	3	3	3
Visit 1 - Yes	0	0	0	0
Visit 1 - Y/N	0	0	0	0
Visit 3 - No	3	3	3	3
Visit 3 - Yes	0	0	0	0
Visit 3 - Y/N	0	0	0	0
Visit 5 - No	3	3	3	3
Visit 5 - Yes	0	0	0	0
Visit 5 - Y/N	0	0	0	0
Visit 6 - No	3	3	3	3
Visit 6 - Yes	0	0	0	0
Visit 6 - Y/N	0	0	0	0
Visit 8 - No	3	2	3	3
Visit 8 - Yes	0	0	0	0
Visit 8 - Y/N	0	1	0	0

No statistical analyses for this end point

Primary: Muscle function: 10-Meter walk/run test during Initial Study Period, by dose group per visit

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End point title

Muscle function: 10-Meter walk/run test during Initial Study Period, by dose group per visit ^[14]

End point description

Intention-to-Treat (ITT) sample. The participant was asked to traverse a marked 10-meter measured walkway as quickly as he safely can. The 10-meter walk/run test was performed preferably barefoot without shoes or orthoses. If this was not possible, testing could have been done with shoes/orthoses. Any use of shoes/orthoses should then be documented. Time was recorded from when his first foot crossed the start line until the second foot crossed the finish line. In case a wall was touched, it was noted how often. Care was taken to ensure that the participant was safe when completing this test. n = Number of observations.

End point type

Primary

End point timeframe

At Visits 2, 3, 4, 5, 6, 7, 8, 10 and 12

Notes
[14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analyses were conducted.

End point values	Group I - 0.5 mg/kg	Group II - 2 mg/kg	Group III - 4 mg/kg	Group IV - 6 mg/kg
Number of subjects analysed	3	3	3	3
Units: sec
arithmetic mean (standard deviation)
Visit 2 (n = 2,3,3,3)	3.90 ± 0.42	4.83 ± 2.55	4.07 ± 0.81	5.63 ± 2.46
Visit 3 (n = 2,3,3,3)	3.60 ± 0.14	4.97 ± 2.40	4.23 ± 0.61	6.30 ± 2.20
Visit 4 (n = 2,3,3,3)	3.90 ± 0.57	4.57 ± 2.21	4.20 ± 0.61	6.07 ± 2.04
Visit 5 (n = 2,3,3,3)	3.85 ± 0.64	5.17 ± 3.12	4.43 ± 0.55	5.90 ± 2.36
Visit 6 (n = 2,3,3,3)	3.90 ± 0.28	4.83 ± 2.27	4.50 ± 0.61	5.93 ± 2.35
Visit 7 (n = 2,3,3,3)	3.90 ± 0.85	4.60 ± 2.10	4.27 ± 0.90	6.07 ± 2.37
Visit 8 (n = 2,3,3,3)	3.90 ± 0.85	4.70 ± 2.10	4.57 ± 0.70	6.17 ± 2.08
Visit 10 (n = 2,3,3,3)	3.70 ± 0.71	5.07 ± 2.85	4.97 ± 1.12	6.17 ± 2.47
Visit 12 (n = 2,3,3,3)	3.30 ± 0.00	6.10 ± 4.93	4.73 ± 0.90	6.17 ± 2.18

No statistical analyses for this end point

Primary: Muscle function: Timed rising from floor during Initial Study Period, by dose group per visit

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End point title

Muscle function: Timed rising from floor during Initial Study Period, by dose group per visit ^[15]

End point description

Intention-to-Treat (ITT) sample. The participant was told to stand up as quickly as possible from supine position with his arms by his side. The participant was allowed to use his arms for support while rising from the floor. Time was recorded from the initiation of movement until the assumption of upright standing. The area was free from furniture and the participant did not wear orthoses or was using any aids. n = Number of observations.

End point type

Primary

End point timeframe

At Visits 2, 3, 4, 5, 6, 7, 8, 10 and 12

Notes
[15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were conducted.

End point values	Group I - 0.5 mg/kg	Group II - 2 mg/kg	Group III - 4 mg/kg	Group IV - 6 mg/kg
Number of subjects analysed	3	3	3	3
Units: sec
arithmetic mean (standard deviation)
Visit 2 (n = 2,3,3,2)	2.05 ± 0.07	6.00 ± 6.19	5.00 ± 4.86	3.95 ± 1.63
Visit 3 (n = 2,3,3,2)	2.25 ± 0.35	6.77 ± 6.46	3.97 ± 2.63	4.05 ± 1.77
Visit 4 (n = 2,3,3,2)	2.45 ± 0.92	6.07 ± 6.64	4.40 ± 3.33	5.30 ± 3.39
Visit 5 (n = 2,3,3,2)	2.65 ± 0.21	7.20 ± 8.10	4.03 ± 2.29	4.00 ± 1.70
Visit 6 (n = 2,3,3,2)	2.65 ± 0.49	5.90 ± 6.67	2.73 ± 0.51	3.95 ± 2.19
Visit 7 (n = 2,3,3,2)	2.50 ± 0.14	6.37 ± 7.57	4.17 ± 2.32	4.40 ± 1.41
Visit 8 (n = 2,3,3,2)	2.85 ± 0.35	5.87 ± 6.45	3.73 ± 2.00	4.15 ± 1.77
Visit 10 (n = 2,3,3,2)	2.55 ± 0.21	6.53 ± 7.62	4.43 ± 2.66	4.85 ± 2.62
Visit 12 (n = 2,3,3,2)	2.15 ± 0.07	9.03 ± 12.03	4.87 ± 4.06	4.70 ± 3.68

No statistical analyses for this end point

Primary: Muscle function: Stair climb during Initial Study Period, by dose group per visit

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End point title

Muscle function: Stair climb during Initial Study Period, by dose group per visit ^[16]

End point description

Intention-to-Treat (ITT) sample. The subject was to ascend four steps. Time was recorded from the initiation of movement until the subject stood on the fourth step. If a flight of steps with handrail was available these were used. If not, a box step was used. A plinth or other immovable object was available to provide support. n = Number of observations.

End point type

Primary

End point timeframe

At Visit 2, 3, 4, 5, 6, 7, 8, 10 and 12

Notes
[16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analyses were conducted.

End point values	Group I - 0.5 mg/kg	Group II - 2 mg/kg	Group III - 4 mg/kg	Group IV - 6 mg/kg
Number of subjects analysed	3	3	3	3
Units: sec
arithmetic mean (standard deviation)
Vsit 2 (n = 2,3,3,3)	1.80 ± 0.14	3.27 ± 3.33	3.67 ± 2.82	6.40 ± 7.37
Vsit 3 (n = 2,3,3,3)	1.80 ± 0.00	3.97 ± 4.20	3.37 ± 2.46	5.70 ± 4.86
Vsit 4 (n = 2,3,3,3)	1.65 ± 0.07	3.50 ± 3.82	3.03 ± 1.50	5.90 ± 5.48
Vsit 5 (n = 2,3,3,3)	1.65 ± 0.21	4.47 ± 5.15	3.10 ± 1.65	6.10 ± 6.52
Vsit 6 (n = 2,3,3,3)	1.60 ± 0.14	3.33 ± 3.29	2.87 ± 1.14	4.67 ± 4.65
Vsit 7 (n = 2,3,3,3)	1.70 ± 0.14	3.73 ± 4.05	2.97 ± 1.10	5.87 ± 5.51
Vsit 8 (n = 2,3,3,3)	1.55 ± 0.07	3.47 ± 3.50	2.77 ± 1.34	5.90 ± 5.94
Vsit 10 (n = 2,3,3,3)	1.65 ± 0.21	4.47 ± 5.23	3.43 ± 2.05	5.83 ± 5.38
Vsit 12 (n = 2,3,3,3)	1.80 ± 0.28	5.37 ± 6.61	3.33 ± 1.97	6.30 ± 6.24

No statistical analyses for this end point

Primary: Muscle function: 6-Minute walk test, time walked during Initial study period, by dose group per visit

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End point title

Muscle function: 6-Minute walk test, time walked during Initial study period, by dose group per visit ^[17]

End point description

Intention-to-Treat (ITT) sample. Subjects were requested to walk for 6-minutes. The subject was asked to walk at his own preferred speed up and down the fixed distance until they were told to stop after six minutes. The test was performed preferably barefoot and without aid. If this was not possible, testing was done with shoes/orthoses/aid. Any use of shoes/orthoses/aid was then documented. The subjects were warned of the time and were told that they may stop earlier if they feel unable to continue. The total time walked within six minutes (or until the subjects stopped in case of early termination of the test) was collected in minutes. n = Number of observations

End point type

Primary

End point timeframe

At Visit 1, Visit 8 and Visit 12

Notes
[17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analyses were conducted.

End point values	Group I - 0.5 mg/kg	Group II - 2 mg/kg	Group III - 4 mg/kg	Group IV - 6 mg/kg
Number of subjects analysed	3	3	3	3
Units: min
arithmetic mean (standard deviation)
Visit 1 (n = 2,3,3,3)	6.00 ± 0.00	6.00 ± 0.00	6.00 ± 0.00	6.00 ± 0.00
Visit 8 (n = 2,3,3,3)	6.00 ± 0.00	6.00 ± 0.00	6.00 ± 0.00	6.00 ± 0.00
Visit 12 (n = 2,3,3,2)	6.00 ± 0.00	6.00 ± 0.00	6.00 ± 0.00	6.00 ± 0.00

No statistical analyses for this end point

Primary: Muscle function: 6-Minute walk test, Distance walked during Initial study period, by dose group per visit

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End point title

Muscle function: 6-Minute walk test, Distance walked during Initial study period, by dose group per visit ^[18]

End point description

Intention-to-Treat (ITT) sample. Subjects were requested to walk for 6-minutes. The subject was asked to walk at his own preferred speed up and down the fixed distance until they were told to stop after six minutes. The test was performed preferably barefoot and without aid. If this was not possible, testing was done with shoes/orthoses/aid. Any use of shoes/orthoses/aid was then documented. The subjects were warned of the time and were told that they may stop earlier if they feel unable to continue. The total distance walked within six minutes (or until the subjects stopped in case of early termination of the test) was collected in meters. n = Number of observations.

End point type

Primary

End point timeframe

At Visit 1, Visit 8 and Visit 12

Notes
[18] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analyses were conducted.

End point values	Group I - 0.5 mg/kg	Group II - 2 mg/kg	Group III - 4 mg/kg	Group IV - 6 mg/kg
Number of subjects analysed	3	3	3	3
Units: metre
arithmetic mean (standard deviation)
Visit 1 (n = 2,3,3,3)	437.00 ± 15.56	422.67 ± 117.80	360.33 ± 15.01	368.33 ± 88.27
Visit 8 (n = 2,3,3,3)	427.50 ± 17.68	402.67 ± 121.93	399.67 ± 46.07	370.00 ± 86.16
Visit 12 (n = 2,3,3,2)	420.00 ± 89.10	399.33 ± 164.39	361.67 ± 28.36	373.50 ± 157.68

No statistical analyses for this end point

Primary: Muscle function: 6-Minute walk test, Distance per minute walked during Initial study period, by dose group per visit

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End point title

Muscle function: 6-Minute walk test, Distance per minute walked during Initial study period, by dose group per visit ^[19]

End point description

Intention-to-Treat (ITT) sample. Subjects were requested to walk for 6-minutes. The subject was asked to walk at his own preferred speed up and down the fixed distance until they were told to stop after six minutes. The test was performed preferably barefoot and without aid. If this was not possible, testing was done with shoes/orthoses/aid. Any use of shoes/orthoses/aid was then documented. The subjects were warned of the time and were told that they may stop earlier if they feel unable to continue. The total distance walked within six minutes (or until the subjects stopped in case of early termination of the test) was collected in metres/meters. n = Number of observations.

End point type

Primary

End point timeframe

At Visit 1, Visit 8 and Visit 12

Notes
[19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analyses were conducted.

End point values	Group I - 0.5 mg/kg	Group II - 2 mg/kg	Group III - 4 mg/kg	Group IV - 6 mg/kg
Number of subjects analysed	3	3	3	3
Units: m/min
arithmetic mean (standard deviation)
Visit 1 (n = 2,3,3,3)	72.83 ± 2.59	70.44 ± 19.63	60.06 ± 2.50	61.39 ± 14.71
Visit 8 (n = 2,3,3,3)	71.25 ± 2.95	67.11 ± 20.32	66.61 ± 7.68	61.67 ± 14.36
Visit 12 (n =2,3,3,2)	70.00 ± 14.85	66.56 ± 27.40	60.28 ± 4.73	62.25 ± 26.28

No statistical analyses for this end point

Primary: Muscle strength: Quantitative muscle testing per muscle site during Initial study period, by dose group per visit, Quantitative muscle (Contraction) testing per muscle site

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End point title

Muscle strength: Quantitative muscle testing per muscle site during Initial study period, by dose group per visit, Quantitative muscle (Contraction) testing per muscle site ^[20]

End point description

Intention-to-Treat (ITT) sample. Quantitative muscle testing was performed for knee flexors, knee extensors, grip, elbow flexors and elbow extensors using the CINRG Quantitative Measuring System (CQMS). n = Number of observations.

End point type

Primary

End point timeframe

At Visit 2, 3, 4, 5, 6, 7, 8, 10 and 12

Notes
[20] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were conducted.

End point values	Group I - 0.5 mg/kg	Group II - 2 mg/kg	Group III - 4 mg/kg	Group IV - 6 mg/kg
Number of subjects analysed	3	3	3	3
Units: lbs
arithmetic mean (standard deviation)
Elbow extensor left: Vist 2(n = 3,3,3,3)	7.80 ± 4.16	10.13 ± 4.43	8.93 ± 2.55	6.30 ± 2.23
Elbow extensor right: Vist 2(n = 3,3,3,3)	10.33 ± 5.66	10.10 ± 5.07	8.50 ± 4.51	8.97 ± 2.22
Elbow flexor left: Vist 2(n = 3,3,3,3)	6.73 ± 2.48	7.53 ± 2.42	6.20 ± 2.43	7.77 ± 2.63
Elbow flexor right: Vist 2(n = 3,3,3,3)	7.30 ± 2.85	7.37 ± 2.64	7.57 ± 1.46	7.80 ± 2.03
Grip left: Vist 2(n = 3,3,3,3)	14.00 ± 5.64	14.77 ± 7.80	12.33 ± 4.66	16.40 ± 1.65
Grip right: Vist 2(n = 3,3,3,3)	14.47 ± 2.54	18.10 ± 7.22	13.10 ± 4.65	18.97 ± 3.36
Knee extensor left: Vist 2(n = 3,3,3,3)	19.20 ± 12.24	16.17 ± 3.51	14.83 ± 5.68	10.53 ± 8.68
Knee extensor right: Vist 2(n = 3,3,3,3)	17.90 ± 11.64	22.07 ± 10.86	16.13 ± 7.72	11.77 ± 9.53
Knee flexor left: Vist 2(n = 3,3,3,3)	13.47 ± 4.75	9.53 ± 5.80	12.95 ± 6.86	9.90 ± 1.23
Knee flexor right: Vist 2(n = 3,3,3,3)	10.60 ± 4.68	9.70 ± 2.21	13.60 ± 4.10	9.83 ± 0.21
Elbow extensor left: Vist 3(n = 3,3,3,3)	7.17 ± 3.45	9.80 ± 4.57	7.37 ± 2.00	10.40 ± 5.92
Elbow extensor right: Vist 3(n = 3,3,3,3)	8.83 ± 4.53	11.30 ± 5.86	9.20 ± 2.33	9.77 ± 5.46
Elbow flexor left: Vist 3(n = 3,3,3,3)	5.33 ± 1.29	8.33 ± 2.82	7.53 ± 1.46	7.97 ± 1.63
Elbow flexor right: Vist 3(n = 3,3,3,3)	5.37 ± 1.66	8.50 ± 2.82	6.43 ± 1.57	8.50 ± 2.54
Grip left: Vist 3(n = 3,3,3,3)	13.20 ± 2.69	14.00 ± 5.01	13.03 ± 4.47	15.90 ± 5.70
Grip right: Vist 3(n = 3,3,3,3)	13.90 ± 3.03	17.83 ± 5.67	14.23 ± 4.94	16.37 ± 4.80
Knee extensor left: Vist 3(n = 3,3,3,3)	19.87 ± 12.50	17.40 ± 5.22	15.10 ± 7.85	12.20 ± 10.92
Knee extensor right: Vist 3(n = 3,3,3,3)	20.97 ± 16.54	20.43 ± 8.97	15.00 ± 5.56	12.47 ± 13.16
Knee flexor left: Vist 3(n = 3,3,3,3)	9.23 ± 0.65	11.40 ± 3.39	9.73 ± 4.26	6.60 ± 2.76
Knee flexor right: Vist 3(n = 3,3,3,3)	11.50 ± 3.38	10.27 ± 4.88	8.80 ± 2.76	8.10 ± 2.40
Elbow extensor left: Vist 4(n = 3,3,3,3)	9.07 ± 5.62	10.70 ± 5.45	8.17 ± 3.81	6.47 ± 2.85
Elbow extensor right: Vist 4(n = 3,3,3,3)	8.53 ± 4.41	12.43 ± 6.78	9.53 ± 2.76	6.90 ± 2.20
Elbow flexor left: Vist 4(n = 3,3,3,3)	6.60 ± 2.63	7.37 ± 1.92	5.77 ± 0.29	7.23 ± 3.01
Elbow flexor right: Vist 4(n = 3,3,3,3)	7.07 ± 3.27	7.47 ± 2.85	7.97 ± 1.33	6.63 ± 3.96
Grip left: Vist 4(n = 3,3,3,3)	14.27 ± 3.01	15.87 ± 3.49	12.83 ± 4.03	17.23 ± 2.89
Grip right: Vist 4(n = 3,3,3,3)	16.23 ± 1.59	17.60 ± 5.02	13.20 ± 4.31	18.17 ± 2.67
Knee extensor left: Vist 4(n = 3,3,3,3)	19.40 ± 13.56	18.87 ± 4.15	13.33 ± 5.80	11.83 ± 10.15
Knee extensor right: Vist 4(n = 3,3,3,3)	16.77 ± 12.27	17.17 ± 6.16	15.17 ± 7.21	11.23 ± 11.29
Knee flexor left: Vist 4(n = 3,3,3,3)	11.47 ± 2.76	11.20 ± 2.78	10.43 ± 4.91	11.13 ± 2.51
Knee flexor right: Vist 4(n = 3,3,3,3)	10.63 ± 1.81	12.23 ± 1.02	10.47 ± 3.59	11.17 ± 0.65
Elbow extensor left: Vist 5(n = 3,2,3,3)	8.13 ± 3.82	7.10 ± 1.27	9.00 ± 2.17	6.27 ± 2.75
Elbow extensor right: Vist 5(n = 3,2,3,3)	8.10 ± 3.50	9.30 ± 3.82	7.50 ± 3.46	6.47 ± 2.57
Elbow flexor left: Vist 5(n = 3,2,3,3)	4.77 ± 0.75	6.85 ± 1.91	5.37 ± 1.05	7.20 ± 3.16
Elbow flexor right: Vist 5(n = 3,2,3,3)	5.17 ± 0.38	5.65 ± 2.05	6.93 ± 0.65	7.83 ± 3.33
Grip left: Vist 5(n = 3,3,3,3)	14.83 ± 2.32	17.63 ± 5.73	12.77 ± 4.46	19.37 ± 3.61
Grip right: Vist 5(n = 3,3,3,3)	15.97 ± 1.89	18.77 ± 4.36	13.60 ± 4.20	17.30 ± 2.23
Knee extensor left: Vist 5(n = 3,2,3,3)	19.87 ± 13.31	18.05 ± 7.99	14.07 ± 6.20	10.83 ± 10.82
Knee extensor right: Vist 5(n = 3,2,3,3)	18.03 ± 14.94	15.40 ± 6.08	14.10 ± 6.84	10.33 ± 10.17
Knee flexor left: Vist 5(n = 3,2,3,3)	11.87 ± 1.70	7.05 ± 1.06	9.07 ± 6.29	14.30 ± 4.15
Knee flexor right: Vist 5(n = 3,2,3,3)	12.60 ± 2.78	7.95 ± 2.62	7.53 ± 4.13	11.57 ± 2.82
Elbow extensor left: Vist 6(n = 3,2,3,3)	7.73 ± 4.12	10.25 ± 7.28	7.60 ± 2.09	5.13 ± 2.82
Elbow extensor right: Vist 6(n = 3,2,3,3)	9.90 ± 4.85	9.05 ± 4.45	8.40 ± 2.09	5.57 ± 3.62
Elbow flexor left: Vist 6(n = 3,2,3,3)	5.90 ± 1.78	7.40 ± 0.85	6.30 ± 1.57	6.10 ± 3.04
Elbow flexor right: Vist 6(n = 3,2,3,3)	6.03 ± 1.53	5.60 ± 0.71	7.97 ± 2.14	6.57 ± 3.96
Grip left: Vist 6(n = 3,3,3,3)	15.50 ± 2.50	18.40 ± 5.58	12.60 ± 5.09	18.13 ± 1.01
Grip right: Vist 6(n = 3,3,3,3)	16.43 ± 3.26	18.47 ± 6.15	14.10 ± 5.07	18.27 ± 1.40
Knee extensor left: Vist 6(n = 3,2,3,3)	20.37 ± 12.14	25.75 ± 10.11	12.97 ± 6.54	10.87 ± 12.70
Knee extensor right: Vist 6(n = 3,2,3,3)	18.37 ± 13.50	27.95 ± 11.67	13.53 ± 5.00	11.40 ± 14.42
Knee flexor left: Vist 6(n = 3,2,3,3)	10.77 ± 3.37	13.80 ± 3.82	10.67 ± 5.75	8.70 ± 3.11
Knee flexor right: Vist 6(n = 3,2,3,3)	11.47 ± 1.19	11.50 ± 2.26	9.87 ± 4.15	9.07 ± 4.32
Elbow extensor left: Vist 7(n = 3,3,3,3)	8.33 ± 4.81	9.73 ± 3.51	8.30 ± 3.84	5.40 ± 2.26
Elbow extensor right: Vist 7(n = 3,3,3,3)	9.07 ± 4.72	9.40 ± 3.37	7.97 ± 3.09	7.10 ± 1.56
Elbow flexor left: Vist 7(n = 3,3,3,3)	7.37 ± 2.35	7.70 ± 3.20	7.40 ± 3.27	6.27 ± 3.01
Elbow flexor right: Vist 7(n = 3,3,3,3)	8.57 ± 4.79	5.20 ± 1.87	6.97 ± 2.17	6.60 ± 3.30
Grip left: Vist 7(n = 3,3,3,3)	14.10 ± 2.52	17.10 ± 5.57	12.33 ± 5.08	18.47 ± 2.81
Grip right: Vist 7(n = 3,3,3,3)	16.67 ± 1.91	19.93 ± 8.00	13.77 ± 4.79	18.57 ± 2.15
Knee extensor left: Vist 7(n = 3,3,3,3)	20.50 ± 13.99	25.17 ± 12.33	13.20 ± 5.72	11.10 ± 7.98
Knee extensor right: Vist 7(n = 3,3,3,3)	17.27 ± 15.53	21.97 ± 11.23	12.87 ± 6.01	12.23 ± 13.05
Knee flexor left: Vist 7(n = 3,3,3,3)	10.07 ± 1.07	9.60 ± 4.69	10.40 ± 5.17	11.37 ± 0.49
Knee flexor right: Vist 7(n = 3,3,3,3)	10.93 ± 1.75	10.87 ± 5.75	10.07 ± 4.22	11.60 ± 1.95
Elbow extensor left: Vist 8(n = 3,3,3,3)	7.63 ± 3.75	9.93 ± 3.67	7.30 ± 2.86	5.30 ± 1.51
Elbow extensor right: Vist 8(n = 3,3,3,3)	10.00 ± 5.10	10.57 ± 4.85	8.00 ± 2.74	5.83 ± 2.10
Elbow flexor left: Vist 8(n = 3,3,3,3)	6.27 ± 0.80	8.40 ± 4.30	6.77 ± 1.31	6.20 ± 4.45
Elbow flexor right: Vist 8(n = 3,3,3,3)	6.53 ± 1.07	8.43 ± 3.39	7.80 ± 2.11	6.33 ± 3.35
Grip left: Vist 8(n = 3,3,3,3)	16.87 ± 3.27	19.03 ± 6.47	15.63 ± 5.53	16.60 ± 1.11
Grip right: Vist 8(n = 3,3,3,3)	17.87 ± 2.58	19.67 ± 8.23	14.47 ± 5.19	16.60 ± 1.04
Knee extensor left: Vist 8(n = 3,3,3,3)	21.87 ± 15.32	21.00 ± 4.29	13.90 ± 7.05	11.37 ± 10.95
Knee extensor right: Vist 8(n = 3,3,3,3)	19.97 ± 16.84	21.83 ± 10.20	13.10 ± 6.43	13.50 ± 15.01
Knee flexor left: Vist 8(n = 3,3,3,3)	13.07 ± 5.49	10.40 ± 2.36	12.13 ± 5.54	9.37 ± 3.26
Knee flexor right: Vist 8(n = 3,3,3,3)	11.87 ± 2.80	11.13 ± 2.25	10.93 ± 6.13	10.17 ± 3.84
Elbow extensor left: Vist 10(n = 2,3,3,2)	6.10 ± 3.68	8.97 ± 4.45	8.77 ± 1.16	5.15 ± 1.48
Elbow extensor right: Vist 10(n = 2,3,3,2)	7.50 ± 5.23	9.60 ± 5.15	7.97 ± 2.28	5.90 ± 2.26
Elbow flexor left: Vist 10(n = 2,3,3,2)	5.75 ± 1.77	7.77 ± 3.48	7.27 ± 0.93	6.80 ± 0.99
Elbow flexor right: Vist 10(n = 2,3,3,2)	5.25 ± 0.64	7.30 ± 1.90	7.63 ± 1.46	6.30 ± 0.57
Grip left: Vist 10(n = 3,3,3,2)	14.03 ± 2.10	21.10 ± 7.52	14.43 ± 3.58	17.05 ± 2.33
Grip right: Vist 10(n = 3,3,3,2)	15.77 ± 3.46	19.70 ± 6.05	15.33 ± 3.40	18.45 ± 0.92
Knee extensor left: Vist 10(n = 2,3,3,2)	15.50 ± 12.16	22.90 ± 9.62	16.33 ± 5.27	6.40 ± 2.69
Knee extensor right: Vist 10(n = 2,3,3,2)	11.05 ± 7.57	20.57 ± 8.95	15.30 ± 5.17	5.80 ± 3.11
Knee flexor left: Vist 10(n = 2,3,3,2)	11.05 ± 1.48	11.97 ± 8.10	11.63 ± 7.10	10.90 ± 5.66
Knee flexor right: Vist 10(n = 2,3,3,2)	11.95 ± 1.91	11.00 ± 5.05	11.27 ± 4.90	9.65 ± 3.61
Elbow extensor left: Vist 12(n = 3,3,3,2)	9.83 ± 6.20	11.43 ± 6.25	9.07 ± 1.42	4.90 ± 0.99
Elbow extensor right: Vist 12(n = 3,3,3,2)	11.37 ± 5.58	9.57 ± 5.90	8.57 ± 2.34	7.20 ± 2.83
Elbow flexor left: Vist 12(n = 3,3,3,2)	6.77 ± 1.76	8.60 ± 3.05	5.97 ± 1.47	6.45 ± 0.07
Elbow flexor right: Vist 12(n = 3,3,3,2)	6.97 ± 2.17	8.43 ± 2.21	6.80 ± 1.44	7.60 ± 1.56
Grip left: Vist 12(n = 3,3,3,2)	16.07 ± 3.18	16.30 ± 5.45	17.43 ± 3.32	19.50 ± 3.68
Grip right: Vist 12(n = 3,3,3,2)	14.73 ± 2.94	20.63 ± 7.48	16.63 ± 2.23	19.95 ± 3.46
Knee extensor left: Vist 12(n = 3,3,3,2)	21.33 ± 14.64	24.83 ± 10.32	16.00 ± 6.16	6.25 ± 0.64
Knee extensor right: Vist 12(n = 3,3,3,2)	16.83 ± 10.88	23.27 ± 12.74	17.57 ± 8.21	4.55 ± 1.20
Knee flexor left: Vist 12(n = 3,3,3,2)	9.73 ± 3.09	13.03 ± 3.46	11.27 ± 4.56	10.30 ± 0.85
Knee flexor right: Vist 12(n = 3,3,3,2)	11.43 ± 3.95	13.30 ± 2.52	12.90 ± 4.67	8.95 ± 0.21

No statistical analyses for this end point

Primary: Muscle strength: Quantitative muscle testing per muscle site during Initial study period, by dose group per visit - Pulmonary function testing

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End point title

Muscle strength: Quantitative muscle testing per muscle site during Initial study period, by dose group per visit - Pulmonary function testing ^[21]

End point description

Intention-to-Treat (ITT) sample. Spirometry assessment for FVC and FEV1 was performed using the CINRG Quantitative Measuring System (CQMS). n = Number of observations FVC = Forced Vital Capacity FEV1 = Forced Expiratory Volume in 1 Second

End point type

Primary

End point timeframe

At Visit 2, 3, 4, 5, 6, 7, 8, 10 and 12

Notes
[21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analyses were conducted.

End point values	Group I - 0.5 mg/kg	Group II - 2 mg/kg	Group III - 4 mg/kg	Group IV - 6 mg/kg
Number of subjects analysed	3	3	3	3
Units: litres
arithmetic mean (standard deviation)
FVC: Visit 2(n = 2,3,3,3)	1.75 ± 0.21	1.70 ± 0.36	1.43 ± 0.55	1.67 ± 0.15
FEV1: Visit 2(n = 2,3,3,3)	1.60 ± 0.28	1.63 ± 0.35	1.30 ± 0.56	1.60 ± 0.20
FVC: Visit 3(n = 3,3,3,3)	1.53 ± 0.29	1.73 ± 0.32	1.50 ± 0.50	1.80 ± 0.10
FEV1: Visit 3(n = 3,3,3,3)	1.43 ± 0.21	1.63 ± 0.32	1.30 ± 0.50	1.60 ± 0.20
FVC: Visit 4(n = 3,3,3,3)	1.67 ± 0.32	1.77 ± 0.29	1.37 ± 0.51	1.67 ± 0.15
FEV1: Visit 4(n = 3,3,3,3)	1.47 ± 0.31	1.60 ± 0.26	1.23 ± 0.57	1.47 ± 0.21
FVC: Visit 5(n = 3,3,3,3)	1.63 ± 0.29	1.73 ± 0.23	1.43 ± 0.57	1.67 ± 0.15
FEV1: Visit 5(n = 3,3,3,3)	1.47 ± 0.23	1.63 ± 0.15	1.20 ± 0.66	1.47 ± 0.21
FVC: Visit 6(n = 3,3,3,3)	1.60 ± 0.26	1.80 ± 0.35	1.40 ± 0.53	1.67 ± 0.15
FEV1: Visit 6(n = 3,3,3,3)	1.47 ± 0.32	1.57 ± 0.47	1.23 ± 0.57	1.53 ± 0.15
FVC: Visit 7(n = 3,3,3,3)	1.63 ± 0.21	1.83 ± 0.32	1.40 ± 0.53	1.77 ± 0.23
FEV1: Visit 7(n = 3,3,3,3)	1.47 ± 0.15	1.67 ± 0.29	1.23 ± 0.67	1.30 ± 0.46
FVC: Visit 8(n = 3,3,3,3)	1.57 ± 0.23	1.87 ± 0.29	1.40 ± 0.62	1.70 ± 0.20
FEV1: Visit 8(n = 3,3,3,3)	1.47 ± 0.15	1.70 ± 0.26	1.20 ± 0.72	1.40 ± 0.30
FVC: Visit 10(n = 3,3,3,3)	1.63 ± 0.38	1.90 ± 0.35	1.40 ± 0.36	1.77 ± 0.23
FEV1: Visit 10(n = 3,3,3,3)	1.57 ± 0.32	1.77 ± 0.29	1.30 ± 0.36	1.67 ± 0.23
FVC: Visit 12(n = 3,3,3,3)	1.67 ± 0.23	1.93 ± 0.35	1.50 ± 0.40	1.85 ± 0.07
FEV1: Visit 12(n = 3,3,3,3)	1.63 ± 0.29	1.77 ± 0.31	1.37 ± 0.45	1.70 ± 0.14

No statistical analyses for this end point

Primary: Muscle strength: Manual muscle testing, total score and separate scores during Initial study period, by dose group per visit - Overall scores

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End point title

Muscle strength: Manual muscle testing, total score and separate scores during Initial study period, by dose group per visit - Overall scores ^[22]

End point description

Intention-to-Treat (ITT) sample. Manual muscle testing was assessed. The Medical Research Council Scale (MRCS) is composed of a rating of 0-5 assigned to each muscle group tested (See section 9.7.1.2.2 for details on muscle groups tested). The MRCS has been modified and formalized to account for more grades of muscle weakness using a plus or minus designation (see Table 5). Overall score of the total muscle score, total sitting position, and total prone, side lying and supine position.

End point type

Primary

End point timeframe

At Visit 1, Visit 8 and Visit 12

Notes
[22] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were conducted.

End point values	Group I - 0.5 mg/kg	Group II - 2 mg/kg	Group III - 4 mg/kg	Group IV - 6 mg/kg
Number of subjects analysed	3	3	3	3
Units: Unit on scale
median (full range (min-max))
Total Muscle Score : Visit 1(n=3,3,3,3)	245.0 (186.0 to 254.0)	246.0 (228.0 to 255.0)	248.0 (219.0 to 263.0)	232.0 (208.0 to 280.0)
Total Muscle Score : Visit 8(n=3,3,3,3)	244.0 (201.0 to 252.0)	259.0 (239.0 to 270.0)	253.0 (185.0 to 259.0)	230.0 (216.0 to 265.0)
Total Muscle Score : Visit 12(n=3,3,3,2)	229.0 (198.0 to 254.0)	248.0 (226.0 to 267.0)	247.0 (237.0 to 271.0)	223.0 (216.0 to 230.0)
Total sitting position: Visit 1(n=3,3,3,3)	152.0 (128.0 to 158.0)	150.0 (136.0 to 162.0)	148.0 (132.0 to 160.0)	136.0 (118.0 to 174.0)
Total sitting position: Visit 8(n=3,3,3,3)	148.0 (137.0 to 150.0)	159.0 (144.0 to 162.0)	154.0 (116.0 to 169.0)	136.0 (125.0 to 158.0)
Total sitting position: Visit 12(n=3,3,3,1)	137.0 (134.0 to 151.0)	148.0 (136.0 to 166.0)	156.0 (141.0 to 168.0)	132.0 (132.0 to 132.0)
Total Prone/Side Lying/Supine: Visit 1(n=3,3,3,3)	93.0 (58.0 to 96.0)	93.0 (92.0 to 96.0)	100.0 (87.0 to 103.0)	96.0 (90.0 to 106.0)
Total prone/side lying/supine: Visit 8(n=3,3,3,3)	96.0 (64.0 to 102.0)	100.0 (95.0 to 108.0)	90.0 (69.0 to 99.0)	94.0 (91.0 to 107.0)
Total prone/side lying/supine: Visit 12(n=3,3,3,1)	92.0 (64.0 to 103.0)	100.0 (90.0 to 101.0)	96.0 (91.0 to 103.0)	84.0 (84.0 to 84.0)

No statistical analyses for this end point

Primary: Number of Subjects with Treatment Emergent Adverse Events during Initial Study Period

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End point title

Number of Subjects with Treatment Emergent Adverse Events during Initial Study Period ^[23]

End point description

Intensity was determined by the Investigator. For symptomatic AEs the following definitions were applied. Mild = AE did not limit usual activities; subject may have experienced slight discomfort. Moderate = AE resulted in some limitation of usual activities; subject may have experienced significant discomfort. Severe = AE resulted in an inability to carry out usual activities; subject may have experienced intolerable discomfort/pain. Relationship to Investigational Medicinal Products (IMP) Unlikely = Slight, but remote, chance that AE was caused by IMP. Possible = Reasonable suspicion that the AE was caused by IMP. Probable = Most likely that AE was caused by IMP.

End point type

Primary

End point timeframe

Upto Visit 12

Notes
[23] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analyses were conducted.

End point values	Group I - 0.5 mg/kg	Group II - 2 mg/kg	Group III - 4 mg/kg	Group IV - 6 mg/kg
Number of subjects analysed	3	3	3	3
Units: Participants
TEAE by severity: Mild	2	3	1	2
TEAE by severity: Moderate	1	0	1	1
TEAE by severity: Severe	0	0	1	0
Relationship to IMP - Not related	0	0	0	0
Relationship to IMP - unlikely	0	0	0	0
Relationship to IMP - Possible	2	3	1	0
Relationship to IMP - Probable	1	0	1	2
Relationship to IMP - Definite	0	0	1	1

No statistical analyses for this end point

Primary: Change from Baseline of 6-Minute Walking Distance (6MWD) in Continued Treatment phase

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End point title

Change from Baseline of 6-Minute Walking Distance (6MWD) in Continued Treatment phase ^[24]

End point description

Intention-to-Treat (ITT) Population are all treated subjects who received at least one dose of study medication and have at least one post-Baseline (where Baseline is Visit 13) efficacy parameter. This is the primary population for evaluation of efficacy variable. Visit 93 to 190 indicate visits during washout.

End point type

Primary

End point timeframe

At Visit 25, 37, 49, 61, 73, 85, 93, 106, 118, 130, 142, 154, 166, 178 and 190

Notes
[24] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analyses were conducted.

End point values	Continued Treatment phase - 6 mg/kg
Number of subjects analysed	12
Units: min
arithmetic mean (standard deviation)
Visit 25 (N = 11)	29.7 ± 32.71
Visit 37 (N = 11)	26.6 ± 65.98
Visit 49 (N = 11)	15.9 ± 59.31
Visit 61 (N = 11)	19.2 ± 81.85
Visit 73 (N = 11)	17.0 ± 113.28
Visit 85 (N = 11)	-8.9 ± 138.59
Visit 93 (N = 11)	2.9 ± 150.45
Visit 106 (N = 11)	3.3 ± 151.37
Visit 118 (N = 11)	-1.5 ± 154.52
Visit 130 (N = 11)	4.9 ± 157.38
Visit 142 (N = 11)	-7.4 ± 157.90
Visit 154 (N = 11)	-14.3 ± 153.97
Visit 166 (N = 11)	-10.6 ± 160.68
Visit 178 (N = 11)	-27.7 ± 147.39
Visit 190 (N = 11)	-29.1 ± 153.29

No statistical analyses for this end point

Primary: Change from Baseline of Timed Tests - 10m Walk/run, Rising from floor and Stair Climb in Continued Treatment phase

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End point title

Change from Baseline of Timed Tests - 10m Walk/run, Rising from floor and Stair Climb in Continued Treatment phase ^[25]

End point description

Intention-to-Treat (ITT) Population Visit 93 to 190 indicate visits during washout.

End point type

Primary

End point timeframe

At Visit 21, 25, 29, 33, 37, 41, 49, 61, 73, 85, 93, 106, 118, 130, 142, 154, 166, 178 and 190

Notes
[25] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were conducted.

End point values	Continued Treatment phase - 6 mg/kg
Number of subjects analysed	12
Units: sec
arithmetic mean (standard deviation)
10m Walk/run Visit 21 (N = 11)	0.08 ± 1.184
10m Walk/run Visit 25 (N = 11)	0.27 ± 0.515
10m Walk/run Visit 29 (N = 11)	0.61 ± 0.621
10m Walk/run Visit 33 (N = 10)	0.56 ± 0.761
10m Walk/run Visit 37 (N = 10)	0.40 ± 0.388
10m Walk/run Visit 41 (N = 10)	0.79 ± 1.133
10m Walk/run Visit 49 (N = 10)	0.51 ± 1.010
10m Walk/run Visit 61 (N = 10)	0.82 ± 1.181
10m Walk/run Visit 73 (N = 10)	0.94 ± 1.696
10m Walk/run Visit 85 (N = 9)	1.32 ± 2.446
10m Walk/run Visit 93 (N = 9)	2.21 ± 5.229
10m Walk/run Visit 106 (N = 8)	0.49 ± 1.080
10m Walk/run Visit 118 (N = 8)	0.72 ± 1.360
10m Walk/run Visit 130 (N = 8)	0.99 ± 1.695
10m Walk/run Visit 142 (N = 8)	1.00 ± 1.360
10m Walk/run Visit 154 (N = 8)	1.29 ± 1.925
10m Walk/run Visit 166 (N = 8)	1.52 ± 1.789
10m Walk/run Visit 178 (N = 8)	1.91 ± 2.059
10m Walk/run Visit 190 (N = 8)	1.61 ± 2.039
Rising from floor Visit 21 (N = 9)	0.50 ± 1.723
Rising from floor Visit 25 (N = 9)	-0.20 ± 0.577
Rising from floor Visit 29 (N = 9)	0.06 ± 0.655
Rising from floor Visit 33 (N = 9)	1.000 ± 2.632
Rising from floor Visit 37 (N = 9)	-0.08 ± 0.923
Rising from floor Visit 41 (N = 9)	0.55 ± 0.789
Rising from floor Visit 49 (N = 9)	0.82 ± 1.620
Rising from floor Visit 61 (N = 8)	0.30 ± 0.656
Rising from floor Visit 73 (N = 8)	1.04 ± 2.620
Rising from floor Visit 85 (N = 8)	1.75 ± 4.031
Rising from floor Visit 93 (N = 8)	1.27 ± 2.472
Rising from floor Visit 106 (N = 8)	1.75 ± 4.588
Rising from floor Visit 118 (N = 8)	3.09 ± 6.439
Rising from floor Visit 130 (N = 7)	1.06 ± 1.976
Rising from floor Visit 142 (N = 6)	0.67 ± 0.904
Rising from floor Visit 154 (N = 6)	0.44 ± 0.497
Rising from floor Visit 166 (N = 6)	0.79 ± 0.625
Rising from floor Visit 178 (N = 6)	1.12 ± 1.097
Rising from floor Visit 190 (N = 6)	1.05 ± 0.914
Stair Climb Visit 21 (N = 11)	-0.85 ± 1.791
Stair Climb Visit 25 (N = 11)	-1.07 ± 2.110
Stair Climb Visit 29 (N = 11)	-0.40 ± 1.603
Stair Climb Visit 33 (N = 10)	-0.45 ± 1.064
Stair Climb Visit 37 (N = 9)	-0.18 ± 1.554
Stair Climb Visit 41 (N = 10)	-0.61 ± 1.690
Stair Climb Visit 49 (N = 9)	-0.37 ± 1.248
Stair Climb Visit 61 (N = 9)	-0.50 ± 0.996
Stair Climb Visit 73 (N = 10)	-0.15 ± 0.677
Stair Climb Visit 85 (N = 9)	0.04 ± 1.201
Stair Climb Visit 93 (N = 9)	0.32 ± 0.859
Stair Climb Visit 106 (N = 9)	0.76 ± 1.422
Stair Climb Visit 118 (N = 8)	1.34 ± 3.041
Stair Climb Visit 130 (N = 8)	0.85 ± 2.063
Stair Climb Visit 142 (N = 8)	1.62 ± 3.469
Stair Climb Visit 154 (N = 8)	1.73 ± 3.446
Stair Climb Visit 166 (N = 7)	1.78 ± 4.061
Stair Climb Visit 178 (N = 8)	3.48 ± 5.654
Stair Climb Visit 190 (N = 7)	4.23 ± 10.382

No statistical analyses for this end point

Primary: Change from Baseline of Muscle Strength Handheld Myometry of Elbow Flexor, Elbow Extensor, Knee Flexor and Knee Extensor in Continued Treatment phase

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End point title

Change from Baseline of Muscle Strength Handheld Myometry of Elbow Flexor, Elbow Extensor, Knee Flexor and Knee Extensor in Continued Treatment phase ^[26]

End point description

Intention-to-Treat (ITT) Population Visit 93 to 190 indicate visits during washout

End point type

Primary

End point timeframe

At Visit 21, 25, 29, 33, 37, 41, 49, 61, 73, 85, 93, 106, 118, 130, 142, 154, 166, 178 and 190

Notes
[26] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analyses were conducted.

End point values	Continued Treatment phase - 6 mg/kg
Number of subjects analysed	12
Units: lbs
arithmetic mean (standard deviation)
Left Elbow Flexor Visit 21 (N = 12)	-1.18 ± 1.968
Left Elbow Flexor Visit 25 (N = 12)	-0.73 ± 1.524
Left Elbow Flexor Visit 29 (N = 12)	-0.59 ± 1.227
Left Elbow Flexor Visit 33 (N = 12)	-0.47 ± 1.828
Left Elbow Flexor Visit 37 (N = 12)	-0.68 ± 1.588
Left Elbow Flexor Visit 41 (N = 12)	-0.07 ± 2.227
Left Elbow Flexor Visit 49 (N = 12)	0.01 ± 1.766
Left Elbow Flexor Visit 61 (N = 12)	-1.63 ± 2.308
Left Elbow Flexor Visit 73 (N = 12)	-0.64 ± 1.975
Left Elbow Flexor Visit 85 (N = 12)	-1.24 ± 1.565
Left Elbow Flexor Visit 93 (N = 12)	-1.24 ± 2.021
Left Elbow Flexor Visit 106 (N = 12)	-1.44 ± 1.832
Left Elbow Flexor Visit 118 (N = 12)	-1.54 ± 2.523
Left Elbow Flexor Visit 130 (N = 12)	-0.28 ± 2.312
Left Elbow Flexor Visit 142 (N = 12)	-1.05 ± 1.934
Left Elbow Flexor Visit 154 (N = 12)	-1.23 ± 2.527
Left Elbow Flexor Visit 166 (N = 12)	-1.26 ± 2.200
Left Elbow Flexor Visit 178 (N = 12)	-1.62 ± 2.063
Left Elbow Flexor Visit 190 (N = 12)	-1.66 ± 1.532
Right Elbow Flexor Visit 21 (N = 12)	-0.48 ± 2.020
Right Elbow Flexor Visit 25 (N = 12)	0.27 ± 1.721
Right Elbow Flexor Visit 29 (N = 12)	-0.88 ± 2.021
Right Elbow Flexor Visit 33 (N = 12)	-0.92 ± 1.946
Right Elbow Flexor Visit 37 (N = 12)	-1.11 ± 2.017
Right Elbow Flexor Visit 41 (N = 12)	-0.18 ± 2.243
Right Elbow Flexor Visit 49 (N = 12)	-0.44 ± 1.947
Right Elbow Flexor Visit 61 (N = 12)	-1.43 ± 1.971
Right Elbow Flexor Visit 73 (N = 12)	-1.07 ± 2.555
Right Elbow Flexor Visit 85 (N = 12)	-1.00 ± 2.558
Right Elbow Flexor Visit 93 (N = 12)	-1.20 ± 2.649
Right Elbow Flexor Visit 106 (N = 12)	-1.60 ± 2.057
Right Elbow Flexor Visit 118 (N = 12)	-1.39 ± 2.564
Right Elbow Flexor Visit 130 (N = 12)	-0.99 ± 2.886
Right Elbow Flexor Visit 142 (N = 12)	-0.73 ± 2.327
Right Elbow Flexor Visit 154 (N = 12)	-1.33 ± 2.089
Right Elbow Flexor Visit 166 (N = 12)	-0.92 ± 2.664
Right Elbow Flexor Visit 178 (N = 12)	-1.80 ± 2.628
Right Elbow Flexor Visit 190 (N = 12)	-1.68 ± 2.482
Left Elbow Extensor Visit 21 (N = 12)	-1.48 ± 1.937
Left Elbow Extensor Visit 25 (N = 12)	-0.77 ± 1.810
Left Elbow Extensor Visit 29 (N = 12)	-1.60 ± 1.063
Left Elbow Extensor Visit 33 (N = 12)	-0.88 ± 1.419
Left Elbow Extensor Visit 37 (N = 12)	-1.38 ± 2.390
Left Elbow Extensor Visit 41 (N = 12)	0.46 ± 1.940
Left Elbow Extensor Visit 49 (N = 12)	-0.17 ± 2.198
Left Elbow Extensor Visit 61 (N = 12)	-1.91 ± 1.441
Left Elbow Extensor Visit 73 (N = 12)	-1.26 ± 1.743
Left Elbow Extensor Visit 85 (N = 12)	-1.31 ± 1.775
Left Elbow Extensor Visit 93 (N = 12)	-1.59 ± 1.508
Left Elbow Extensor Visit 106 (N = 12)	-2.38 ± 2.767
Left Elbow Extensor Visit 118 (N = 12)	-1.49 ± 1.714
Left Elbow Extensor Visit 130 (N = 12)	-1.25 ± 2.482
Left Elbow Extensor Visit 142 (N = 12)	-1.52 ± 2.057
Left Elbow Extensor Visit 154 (N = 12)	-1.73 ± 2.537
Left Elbow Extensor Visit 166 (N = 12)	-1.77 ± 2.117
Left Elbow Extensor Visit 178 (N = 12)	-2.14 ± 2.696
Left Elbow Extensor Visit 190 (N = 12)	-1.97 ± 2.414
Right Elbow Extensor Visit 21 (N = 12)	-0.13 ± 2.401
Right Elbow Extensor Visit 25 (N = 12)	-0.15 ± 3.122
Right Elbow Extensor Visit 29 (N = 12)	-0.87 ± 2.097
Right Elbow Extensor Visit 33 (N = 12)	-0.37 ± 2.447
Right Elbow Extensor Visit 37 (N = 12)	-1.61 ± 2.378
Right Elbow Extensor Visit 41 (N = 12)	-0.08 ± 2.292
Right Elbow Extensor Visit 49 (N = 12)	-0.63 ± 2.782
Right Elbow Extensor Visit 61 (N = 12)	-1.88 ± 2.398
Right Elbow Extensor Visit 73 (N = 12)	-0.38 ± 1.910
Right Elbow Extensor Visit 85 (N = 12)	-1.43 ± 2.969
Right Elbow Extensor Visit 93 (N = 12)	-1.54 ± 3.529
Right Elbow Extensor Visit 106 (N = 12)	-1.88 ± 3.768
Right Elbow Extensor Visit 118 (N = 12)	-1.12 ± 3.164
Right Elbow Extensor Visit 130 (N = 12)	-1.63 ± 3.992
Right Elbow Extensor Visit 142 (N = 12)	-1.54 ± 2.850
Right Elbow Extensor Visit 154 (N = 12)	-1.63 ± 2.842
Right Elbow Extensor Visit 166 (N = 12)	-1.87 ± 2.873
Right Elbow Extensor Visit 178 (N = 12)	-1.67 ± 2.760
Right Elbow Extensor Visit 190 (N = 12)	-1.55 ± 1.614
Left Knee Flexor Visit 21 (N = 12)	-0.88 ± 2.982
Left Knee Flexor Visit 25 (N = 12)	-0.99 ± 3.170
Left Knee Flexor Visit 29 (N = 12)	-1.06 ± 5.171
Left Knee Flexor Visit 33 (N = 11)	-1.42 ± 4.101
Left Knee Flexor Visit 37 (N = 11)	-1.31 ± 3.894
Left Knee Flexor Visit 41 (N = 11)	-0.74 ± 2.604
Left Knee Flexor Visit 49 (N = 12)	-1.36 ± 3.282
Left Knee Flexor Visit 61 (N = 12)	-2.50 ± 3.177
Left Knee Flexor Visit 73 (N = 12)	-1.89 ± 4.518
Left Knee Flexor Visit 85 (N = 11)	-1.88 ± 4.602
Left Knee Flexor Visit 93 (N = 12)	-1.64 ± 4.498
Left Knee Flexor Visit 106 (N = 12)	-4.04 ± 4.782
Left Knee Flexor Visit 118 (N = 12)	-3.06 ± 4.522
Left Knee Flexor Visit 130 (N = 11)	-2.41 ± 5.280
Left Knee Flexor Visit 142 (N = 12)	-2.95 ± 5.588
Left Knee Flexor Visit 154 (N = 12)	-3.37 ± 4.673
Left Knee Flexor Visit 166 (N = 12)	-3.01 ± 4.751
Left Knee Flexor Visit 178 (N = 12)	-3.91 ± 4.284
Left Knee Flexor Visit 190 (N = 11)	-3.74 ± 4.801
Right Knee Flexor Visit 21 (N = 12)	-1.14 ± 1.874
Right Knee Flexor Visit 25 (N = 12)	-0.54 ± 3.358
Right Knee Flexor Visit 29 (N = 12)	-1.74 ± 3.504
Right Knee Flexor Visit 33 (N = 11)	-1.08 ± 3.563
Right Knee Flexor Visit 37 (N = 11)	-1.45 ± 4.435
Right Knee Flexor Visit 41 (N = 11)	-1.99 ± 2.221
Right Knee Flexor Visit 49 (N = 12)	-2.13 ± 4.209
Right Knee Flexor Visit 61 (N = 12)	-2.46 ± 3.520
Right Knee Flexor Visit 73 (N = 12)	-1.58 ± 5.070
Right Knee Flexor Visit 85 (N = 11)	-2.24 ± 4.360
Right Knee Flexor Visit 93 (N = 12)	-2.16 ± 3.830
Right Knee Flexor Visit 106 (N = 12)	-3.89 ± 4.880
Right Knee Flexor Visit 118 (N = 12)	-3.14 ± 4.848
Right Knee Flexor Visit 130 (N = 11)	-2.68 ± 4.706
Right Knee Flexor Visit 142 (N = 12)	-3.87 ± 5.562
Right Knee Flexor Visit 154 (N = 12)	-4.03 ± 5.447
Right Knee Flexor Visit 166 (N = 12)	-3.74 ± 5.233
Right Knee Flexor Visit 178 (N = 11)	-4.79 ± 5.185
Right Knee Flexor Visit 190 (N = 11)	-3.68 ± 5.214
Left Knee Extensor Visit 21 (N = 12)	-0.99 ± 5.692
Left Knee Extensor Visit 25 (N = 12)	0.01 ± 2.325
Left Knee Extensor Visit 29 (N = 12)	-0.39 ± 2.121
Left Knee Extensor Visit 33 (N = 11)	-0.76 ± 3.507
Left Knee Extensor Visit 37 (N = 11)	-0.32 ± 3.285
Left Knee Extensor Visit 41 (N = 11)	-0.79 ± 2.673
Left Knee Extensor Visit 49 (N = 12)	-0.78 ± 3.508
Left Knee Extensor Visit 61 (N = 12)	-2.32 ± 3.755
Left Knee Extensor Visit 73 (N = 12)	-1.69 ± 3.700
Left Knee Extensor Visit 85 (N = 11)	-2.13 ± 2.713
Left Knee Extensor Visit 93 (N = 12)	-1.76 ± 3.683
Left Knee Extensor Visit 106 (N = 12)	-1.91 ± 4.678
Left Knee Extensor Visit 118 (N = 12)	-1.98 ± 4.215
Left Knee Extensor Visit 130 (N = 11)	-2.54 ± 4.206
Left Knee Extensor Visit 142 (N = 12)	-1.94 ± 4.891
Left Knee Extensor Visit 154 (N = 12)	-2.51 ± 4.516
Left Knee Extensor Visit 166 (N = 12)	-2.23 ± 4.845
Left Knee Extensor Visit 178 (N = 12)	-2.15 ± 3.967
Left Knee Extensor Visit 190 (N = 11)	-3.53 ± 2.770
Right Knee Extensor Visit 21 (N = 12)	-0.47 ± 2.534
Right Knee Extensor Visit 25 (N = 12)	-0.62 ± 3.525
Right Knee Extensor Visit 29 (N = 12)	-1.80 ± 2.842
Right Knee Extensor Visit 33 (N = 11)	-1.26 ± 2.045
Right Knee Extensor Visit 37 (N = 11)	-2.65 ± 2.040
Right Knee Extensor Visit 41 (N = 11)	-1.52 ± 3.095
Right Knee Extensor Visit 49 (N = 12)	-1.02 ± 3.939
Right Knee Extensor Visit 61 (N = 12)	-3.35 ± 4.414
Right Knee Extensor Visit 73 (N = 12)	-1.77 ± 4.162
Right Knee Extensor Visit 85 (N = 11)	-2.25 ± 4.913
Right Knee Extensor Visit 93 (N = 12)	-2.28 ± 3.753
Right Knee Extensor Visit 106 (N = 12)	-2.24 ± 3.677
Right Knee Extensor Visit 118 (N = 12)	-2.61 ± 4.893
Right Knee Extensor Visit 130 (N = 11)	-3.04 ± 3.712
Right Knee Extensor Visit 142 (N = 12)	-1.99 ± 5.538
Right Knee Extensor Visit 154 (N = 12)	-4.22 ± 7.410
Right Knee Extensor Visit 166 (N = 12)	-2.89 ± 6.024
Right Knee Extensor Visit 178 (N = 11)	-3.17 ± 5.167
Right Knee Extensor Visit 190 (N = 11)	-4.41 ± 5.490

No statistical analyses for this end point

Primary: Change from Baseline Spirometry of Forced vital capacity (FVC) and Forced expiratory volume in 1 second (FEV1) in Continued Treatment phase

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End point title

Change from Baseline Spirometry of Forced vital capacity (FVC) and Forced expiratory volume in 1 second (FEV1) in Continued Treatment phase ^[27]

End point description

Intention-to-Treat (ITT) Population Visit 93 to 190 indicate visits during washout

End point type

Primary

End point timeframe

At Visit 21, 25, 29, 33, 37, 41, 49, 61, 73, 85, 93, 106, 118, 130, 142, 154, 166, 178 and 190

Notes
[27] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were conducted.

End point values	Continued Treatment phase - 6 mg/kg
Number of subjects analysed	12
Units: Litre
arithmetic mean (standard deviation)
FVC absolute Visit 21 (N = 12)	0.008 ± 0.1472
FVC absolute Visit 25 (N = 12)	-0.030 ± 0.1563
FVC absolute Visit 29 (N = 11)	0.029 ± 0.2077
FVC absolute Visit 33 (N = 12)	0.023 ± 0.1795
FVC absolute Visit 37 (N = 11)	0.039 ± 0.2944
FVC absolute Visit 41 (N = 12)	0.048 ± 0.2166
FVC absolute Visit 49 (N = 12)	0.058 ± 0.1593
FVC absolute Visit 61 (N = 12)	0.079 ± 0.2553
FVC absolute Visit 73 (N = 12)	0.078 ± 0.1927
FVC absolute Visit 85 (N = 12)	0.045 ± 0.2135
FVC absolute Visit 93 (N = 12)	0.061 ± 0.1507
FVC absolute Visit 106 (N = 12)	0.150 ± 0.1897
FVC absolute Visit 118 (N = 12)	0.092 ± 0.2661
FVC absolute Visit 130 (N = 12)	0.073 ± 0.3290
FVC absolute Visit 142 (N = 12)	0.066 ± 0.2423
FVC absolute Visit 154 (N = 11)	0.053 ± 0.2172
FVC absolute Visit 166 (N = 12)	0.057 ± 0.2833
FVC absolute Visit 178 (N = 12)	0.063 ± 0.2843
FVC absolute Visit 190 (N = 12)	0.057 ± 0.2891
FEV1 absolute Visit 21 (N = 12)	-0.006 ± 0.2193
FEV1 absolute Visit 25 (N = 12)	-0.040 ± 0.1861
FEV1 absolute Visit 29 (N = 11)	0.032 ± 0.1542
FEV1 absolute Visit 33 (N = 12)	0.036 ± 0.1841
FEV1 absolute Visit 37 (N = 11)	0.035 ± 0.2536
FEV1 absolute Visit 41 (N = 12)	0.025 ± 0.2121
FEV1 absolute Visit 49 (N = 12)	0.058 ± 0.1668
FEV1 absolute Visit 61 (N = 12)	0.066 ± 0.2619
FEV1 absolute Visit 73 (N = 12)	0.089 ± 0.1723
FEV1 absolute Visit 85 (N = 12)	0.029 ± 0.1900
FEV1 absolute Visit 93 (N = 12)	0.043 ± 0.1307
FEV1 absolute Visit 106 (N = 12)	0.134 ± 0.1787
FEV1 absolute Visit 118 (N = 12)	0.109 ± 0.2309
FEV1 absolute Visit 130 (N = 12)	0.076 ± 0.3121
FEV1 absolute Visit 142 (N = 12)	0.068 ± 0.2207
FEV1 absolute Visit 154 (N = 11)	0.052 ± 0.1670
FEV1 absolute Visit 166 (N = 12)	0.078 ± 0.2583
FEV1 absolute Visit 178 (N = 12)	0.099 ± 0.2562
FEV1 absolute Visit 190 (N = 12)	0.065 ± 0.2878

No statistical analyses for this end point

Primary: Change from Baseline Spirometry of maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) in Continued Treatment phase

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End point title

Change from Baseline Spirometry of maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) in Continued Treatment phase ^[28]

End point description

Intention-to-Treat (ITT) Population Visit 93 to 190 indicate visits during washout

End point type

Primary

End point timeframe

At Visit 21, 25, 29, 33, 37, 41, 49, 61, 73, 85, 93, 106, 118, 130, 142, 154, 166, 178 and 190

Notes
[28] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were conducted.

End point values	Continued Treatment phase - 6 mg/kg
Number of subjects analysed	12
Units: cm H2O
arithmetic mean (standard deviation)
MIP absolute Visit 21 (N = 12)	4.0 ± 15.82
MIP absolute Visit 25 (N = 12)	-3.7 ± 14.00
MIP absolute Visit 29 (N = 11)	6.4 ± 18.51
MIP absolute Visit 33 (N = 12)	-1.8 ± 12.88
MIP absolute Visit 37 (N = 11)	-6.1 ± 28.58
MIP absolute Visit 41 (N = 12)	1.5 ± 12.31
MIP absolute Visit 49 (N = 12)	-5.1 ± 14.98
MIP absolute Visit 61 (N = 12)	-3.3 ± 12.04
MIP absolute Visit 73 (N = 12)	0.4 ± 15.51
MIP absolute Visit 85 (N = 12)	1.8 ± 15.15
MIP absolute Visit 93 (N = 12)	1.2 ± 14.12
MIP absolute Visit 106 (N = 12)	-7.7 ± 17.59
MIP absolute Visit 118 (N = 12)	-7.0 ± 17.92
MIP absolute Visit 130 (N = 12)	-2.8 ± 15.46
MIP absolute Visit 142 (N = 12)	3.3 ± 22.06
MIP absolute Visit 154 (N = 11)	5.5 ± 19.21
MIP absolute Visit 166 (N = 12)	-0.3 ± 17.51
MIP absolute Visit 178 (N = 12)	0.8 ± 15.64
MIP absolute Visit 190 (N = 12)	3.7 ± 21.96
MEP absolute Visit 21 (N = 12)	-11.2 ± 14.55
MEP absolute Visit 25 (N = 12)	-3.3 ± 13.01
MEP absolute Visit 29 (N = 11)	-3.5 ± 14.40
MEP absolute Visit 33 (N = 12)	-3.6 ± 14.23
MEP absolute Visit 37 (N = 11)	-2.7 ± 15.28
MEP absolute Visit 41 (N = 12)	-7.6 ± 19.24
MEP absolute Visit 49 (N = 12)	-5.7 ± 13.96
MEP absolute Visit 61 (N = 12)	-8.7 ± 15.98
MEP absolute Visit 73 (N = 12)	-6.0 ± 14.55
MEP absolute Visit 85 (N = 12)	-9.6 ± 14.32
MEP absolute Visit 93 (N = 12)	-11.9 ± 15.72
MEP absolute Visit 106 (N = 12)	-0.8 ± 13.18
MEP absolute Visit 118 (N = 12)	-0.5 ± 16.01
MEP absolute Visit 130 (N = 12)	-7.6 ± 13.58
MEP absolute Visit 142 (N = 12)	-12.5 ± 13.14
MEP absolute Visit 154 (N = 11)	-12.7 ± 17.72
MEP absolute Visit 166 (N = 12)	-2.6 ± 19.09
MEP absolute Visit 178 (N = 12)	-5.7 ± 14.95
MEP absolute Visit 190 (N = 12)	-11.4 ± 16.71

No statistical analyses for this end point

Primary: Change from Baseline Spirometry of Peak flow (PF) and Peak cough flow (PCF) in Continued Treatment phase

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End point title

Change from Baseline Spirometry of Peak flow (PF) and Peak cough flow (PCF) in Continued Treatment phase ^[29]

End point description

Intention-to-Treat (ITT) Population Visit 93 to 190 indicate visits during washout

End point type

Primary

End point timeframe

At Visit 21, 25, 29, 33, 37, 41, 49, 61, 73, 85, 93, 106, 118, 130, 142, 154, 166, 178 and 190

Notes
[29] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analyses were conducted.

End point values	Continued Treatment phase - 6 mg/kg
Number of subjects analysed	12
Units: L/min
arithmetic mean (standard deviation)
PF absolute Visit 21 (N = 12)	-3.7 ± 22.38
PF absolute Visit 25 (N = 9)	-45.8 ± 29.45
PF absolute Visit 29 (N = 9)	13.7 ± 24.05
PF absolute Visit 33 (N = 12)	9.0 ± 45.58
PF absolute Visit 37 (N = 11)	-2.1 ± 51.17
PF absolute Visit 41 (N = 12)	-1.3 ± 36.88
PF absolute Visit 49 (N = 12)	15.4 ± 40.37
PF absolute Visit 61 (N = 12)	12.9 ± 54.04
PF absolute Visit 73 (N = 12)	12.6 ± 36.53
PF absolute Visit 85 (N = 12)	9.0 ± 41.13
PF absolute Visit 93 (N = 12)	37.8 ± 54.20
PF absolute Visit 106 (N = 12)	26.1 ± 44.65
PF absolute Visit 118 (N = 11)	31.7 ± 39.46
PF absolute Visit 130 (N = 12)	35.5 ± 40.95
PF absolute Visit 142 (N = 12)	27.8 ± 53.54
PF absolute Visit 154 (N = 11)	33.5 ± 34.17
PF absolute Visit 166 (N = 9)	20.9 ± 33.07
PF absolute Visit 178 (N = 12)	22.8 ± 42.55
PF absolute Visit 190 (N = 12)	9.4 ± 73.06
PCF absolute Visit 21 (N = 12)	-4.7 ± 65.20
PCF absolute Visit 25 (N = 12)	-6.7 ± 51.93
PCF absolute Visit 29 (N = 11)	30.9 ± 55.04
PCF absolute Visit 33 (N = 12)	19.2 ± 53.16
PCF absolute Visit 37 (N = 11)	19.1 ± 47.63
PCF absolute Visit 41 (N = 12)	29.2 ± 63.60
PCF absolute Visit 49 (N = 12)	44.2 ± 58.38
PCF absolute Visit 61 (N = 12)	19.2 ± 55.83
PCF absolute Visit 73 (N = 12)	41.7 ± 66.68
PCF absolute Visit 85 (N = 12)	34.2 ± 66.26
PCF absolute Visit 93 (N = 12)	50.0 ± 67.01
PCF absolute Visit 106 (N = 12)	31.7 ± 53.06
PCF absolute Visit 118 (N = 12)	45.8 ± 51.60
PCF absolute Visit 130 (N = 12)	70.0 ± 65.51
PCF absolute Visit 142 (N = 12)	52.5 ± 69.17
PCF absolute Visit 154 (N = 11)	50.0 ± 59.33
PCF absolute Visit 166 (N = 12)	42.5 ± 72.13
PCF absolute Visit 178 (N = 12)	42.5 ± 66.35
PCF absolute Visit 190 (N = 12)	22.5 ± 81.14

No statistical analyses for this end point

Primary: Responses Summary of Parent Questionnaire to change in condition over the Continued Treatment phase

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End point title

Responses Summary of Parent Questionnaire to change in condition over the Continued Treatment phase ^[30]

End point description

Intention-to-Treat (ITT) Population The questionnaires completed at either 4 or 5 visits depending on the study site and the actual visit number varied between subjects.

End point type

Primary

End point timeframe

At Visit 81 to 89, Visit 109 to 123, Visit 154 to 157 and Visit 178

Notes
[30] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were conducted.

End point values	Continued Treatment phase - 6 mg/kg
Number of subjects analysed	12
Units: Number of subjects
General condition: Better at Visit 81-89 (N=11)	4
General condition: Same at Visit 81-89 (N=11)	5
General condition: Worse Visit 81-89 (N=11)	2
General condition: Better at Visit 109-123 (N=12)	3
General condition: Same at Visit 109-123 (N=12)	5
General condition: Worse at Visit 109-123 (N=12)	4
General condition: Better at Visit 154-157 (N=11)	1
General condition: Same at Visit 154-157 (N=11)	4
General condition: Worse at Visit 154-157 (N=11)	6
General condition: Better at Visit 178 (N=12)	1
General condition: Same at Visit 178 (N=12)	8
General condition: Worse at Visit 178 (N=12)	3
Walking: Better at Visit 81-89 (N=11)	4
Walking: Same at Visit 81-89 (N=11)	5
Walking: Worse at Visit 81-89 (N=11)	2
Walking: Better at Visit 109-123 (N=12)	3
Walking: Same Visit at 109-123 (N=12)	5
Walking: Worse Visit at 109-123 (N=12)	4
Walking: Better at Visit 154-157 (N=12)	2
Walking: Same at Visit 154-157 (N=12)	6
Walking: Worse at Visit 154-157 (N=12)	4
Walking: Better at Visit 178 (N=12)	1
Walking: Same at Visit 178 (N=12)	6
Walking: Worse at Visit 178 (N=12)	5
Taking stairs: Better at Visit 81-89 (N=11)	3
Taking stairs: Same at Visit 81-89 (N=11)	3
Taking stairs: Worse at Visit 81-89 (N=11)	5
Taking stairs: Better at Visit 109-123 (N=12)	1
Taking stairs: Same Visit at 109-123 (N=12)	6
Taking stairs: Worse Visit at 109-123 (N=12)	5
Taking stairs: Better at Visit 154-157 (N=12)	1
Taking stairs: Same at Visit 154-157 (N=12)	4
Taking stairs: Worse at Visit 154-157 (N=12)	7
Taking stairs: Better at Visit 178 (N=12)	1
Taking stairs: Same at Visit 178 (N=12)	3
Taking stairs: Worse at Visit 178 (N=12)	8
Endurance: Better at Visit 81-89 (N=11)	4
Endurance: Same at Visit 81-89 (N=11)	7
Endurance: Worse at Visit 81-89 (N=11)	0
Endurance: Better at Visit 109-123 (N=12)	0
Endurance: Same Visit at 109-123 (N=12)	10
Endurance: Worse Visit at 109-123 (N=12)	2
Endurance: Better at Visit 154-157 (N=12)	2
Endurance: Same at Visit 154-157 (N=12)	7
Endurance: Worse at Visit 154-157 (N=12)	3
Endurance: Better at Visit 178 (N=12)	2
Endurance: Same at Visit 178 (N=12)	8
Endurance: Worse at Visit 178 (N=12)	2

No statistical analyses for this end point

Primary: Muscle Biopsy Summary of Exon 51 Skip in Continued Treatment phase

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End point title

Muscle Biopsy Summary of Exon 51 Skip in Continued Treatment phase ^[31]

End point description

Intention-to-Treat (ITT) Population Y = Clear exon 51 skipping observed, confirmed by sequencing * = Sequence skip confirmed after additional Polymerase Chain Reaction, despite low quality Ribonucleic Acid RT-PCR (Reverse Transcription-Polymerase Chain Reaction)

End point type

Primary

End point timeframe

At Visit 37

Notes
[31] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were conducted.

End point values	Continued Treatment phase - 6 mg/kg
Number of subjects analysed	12
Units: Number of Subjects
Exon skip by RT_PCR – Y	6
Exon skip by RT_PCR - Y*	6

No statistical analyses for this end point

Primary: Muscle Biopsy Summary of Immunofluorescence Qualitative Dystrophin Expression in Continued Treatment phase

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End point title

Muscle Biopsy Summary of Immunofluorescence Qualitative Dystrophin Expression in Continued Treatment phase ^[32]

End point description

Intention-to-Treat (ITT) Population Y = dystrophin protein detected at the sarcolemmal membrane No result = poor quality not allowing analysis

End point type

Primary

End point timeframe

At Visit 37

Notes
[32] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were conducted.

End point values	Continued Treatment phase - 6 mg/kg
Number of subjects analysed	12
Units: Number of Subjects
Immunofluorescence – Y	10
Immunofluorescence - No result	2

No statistical analyses for this end point

Primary: Muscle Biopsy Summary of Western Blot Qualitative Dystrophin Expression in Continued Treatment phase

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End point title

Muscle Biopsy Summary of Western Blot Qualitative Dystrophin Expression in Continued Treatment phase ^[33]

End point description

Intention-to-Treat (ITT) Population Y = suggestive increase of dystrophin levels when compared to earlier visit biopsies and/or pre-treatment samples N = no clear increase of dystrophin levels when compared to earlier visit No result = protein degradation not allowing analysis Inconclusive = no conclusion to be drawn due to presence of revertant fibres or lacking/conflicting data in subsequent experiments # Compared to earlier sample (on the same gel) from the initial study period

End point type

Primary

End point timeframe

At Visit 37

Notes
[33] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were conducted.

End point values	Continued Treatment phase - 6 mg/kg
Number of subjects analysed	12
Units: Number of Subjects
Western Blot – N	1
Western Blot - Y	5
Western Blot – Inconclusive	3
Western Blot - No result (degraded)	3

No statistical analyses for this end point

Secondary: Maximum Observed Plasma Concentration (Cmax) of Drisapersen during Initial Study Period

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End point title

Maximum Observed Plasma Concentration (Cmax) of Drisapersen during Initial Study Period

End point description

Pharmacokinetic (PK) sample are all treated subjects who had at least one PK assessment post-baseline. Pharmacokinetic Parameter Cmax (Maximum measured plasma concentration)

End point type

Secondary

End point timeframe

0.5, 2, 3, 4, 6, 9, 12 and 24 ±3 hours

End point values	Group I - 0.5 mg/kg	Group II - 2 mg/kg	Group III - 4 mg/kg	Group IV - 6 mg/kg
Number of subjects analysed	3	3	3	3
Units: µg/mL
arithmetic mean (standard deviation)
Day 1	1.98 ± 1.38	4.09 ± 2.45	5.28 ± 0.38	9.36 ± 2.68
Day 29	1.03 ± 0.22	4.41 ± 1.86	7.18 ± 3.06	11.20 ± 2.30

No statistical analyses for this end point

Secondary: Time to Maximum Observed Concentration (Tmax) of Drisapersen during Initial Study Period

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End point title

Time to Maximum Observed Concentration (Tmax) of Drisapersen during Initial Study Period

End point description

Pharmacokinetic (PK) sample Pharmacokinetic Parameter (Tmax) Time of the maximum measured plasma concentration.

End point type

Secondary

End point timeframe

0.5, 2, 3, 4, 6, 9, 12 and 24 ±3 hours

End point values	Group I - 0.5 mg/kg	Group II - 2 mg/kg	Group III - 4 mg/kg	Group IV - 6 mg/kg
Number of subjects analysed	3	3	3	3
Units: hr
arithmetic mean (standard deviation)
Day 1	2.67 ± 0.58	4.56 ± 3.53	2.33 ± 0.58	3.22 ± 2.26
Day 29	2.33 ± 0.58	1.89 ± 1.33	2.39 ± 0.54	2.03 ± 0.05

No statistical analyses for this end point

Secondary: Plasma concentration measured 7 days after the injection(Ctrough-D7) of Drisapersen during Initial Study Period

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End point title

Plasma concentration measured 7 days after the injection(Ctrough-D7) of Drisapersen during Initial Study Period ^[34]

End point description

Pharmacokinetic (PK) sample Pharmacokinetic Parameter Ctrough-D7 is the Plasma concentration measured 7 days after the injection.

End point type

Secondary

End point timeframe

0.5, 2, 3, 4, 6, 9, 12 and 24 ±3 hours

Notes
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No formal statistical analyses were conducted.

End point values	Group II - 2 mg/kg	Group III - 4 mg/kg	Group IV - 6 mg/kg
Number of subjects analysed	3	3	3
Units: µg/mL
arithmetic mean (standard deviation)
Day 1	0.0026 ± 0.0006	0.0024 ± 0.0012	0.0064 ± 0.0061
Day 29	0.0047 ± 0.0027	0.0075 ± 0.0045	0.0150 ± 0.0056

No statistical analyses for this end point

Secondary: Area under the plasma concentration-time curve from time 0 to 24h(AUC0-24h) of Drisapersen during Initial Study Period

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End point title

Area under the plasma concentration-time curve from time 0 to 24h(AUC0-24h) of Drisapersen during Initial Study Period

End point description

Pharmacokinetic (PK) sample Pharmacokinetic Parameter AUC0-24h Area under the plasma concentration-time curve from time 0 to 24 h.

End point type

Secondary

End point timeframe

0.5, 2, 3, 4, 6, 9, 12 and 24 ±3 hours

End point values	Group I - 0.5 mg/kg	Group II - 2 mg/kg	Group III - 4 mg/kg	Group IV - 6 mg/kg
Number of subjects analysed	3	3	3	3
Units: h*µg/mL
arithmetic mean (standard deviation)
Day 1	7.6 ± 1.7	27.0 ± 2.3	41.0 ± 5.4	78.9 ± 21.7
Day 29	5.9 ± 1.1	26.1 ± 4.1	44.8 ± 9.6	106.0 ± 29.8

No statistical analyses for this end point

Secondary: Area under the plasma concentration-time curve during one dosing interval (AUC0-D7) of Drisapersen during Initial Study Period

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End point title

Area under the plasma concentration-time curve during one dosing interval (AUC0-D7) of Drisapersen during Initial Study Period

End point description

Pharmacokinetic (PK) sample Pharmacokinetic Parameter AUC0-D7 is the Area under the plasma concentration-time curve during one dosing interval.

End point type

Secondary

End point timeframe

0.5, 2, 3, 4, 6, 9, 12 and 24 ±3 hours

End point values	Group I - 0.5 mg/kg	Group II - 2 mg/kg	Group III - 4 mg/kg	Group IV - 6 mg/kg
Number of subjects analysed	3	3	3	3
Units: h*µg/mL
arithmetic mean (standard deviation)
Day 1	8.8 ± 2.6	30.6 ± 4.2	45.4 ± 5.7	93.1 ± 32.2
Day 29	6.2 ± 1.0	29.7 ± 7.5	52.7 ± 18.7	126.7 ± 31.7

No statistical analyses for this end point

Secondary: Apparent plasma clearance (CL/F) of Drisapersen during Initial Study Period

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End point title

Apparent plasma clearance (CL/F) of Drisapersen during Initial Study Period

End point description

Pharmacokinetic (PK) sample Pharmacokinetic Parameter CL/F is the Apparent plasma clearance.

End point type

Secondary

End point timeframe

0.5, 2, 3, 4, 6, 9, 12 and 24 ±3 hours

End point values	Group I - 0.5 mg/kg	Group II - 2 mg/kg	Group III - 4 mg/kg	Group IV - 6 mg/kg
Number of subjects analysed	3	3	3	3
Units: mL/min
arithmetic mean (standard deviation)
Day 1	26.6 ± 6.3	33.8 ± 12.9	31.5 ± 7.5	34.6 ± 11.7
Day 29	39.2 ± 13.5	35.0 ± 9.0	29.1 ± 13.1	24.6 ± 5.5

No statistical analyses for this end point

Secondary: Maximum Observed Plasma Concentration (Cmax) of Drisapersen during Continued Treatment phase

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End point title

Maximum Observed Plasma Concentration (Cmax) of Drisapersen during Continued Treatment phase

End point description

Pharmacokinetic (PK) Population are all subjects who had a PK blood sample collected and analyzed for drisapersen. Pharmacokinetic Parameter Cmax (Maximum measured plasma concentration)

End point type

Secondary

End point timeframe

0.5 hr (± 5 min), 2 hr (± 15 min), 3 hr (± 15 min), 4 hr (± 15 min), 6 hr (± 15 min), 9 hr (± 30 min), 12 hr (± 30 min) and 24 hr (±3 hrs) at Visit 33.

End point values	Continued Treatment phase - 6 mg/kg
Number of subjects analysed	12
Units: ng/mL
arithmetic mean (standard deviation)	9410.83 ± 4051.38

No statistical analyses for this end point

Secondary: Time to Maximum Observed Concentration (Tmax) of Drisapersen during Continued Treatment phase

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End point title

Time to Maximum Observed Concentration (Tmax) of Drisapersen during Continued Treatment phase

End point description

Pharmacokinetic (PK) population Pharmacokinetic Parameter (Tmax) Time of the maximum measured plasma concentration.

End point type

Secondary

End point timeframe

0.5 hr (± 5 min), 2 hr (± 15 min), 3 hr (± 15 min), 4 hr (± 15 min), 6 hr (± 15 min), 9 hr (± 30 min), 12 hr (± 30 min) and 24 hr (±3 hrs) at Visit 33.

End point values	Continued Treatment phase - 6 mg/kg
Number of subjects analysed	12
Units: hr
arithmetic mean (standard deviation)	3.987 ± 2.758

No statistical analyses for this end point

Secondary: Area under the plasma concentration-time curve from time 0 to 24h(AUC0-24h) of Drisapersen during Continued Treatment phase

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End point title

Area under the plasma concentration-time curve from time 0 to 24h(AUC0-24h) of Drisapersen during Continued Treatment phase

End point description

Pharmacokinetic (PK) population. Pharmacokinetic Parameter AUC0-24h Area under the plasma concentration-time curve from time 0 to 24 h.

End point type

Secondary

End point timeframe

0.5 hr (± 5 min), 2 hr (± 15 min), 3 hr (± 15 min), 4 hr (± 15 min), 6 hr (± 15 min), 9 hr (± 30 min), 12 hr (± 30 min) and 24 hr (±3 hrs) at Visit 33.

End point values	Continued Treatment phase - 6 mg/kg
Number of subjects analysed	12
Units: h*ng/mL
arithmetic mean (standard deviation)	110693 ± 45227.8

No statistical analyses for this end point

Secondary: Apparent plasma clearance (CL/F) of Drisapersen during Continued Treatment phase

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End point title

Apparent plasma clearance (CL/F) of Drisapersen during Continued Treatment phase

End point description

Pharmacokinetic (PK) population Pharmacokinetic Parameter CL/F is the Apparent plasma clearance.

End point type

Secondary

End point timeframe

0.5 hr (± 5 min), 2 hr (± 15 min), 3 hr (± 15 min), 4 hr (± 15 min), 6 hr (± 15 min), 9 hr (± 30 min), 12 hr (± 30 min) and 24 hr (±3 hrs) at Visit 33.

End point values	Continued Treatment phase - 6 mg/kg
Number of subjects analysed	12
Units: mL/min
arithmetic mean (standard deviation)	28.675 ± 6.527

No statistical analyses for this end point

Secondary: Cpre of Drisapersen during Continued Treatment phase

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End point title

Cpre of Drisapersen during Continued Treatment phase

End point description

Pharmacokinetic (PK) Population

End point type

Secondary

End point timeframe

0.5 hr (± 5 min), 2 hr (± 15 min), 3 hr (± 15 min), 4 hr (± 15 min), 6 hr (± 15 min), 9 hr (± 30 min), 12 hr (± 30 min) and 24 hr (±3 hrs) at Visit 33.

End point values	Continued Treatment phase - 6 mg/kg
Number of subjects analysed	12
Units: ng/mL
arithmetic mean (standard deviation)	111.417 ± 105.947

No statistical analyses for this end point

Secondary: C34 of Drisapersen during Continued Treatment phase

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End point title

C34 of Drisapersen during Continued Treatment phase

End point description

Pharmacokinetic (PK) Population

End point type

Secondary

End point timeframe

0.5 hr (± 5 min), 2 hr (± 15 min), 3 hr (± 15 min), 4 hr (± 15 min), 6 hr (± 15 min), 9 hr (± 30 min), 12 hr (± 30 min) and 24 hr (±3 hrs) at Visit 33.

End point values	Continued Treatment phase - 6 mg/kg
Number of subjects analysed	12
Units: ng/mL
arithmetic mean (standard deviation)	1697.92 ± 1784.74

No statistical analyses for this end point

Secondary: Maximum Observed Plasma Concentration (Cmax) of Drisapersen during IV sub-study

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End point title

Maximum Observed Plasma Concentration (Cmax) of Drisapersen during IV sub-study

End point description

Pharmacokinetic (PK) Population Pharmacokinetic Parameter Cmax (Maximum measured plasma concentration)

End point type

Secondary

End point timeframe

Predose, 1, 2, 4, 6, 10.5 and 24hrs at Visit 202, 205, 208, 211 and 214

End point values	IV sub-study - 0.5 mg/kg over 4 hours	IV sub-study - 1.4 mg/kg over 4 hours	IV sub-study - 2.7 mg/kg over 4 hours	IV sub-study - 2.7 mg/kg over 2 hours	IV sub-study - 2.7 mg/kg over 1 hour
Number of subjects analysed	7	7	7	7	7
Units: ng/mL
arithmetic mean (standard deviation)	1784.02 ± 549.816	5222.78 ± 1413.38	9907.50 ± 1952.11	14652.3 ± 3056.57	22261.3 ± 2556.72

No statistical analyses for this end point

Secondary: C24 of Drisapersen during IV sub-study

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End point title

C24 of Drisapersen during IV sub-study

End point description

Pharmacokinetic (PK) Population

End point type

Secondary

End point timeframe

Predose, 1, 2, 4, 6, 10.5 and 24hrs at Visit 202, Visit 205, Visit 208, Visit 211 and Visit 214

End point values	IV sub-study - 0.5 mg/kg over 4 hours	IV sub-study - 1.4 mg/kg over 4 hours	IV sub-study - 2.7 mg/kg over 4 hours	IV sub-study - 2.7 mg/kg over 2 hours	IV sub-study - 2.7 mg/kg over 1 hour
Number of subjects analysed	7	7	7	7	7
Units: ng/mL
arithmetic mean (standard deviation)	73.874 ± 88.310	105.001 ± 78.786	146.959 ± 98.241	130.147 ± 111.516	113.353 ± 114.984

No statistical analyses for this end point

Secondary: C168 of Drisapersen during IV sub-study

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End point title

C168 of Drisapersen during IV sub-study

End point description

Intention-to-Treat (ITT) Population

End point type

Secondary

End point timeframe

Predose, 1, 2, 4, 6, 10.5 and 24hrs at Visit 202, Visit 205, Visit 208, Visit 211 and Visit 214

End point values	IV sub-study - 0.5 mg/kg over 4 hours	IV sub-study - 1.4 mg/kg over 4 hours	IV sub-study - 2.7 mg/kg over 4 hours	IV sub-study - 2.7 mg/kg over 2 hours
Number of subjects analysed	7	7	7	7
Units: ng/mL
arithmetic mean (standard deviation)	50.270 ± 41.325	47.811 ± 39.649	56.637 ± 60.946	62.123 ± 81.155

No statistical analyses for this end point

Secondary: Time to Maximum Observed Concentration (Tmax) of Drisapersen during IV sub-study

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End point title

Time to Maximum Observed Concentration (Tmax) of Drisapersen during IV sub-study

End point description

Pharmacokinetic (PK) population Pharmacokinetic Parameter (Tmax) Time of the maximum measured plasma concentration

End point type

Secondary

End point timeframe

Predose, 1, 2, 4, 6, 10.5 and 24hrs at Visit 202, Visit 205, Visit 208, Visit 211 and Visit 214

End point values	IV sub-study - 0.5 mg/kg over 4 hours	IV sub-study - 1.4 mg/kg over 4 hours	IV sub-study - 2.7 mg/kg over 4 hours	IV sub-study - 2.7 mg/kg over 2 hours	IV sub-study - 2.7 mg/kg over 1 hour
Number of subjects analysed	7	7	7	7	7
Units: hr
arithmetic mean (standard deviation)	4.120 ± 0.112	3.709 ± 0.721	3.519 ± 0.941	1.926 ± 0.428	1.003 ± 0.014

No statistical analyses for this end point

Secondary: Area under the plasma concentration-time curve from time 0 to24h(AUC0-24h) of Drisapersen during IV sub-study

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End point title

Area under the plasma concentration-time curve from time 0 to24h(AUC0-24h) of Drisapersen during IV sub-study

End point description

Pharmacokinetic (PK) population. Pharmacokinetic Parameter AUC0-24h Area under the plasma concentration-time curve from time 0 to 24 h.

End point type

Secondary

End point timeframe

Predose, 1, 2, 4, 6, 10.5 and 24hrs at Visit 202, Visit 205, Visit 208, Visit 211 and Visit 214

End point values	IV sub-study - 0.5 mg/kg over 4 hours	IV sub-study - 1.4 mg/kg over 4 hours	IV sub-study - 2.7 mg/kg over 4 hours	IV sub-study - 2.7 mg/kg over 2 hours	IV sub-study - 2.7 mg/kg over 1 hour
Number of subjects analysed	7	7	7	7	7
Units: h*ng/mL
arithmetic mean (standard deviation)	9240.92 ± 3921.20	26499.0 ± 8043.45	51038.5 ± 12998.2	50439.6 ± 13034.3	48330.0 ± 12668.8

No statistical analyses for this end point

Secondary: AUC0-168 of Drisapersen during IV sub-study

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End point title

AUC0-168 of Drisapersen during IV sub-study

End point description

Pharmacokinetic (PK) population

End point type

Secondary

End point timeframe

Predose, 1, 2, 4, 6, 10.5 and 24hrs at Visit 202, Visit 205, Visit 208, Visit 211 and Visit 214

End point values	IV sub-study - 0.5 mg/kg over 4 hours	IV sub-study - 1.4 mg/kg over 4 hours	IV sub-study - 2.7 mg/kg over 4 hours	IV sub-study - 2.7 mg/kg over 2 hours
Number of subjects analysed	7	7	7	7
Units: h*ng/mL
arithmetic mean (standard deviation)	17961.7 ± 12357.8	36804.6 ± 15267.7	64647.6 ± 23937.2	63386.7 ± 24050.7

No statistical analyses for this end point

Secondary: Number of Subjects with Treatment Emergent Adverse Events during Continued Treatment phase

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End point title

Number of Subjects with Treatment Emergent Adverse Events during Continued Treatment phase

End point description

Safety population Related indicate as definite, probable or possible (or missing) Intensity was determined by the Investigator. For symptomatic AEs the following definitions were applied. Mild = AE did not limit usual activities; subject may have experienced slight discomfort. Moderate = AE resulted in some limitation of usual activities; subject may have experienced significant discomfort. Severe = AE resulted in an inability to carry out usual activities; subject may have experienced intolerable discomfort/pain. Relationship to Investigational Medicinal Products (IMP) Unlikely = Slight, but remote, chance that AE was caused by IMP. Possible = Reasonable suspicion that the AE was caused by IMP. Probable = Most likely that AE was caused by IMP.

End point type

Secondary

End point timeframe

Up to Visit 205

End point values	Continued Treatment phase - 6 mg/kg
Number of subjects analysed	12
Units: Participants
Severity: Mild	2
Severity: Moderate	5
Severity: Severe	5
Drug Related Serious Adverse Event	0
Drug Related Adverse Event	12

No statistical analyses for this end point

Secondary: Number of Subjects with Treatment Emergent Adverse Events during IV sub-study

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End point title

Number of Subjects with Treatment Emergent Adverse Events during IV sub-study

End point description

End point type

Secondary

End point timeframe

Up to Visit 229

End point values	IV Sub-Set - All Doses
Number of subjects analysed	7
Units: Participants
Severity: Mild	3
Severity: Moderate	3
Severity: Severe	1
Drug Related Serious Adverse Event	0
Drug Related Adverse Event	7

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to Visit 229

Adverse event reporting additional description

MedDRA 11.0, 11.1 and 12.0 used for the Group I - 0.5 mg/kg, Group II - 2 mg/kg, Group III - 4 mg/kg and Group IV - 6 mg/kg Adverse Event.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

12.1

Reporting group title

Group I - 0.5 mg/kg

Reporting group description

Reporting group title

Group II - 2 mg/kg

Reporting group description

Reporting group title

Group III - 4 mg/kg

Reporting group description

Reporting group title

Group IV - 6 mg/kg

Reporting group description

Reporting group title

Continued Treatment phase - 6 mg/kg

Reporting group description

Reporting group title

IV sub-study

Reporting group description

Serious adverse events	Group I - 0.5 mg/kg	Group II - 2 mg/kg	Group III - 4 mg/kg	Group IV - 6 mg/kg	Continued Treatment phase - 6 mg/kg	IV sub-study
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 12 (41.67%)	1 / 7 (14.29%)
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
Tibia fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (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
Femur fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (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
Surgical and medical procedures
Postoperative care
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (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
Nervous system disorders
Convulsion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (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
Ear and labyrinth disorders
Tympanic membrane perforation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (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
Reproductive system and breast disorders
Scrotal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (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
Gastrointestinal disorders
Gastritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 7 (14.29%)
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
Musculoskeletal and connective tissue disorders
Tendinous contracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (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
Scoliosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (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

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Group I - 0.5 mg/kg	Group II - 2 mg/kg	Group III - 4 mg/kg	Group IV - 6 mg/kg	Continued Treatment phase - 6 mg/kg	IV sub-study
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	12 / 12 (100.00%)	7 / 7 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0
Vascular disorders
Haematoma
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Hypertension
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0
Surgical and medical procedures
Tooth extraction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Postoperative care
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
General disorders and administration site conditions
Injection site bruising
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	0 / 3 (0.00%)	3 / 3 (100.00%)	0 / 12 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	2	0	7	0	0
Peripheral swelling
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0
Injection site induration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	12 / 12 (100.00%)	4 / 7 (57.14%)
occurrences all number	0	0	0	0	41	7
Injection site atrophy
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 12 (50.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	8	0
Injection site pruritus
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 12 (50.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	15	0
Injection site discolouration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	9 / 12 (75.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	33	0
Injection site erosion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Injection site pain
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 3 (66.67%)	2 / 3 (66.67%)	10 / 12 (83.33%)	0 / 7 (0.00%)
occurrences all number	1	2	2	3	58	0
Injection site erythema
subjects affected / exposed	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	12 / 12 (100.00%)	4 / 7 (57.14%)
occurrences all number	6	5	9	18	60	7
Injection site inflammation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	11	1
Injection site vesicles
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Injection site ulcer
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	6	0
Injection site nodule
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	9 / 12 (75.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	20	0
Injection site dryness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 3 (100.00%)	0 / 12 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	5	0	0
Influenza like illness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	11	0
Chills
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	4	0
Injection site reaction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	3	0
Application site erosion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0
Injection site eczema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Fatigue
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 12 (33.33%)	1 / 7 (14.29%)
occurrences all number	0	3	0	0	8	1
Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0
Injection site haematoma
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	2 / 7 (28.57%)
occurrences all number	0	0	0	0	0	2
Injection site calcification
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	1
Local swelling
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	1
Vaccination site pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Application site erythema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0
Injection site rash
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Injection site irritation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	4	0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Reproductive system and breast disorders
Scrotal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	4	0
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 7 (14.29%)
occurrences all number	0	1	0	0	1	1
Cough
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 12 (41.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	10	0
Oropharyngeal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 12 (33.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	5	0
Investigations
Alpha 1 microglobulin urine increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	12 / 12 (100.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	24	0
Haemoglobin decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0
Haematocrit decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0
Cystatin C increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	10 / 12 (83.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	18	0
Complement factor C3 decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	5	0
Glutamate dehydrogenase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	9 / 12 (75.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	13	1
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	7	0
Haptoglobin increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	4	0
Blood fibrinogen increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Red blood cell count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	3	0
White blood cell count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Urinary sediment abnormal
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 12 (41.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	14	0
Complement factor C3 increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Blood pressure increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
White blood cells urine positive
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	4	0
Protein total decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Blood albumin decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Weight decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
pH urine increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Lymphocyte count decreased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	1	0
Troponin I increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Light chain analysis increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	4	0
Bacteria urine identified
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Urine protein/creatinine ratio increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Eosinophil count decreased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0
Platelet count increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0
Azotaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0
Heart rate decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0
Reticulocyte count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0
Cystatin C increased (serum)
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	2
MONOCYTE CHEMOTACTIC PROTEIN-1 INCREASED
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 12 (41.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	18	0
Injury, poisoning and procedural complications
Joint sprain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	3	0
Open wound
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Arthropod sting
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Tibia fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Femur fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Joint injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0
Lower limb fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Tendon rupture
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Foot fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Limb injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Wound
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 7 (14.29%)
occurrences all number	0	1	0	0	1	1
Eyelid hematoma
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0
Cardiac disorders
Tachycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1	1
Ventricular extrasystoles
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Nervous system disorders
Headache
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	11 / 12 (91.67%)	1 / 7 (14.29%)
occurrences all number	0	0	1	1	25	1
Dizziness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Convulsion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Post-traumatic headache
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Dizziness postural
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Dyskinesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Paraesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	1
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 12 (41.67%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	15	3
Leukopenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	3	0
Leukocytosis
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0
Ear and labyrinth disorders
Tympanic membrane perforation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Eye disorders
Lenticular opacities
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Cataract
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	1
Gastrointestinal disorders
Aptyalism
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Dental caries
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Diarrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	7 / 12 (58.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	9	0
Abdominal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1	1
Vomiting
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	8 / 12 (66.67%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	29	1
Nausea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 12 (41.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	10	0
Abdominal pain upper
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	4 / 12 (33.33%)	1 / 7 (14.29%)
occurrences all number	0	0	0	1	8	1
Haemorrhoids
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	3	1
Gastritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	2	1
Constipation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 12 (33.33%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	4	1
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	2	1
Nail bed inflammation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Skin irritation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Dermatitis allergic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Urticaria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	3	0
Dry skin
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	3	0
Alopecia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0
Blister
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Erythema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	3	0
Rash
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	1
Renal and urinary disorders
Proteinuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	12 / 12 (100.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	24	1
Haematuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0
Haemoglobinuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Albuminuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	11 / 12 (91.67%)	2 / 7 (28.57%)
occurrences all number	0	0	0	0	24	2
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	3	0
Myalgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	2	0
Tendinous contracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0
Back pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 12 (33.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	7	0
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	3	0
Neck pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Scoliosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Muscle spasms
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	7	0
Musculoskeletal stiffness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Musculoskeletal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0
Muscle tightness
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0
Duchenne muscular dystrophy
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0
Tendon pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	1
Infections and infestations
Gastroenteritis
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 3 (66.67%)	2 / 3 (66.67%)	9 / 12 (75.00%)	0 / 7 (0.00%)
occurrences all number	0	1	2	2	22	0
Rhinitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	4 / 12 (33.33%)	1 / 7 (14.29%)
occurrences all number	0	0	0	1	7	1
Respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	4	0
Upper respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 12 (50.00%)	2 / 7 (28.57%)
occurrences all number	0	0	0	0	10	2
Pharyngitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0
Nasopharyngitis
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	6 / 12 (50.00%)	0 / 7 (0.00%)
occurrences all number	1	0	1	1	46	0
Viral infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	4	0
Fungal infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 12 (33.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	6	0
Paronychia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0
Cellulitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Infected bites
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0
Injection site infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0
Folliculitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Onychomycosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0
Influenza
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	4	0
Localised infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1	2
Sinusitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1	1
Body tinea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	3	0
Infective tenosynovitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Bacterial infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Tooth infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Otitis media
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	10	0
Nail infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Skin infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Impetigo
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	3	0
Eye infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0
Metabolism and nutrition disorders
Insulin resistance
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0
Decreased appetite
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

21 Mar 2008

- Extension of the duration of the screening period for skin biopsy and MRI from 4 to 6 weeks, - Validation of a novel, exploratory assay for subject screening, based on confirmation of mutation and PRO051 response on RNA level in peripheral blood mononuclear cells, - Reporting serious adverse events and/or unexpected adverse drug reactions, - Addition of TNF- at assessment of inflammatory response, - Change in choice of complement split factors, - Pre-study diagnostic muscle biopsy, - Manual muscle testing grading scale changed, - Corrections to Schedules of assessments (Tables) and Methodology of assessments (Protocol text sections), - Blood volume of pharmacokinetic samples changed, - All urine samples processed by the local laboratories, and - Minor formatting and typographical errors to improve the clarity and accuracy of the protocol text.

05 May 2008

- Increased monitoring of urine for potential renal effects of PRO051, - Increased frequency of monitoring blood biochemistry parameters, - Clarifications in study design, - List of parameters for routine hematology, biochemistry and urinalysis assessment updated, - Corrections to Schedules of assessment (Table) and Methodology of assessments (Protocol text section), - Sponsor details changed, and - Minor formatting and typographical errors to improve the clarity and accuracy of the protocol text.

27 Apr 2009

- Implementation of a new template for clinical study protocol, - Muscle biopsy in treatment beyond study period, - Addition of 6-minute walk test in treatment beyond study period, - Replacement of QMT-CINRG by handheld myometry in treatment beyond study period, - Changes in urine analysis, biochemistry parameters and hematology parameters for potential adverse effects of PRO051 in the treatment beyond study period, - Replacement of complement assays at external laboratory by marker complement measurement by the hospitals in treatment beyond study period, - Inflammatory response assay removed from treatment beyond study period, - Pharmacokinetic sampling in treatment beyond study period, - Storage period of the clinical trial samples, - Total blood volumes during treatment beyond study period, - Clarifications on the conditions for the treatment beyond study period, - Clarifications on the subject withdrawal criteria, - New batch of study medication to be used in treatment beyond study period, - Assessment of PRO051 in the muscle biopsy, - Clarification on the methods of the muscle function tests, - Effect parameters adjusted to current technical status of the assay development, - Study centers changed, and - Minor formatting and typographical errors to improve the clarity and accuracy of the protocol text.

02 Sep 2009

Changes in safety parameters for potential adverse effects of drisapersen in the treatment beyond study period (Continued Treatment phase). These changes included addition of measurements of troponin, fibrinogen, haptoglobin and CRP plus extra measurements of aPTT, cystatin C and ECG recordings, and Addition of echocardiography. Minor formatting and typographical errors to improve the clarity and accuracy of the protocol text. Assessment of drisapersen levels in muscle tissue was to be assessed at the Prosensa laboratory in the remaining material from the muscle biopsy after the results were obtained for the mRNA production and dystrophin expression in the muscle tissue. However, this assessment was not performed as the assay was still being optimized. drisapersen levels in the remaining muscle tissue were to be measured at a later time point and the results reported separately. The anti-dystrophin antibody assay was planned to detect potential IgM and IgG antibodies against dystrophin. IgM antibodies were however not assessed. Different to the original protocol, an assay for IgG but not IgM anti-dystrophin reactivity was performed, because IgM control dystrophin antibodies were not available. Formation of antibodies to dystrophin in blood was to be determined at Visits 13, 25, 37 and 61.

16 Jul 2010

• Enhanced safety monitoring. • Addition of stopping criteria. • Addition of alternative injection sites for drug administration. • Addition of DEXA scans. • Additional muscle biopsy at 12 months. • Dose capping according to weight. • Allowance for intermittent dosing for any subject reaching any of the study stopping criteria. • Addition of a parent questionnaire. • Change in Clinical Research Manager. • Other minor clarification and corrections. The enhanced safety monitoring was to enable the Sponsor to closely monitor for early signs of potentially drug-related hepatotoxicity and nephrotoxicity as well as thrombocytopenia. Enhanced monitoring consisted of more frequent assessments as well as some changes to the parameters themselves e.g. addition of glutamate dehydrogenase, albumin/globulin ratio and PTT (international normalized ratio [INR]). Changes to urinalysis parameters were also made including removal of the dipstick analysis, and addition of quantitative analysis of glucose, albumin, protein, creatinine, 1 microglobulin, protein/creatinine ratio and microscopy of urine sediment for erythrocytes, leukocytes and casts. The requirement for troponin I concentrations (introduced in Amendment 5) was removed as the relationship of any change in troponin levels in DMD patients (which may be very variable) is not understood relative to any cardiac condition (personal communication, Kate Bushby, Professor of Neuromuscular Genetics, Newcastle University), and were considered to be unlikely to be useful in detecting incipient cardiac damage.

15 Nov 2010

Further additions to the enhanced safety monitoring implemented in Amendment 6. •Additional detail for stopping criteria. •Change in dosing regimen for all subjects. •Addition of pre-dose pharmacokinetic sampling on a monthly basis from Visit 85 (or as soon as approval of Amendment 7). Ad hoc pharmacokinetic sampling. •Additional instructions on the assessment of local injection site reactions. •Change in blood volumes. •Additions to safety monitoring. •Muscle function (adjustment in visit schedule) •Other minor clarifications and corrections. The amended dosing regimen involved an 8 week washout period for all subjects (Visits 86-93 inclusive). Subjects were then restarted on an intermittent regimen involving 8 weeks of once weekly treatment followed by 4 weeks off drug. New safety monitoring included addition of blood smear for schistocytes (haematology), kidney injury molecule-1 (KIM-1) and cystatin C (urinalysis) and MCP 1 (inflammatory response). Fibrin split products and D dimer were also to be assessed if predefined criteria were met.

09 Mar 2011

• Extension of the study until 2013. • Change in frequency of efficacy measured in order to reduce the • burden on the subjects. • Change in visit schedule in order to reduce the travel burden on the • families. • Change in blood volumes. • Other minor clarifications and corrections. The frequency of the efficacy measures was changed to every 12 weeks in order to fit in with the new assessment schedule and to assess the effect of the intermittent dosing regimen introduced in Amendment 7. Subjects did not have to return to the hospital for laboratory safety testing during the 4 week treatment break unless there was a medical/safety concern, in which case the subject would be asked to return for further monitoring as determined by the investigator.

14 Apr 2011

•Change in legal sponsorship from Prosensa Therapeutics B.V. to GlaxoSmithKline (implemented on 21 July 2011). •Change in supply of drisapersen. •Change in frequency of cystatin C measurements to enhance safety monitoring (every 4 weeks rather than every 12 weeks). •Other minor clarifications and corrections.

10 Aug 2011

•Enhanced safety monitoring and stopping criteria. •Enhanced monitoring and stopping criteria for inflammation. •Modified stopping criteria for coagulation. •Modified stopping criteria for hepatic toxicity. •Change in primary medical contact. •Change in definition of serious adverse events (SAEs). •Other minor clarifications

17 May 2012

•Enhanced safety monitoring and stopping criteria •Enhanced renal monitoring •Modified renal stopping criteria •Clarification to the Disseminated Intravascular Coagulation criteria •Update sponsor signature page •Change in Definition of AEs •Change in study schedule for taking subject height and weight / Parent questionnaire added to flowchart •Option to return to weekly dosing at 6 mg/kg drisapersen

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Production of exon 51 skip mRNA in muscle biopsy during Initial study period by dose group per visit - 0.5 mg/kg

Primary: Production of exon 51 skip mRNA in muscle biopsy during Initial study period by dose group per visit - 0.5 mg/kg

Primary: Production of exon 51 skip mRNA in muscle biopsy during Initial study period by dose group per visit - 2, 4 and 6mg/kg

Primary: Production of exon 51 skip mRNA in muscle biopsy during Initial study period by dose group per visit - 2, 4 and 6mg/kg

Primary: Presence of dystrophin in cross sections of muscle biopsy during Initial study period, by dose group per visit - 0.5 mg/kg

Primary: Presence of dystrophin in cross sections of muscle biopsy during Initial study period, by dose group per visit - 0.5 mg/kg

Primary: Presence of dystrophin in cross sections of muscle biopsy during Initial study period, by dose group per visit - 2, 4 and 6 mg/kg

Primary: Presence of dystrophin in cross sections of muscle biopsy during Initial study period, by dose group per visit - 2, 4 and 6 mg/kg

Primary: Presence of dystrophin in total protein extract during Initial study period, by dose group per visit - 0.5 mg/kg

Primary: Presence of dystrophin in total protein extract during Initial study period, by dose group per visit - 0.5 mg/kg

Primary: Presence of dystrophin in total protein extract during Initial study period, by dose group per visit - 2, 4 and 6 mg/kg

Primary: Presence of dystrophin in total protein extract during Initial study period, by dose group per visit - 2, 4 and 6 mg/kg

Primary: Production of exon 51 skip mRNA in peripheral blood mononuclear cells, during Initial Study Period, by dose group per visit

Primary: Production of exon 51 skip mRNA in peripheral blood mononuclear cells, during Initial Study Period, by dose group per visit

Primary: Muscle function: 10-Meter walk/run test during Initial Study Period, by dose group per visit

Primary: Muscle function: 10-Meter walk/run test during Initial Study Period, by dose group per visit

Primary: Muscle function: Timed rising from floor during Initial Study Period, by dose group per visit

Primary: Muscle function: Timed rising from floor during Initial Study Period, by dose group per visit

Primary: Muscle function: Stair climb during Initial Study Period, by dose group per visit

Primary: Muscle function: Stair climb during Initial Study Period, by dose group per visit

Primary: Muscle function: 6-Minute walk test, time walked during Initial study period, by dose group per visit

Primary: Muscle function: 6-Minute walk test, time walked during Initial study period, by dose group per visit

Primary: Muscle function: 6-Minute walk test, Distance walked during Initial study period, by dose group per visit

Primary: Muscle function: 6-Minute walk test, Distance walked during Initial study period, by dose group per visit

Primary: Muscle function: 6-Minute walk test, Distance per minute walked during Initial study period, by dose group per visit

Primary: Muscle function: 6-Minute walk test, Distance per minute walked during Initial study period, by dose group per visit

Primary: Muscle strength: Quantitative muscle testing per muscle site during Initial study period, by dose group per visit, Quantitative muscle (Contraction) testing per muscle site

Primary: Muscle strength: Quantitative muscle testing per muscle site during Initial study period, by dose group per visit, Quantitative muscle (Contraction) testing per muscle site

Primary: Muscle strength: Quantitative muscle testing per muscle site during Initial study period, by dose group per visit - Pulmonary function testing

Primary: Muscle strength: Quantitative muscle testing per muscle site during Initial study period, by dose group per visit - Pulmonary function testing

Primary: Muscle strength: Manual muscle testing, total score and separate scores during Initial study period, by dose group per visit - Overall scores

Primary: Muscle strength: Manual muscle testing, total score and separate scores during Initial study period, by dose group per visit - Overall scores

Primary: Number of Subjects with Treatment Emergent Adverse Events during Initial Study Period

Primary: Number of Subjects with Treatment Emergent Adverse Events during Initial Study Period

Primary: Change from Baseline of 6-Minute Walking Distance (6MWD) in Continued Treatment phase

Primary: Change from Baseline of 6-Minute Walking Distance (6MWD) in Continued Treatment phase

Primary: Change from Baseline of Timed Tests - 10m Walk/run, Rising from floor and Stair Climb in Continued Treatment phase

Primary: Change from Baseline of Timed Tests - 10m Walk/run, Rising from floor and Stair Climb in Continued Treatment phase

Primary: Change from Baseline of Muscle Strength Handheld Myometry of Elbow Flexor, Elbow Extensor, Knee Flexor and Knee Extensor in Continued Treatment phase

Primary: Change from Baseline of Muscle Strength Handheld Myometry of Elbow Flexor, Elbow Extensor, Knee Flexor and Knee Extensor in Continued Treatment phase

Primary: Change from Baseline Spirometry of Forced vital capacity (FVC) and Forced expiratory volume in 1 second (FEV1) in Continued Treatment phase

Primary: Change from Baseline Spirometry of Forced vital capacity (FVC) and Forced expiratory volume in 1 second (FEV1) in Continued Treatment phase

Primary: Change from Baseline Spirometry of maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) in Continued Treatment phase

Primary: Change from Baseline Spirometry of maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) in Continued Treatment phase

Primary: Change from Baseline Spirometry of Peak flow (PF) and Peak cough flow (PCF) in Continued Treatment phase

Primary: Change from Baseline Spirometry of Peak flow (PF) and Peak cough flow (PCF) in Continued Treatment phase

Primary: Responses Summary of Parent Questionnaire to change in condition over the Continued Treatment phase

Primary: Responses Summary of Parent Questionnaire to change in condition over the Continued Treatment phase

Primary: Muscle Biopsy Summary of Exon 51 Skip in Continued Treatment phase

Primary: Muscle Biopsy Summary of Exon 51 Skip in Continued Treatment phase

Primary: Muscle Biopsy Summary of Immunofluorescence Qualitative Dystrophin Expression in Continued Treatment phase

Primary: Muscle Biopsy Summary of Immunofluorescence Qualitative Dystrophin Expression in Continued Treatment phase

Primary: Muscle Biopsy Summary of Western Blot Qualitative Dystrophin Expression in Continued Treatment phase

Primary: Muscle Biopsy Summary of Western Blot Qualitative Dystrophin Expression in Continued Treatment phase

Secondary: Maximum Observed Plasma Concentration (Cmax) of Drisapersen during Initial Study Period

Secondary: Maximum Observed Plasma Concentration (Cmax) of Drisapersen during Initial Study Period

Secondary: Time to Maximum Observed Concentration (Tmax) of Drisapersen during Initial Study Period

Secondary: Time to Maximum Observed Concentration (Tmax) of Drisapersen during Initial Study Period

Secondary: Plasma concentration measured 7 days after the injection(Ctrough-D7) of Drisapersen during Initial Study Period

Secondary: Plasma concentration measured 7 days after the injection(Ctrough-D7) of Drisapersen during Initial Study Period

Secondary: Area under the plasma concentration-time curve from time 0 to 24h(AUC0-24h) of Drisapersen during Initial Study Period

Secondary: Area under the plasma concentration-time curve from time 0 to 24h(AUC0-24h) of Drisapersen during Initial Study Period

Secondary: Area under the plasma concentration-time curve during one dosing interval (AUC0-D7) of Drisapersen during Initial Study Period

Secondary: Area under the plasma concentration-time curve during one dosing interval (AUC0-D7) of Drisapersen during Initial Study Period

Secondary: Apparent plasma clearance (CL/F) of Drisapersen during Initial Study Period

Secondary: Apparent plasma clearance (CL/F) of Drisapersen during Initial Study Period

Secondary: Maximum Observed Plasma Concentration (Cmax) of Drisapersen during Continued Treatment phase

Secondary: Maximum Observed Plasma Concentration (Cmax) of Drisapersen during Continued Treatment phase

Secondary: Time to Maximum Observed Concentration (Tmax) of Drisapersen during Continued Treatment phase

Secondary: Time to Maximum Observed Concentration (Tmax) of Drisapersen during Continued Treatment phase

Secondary: Area under the plasma concentration-time curve from time 0 to 24h(AUC0-24h) of Drisapersen during Continued Treatment phase