Download PDF

Clinical Trial Results:
A 2-Part, Randomized, Double-Blind, Placebo-Controlled, Dose Titration, Safety, Tolerability, and Pharmacokinetics Study (Part 1) Followed by an Open-Label Efficacy and Safety Evaluation (Part 2) of SRP-4053 in Patients with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping

Summary
EudraCT number	2014-002008-25
Trial protocol	GB IT FR
Global end of trial date	25 Mar 2019

Results information
Results version number	v2(current)
This version publication date	23 Dec 2020
First version publication date	25 Sep 2020
Other versions	v1
Version creation reason	New data added to full data set Changes to summary attachments Need to update few statements

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

4053-101

ISRCTN number

US NCT number

NCT02310906

WHO universal trial number (UTN)

Sponsor organisation name

Sarepta Therapeutics, Inc.

Sponsor organisation address

215 First Street, Cambridge,MA, United States, 02142

Public contact

Medical Director, Sarepta Therapeutics, Inc., +1 800-690- 2003, clinicaltrials@sarepta.com

Scientific contact

Medical Director, Sarepta Therapeutics, Inc., +1 800-690- 2003, clinicaltrials@sarepta.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-001722-PIP01-14

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

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

Analysis stage

Final

Date of interim/final analysis

25 Mar 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

25 Mar 2019

Was the trial ended prematurely?

Main objective of the trial

PART 1: To evaluate the safety and tolerability of four escalating doses of golodirsen administered once weekly for at least 2 weeks per dose level compared to placebo. PART 2: - To assess ambulation, endurance, and muscle function as measured by change from Baseline at Week 144 on the 6-Minute Walk Test (6MWT) in treated and untreated subjects. - To assess the biological activity of golodirsen via dystrophin expression at Week 48 compared to pre-treatment.

Protection of trial subjects

Written informed consent from each subject or subject's parent(s) or legal guardian(s), if applicable, and written assent from each subject, if applicable, were obtained before any study-specific screening or baseline period evaluations were performed. The anonymity of participating subject will be maintained to the extent required by applicable laws and in accordance with current HIPAA standards. This study was designed and monitored in accordance with Sponsor procedures, which complied with the ethical principles of Good Clinical Practice (GCP) as required by the major regulatory authorities, and in accordance with the Declaration of Helsinki.

Background therapy

Evidence for comparator

Actual start date of recruitment

13 Jan 2015

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

33 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 16

Country: Number of subjects enrolled

France: 15

Country: Number of subjects enrolled

Italy: 8

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

Top of page

Recruitment details

The study was conducted at 5 sites in the France, Italy, and United Kingdom from 13 January 2015 to 25 March 2019.

Screening details

Study conducted in 2 parts: Part 1 and Part 2. When Part 1 was completed and cumulative safety data was reviewed by an independent Data Safety Monitoring Board (DSMB), Part 2 was conducted.

Period 1 title

Part 1

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Part 1: Placebo

Arm description

Participants received placebo-matched to golodirsen intravenous (IV) infusions, once weekly up to 12 weeks in Part 1.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Placebo

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received placebo-matched to golodirsen IV infusions, once weekly up to 12 weeks in Part 1.

Part 1: Golodirsen

Arm description

Subjects received golodirsen IV infusions, at four dose levels of 4 milligrams per kilograms (mg/kg) once weekly for 2 weeks, followed by 10 mg/kg once weekly for the next 2 weeks (i.e., up to Week 4), followed by 20 mg/kg once weekly for the next 2 weeks (i.e., up to Week 6), followed by 30 mg/kg once weekly from Week 7 to Week 12 in Part 1.

Arm type

Experimental

Investigational medicinal product name

Golodirsen

Investigational medicinal product code

SRP-4053

Other name

SRP-4053

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received golodirsen IV infusions at dose levels of 4 mg/kg, 10 mg/kg , 20 mg/kg , 30 mg/kg weekly on weeks 1, 3, 5, 7.

Number of subjects in period 1	Part 1: Placebo	Part 1: Golodirsen
Started	4	8
Received 4 mg/kg	0 ^[1]	8
Received 10 mg/kg	0 ^[2]	8
Received 20 mg/kg	0 ^[3]	8
Received 30 mg/kg	0 ^[4]	8
Completed	4	8

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: There were no separate or defined dose level for Placebo.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: There were no separate or defined dose level for Placebo.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: There were no separate or defined dose level for Placebo.
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: There were no separate or defined dose level for Placebo.

Period 2 title

Part 2

Is this the baseline period?

Yes ^[5]

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst

Are arms mutually exclusive

Part 2a: Total Golodirsen Group

Arm description

All subjects from Part 1 (who previously received placebo or golodirsen) and including additional new subjects received Golodirsen 30 milligram (mg)/kilogram (kg) once weekly, for up to 168 weeks. Dosing was interrupted or halted when any specific predefined stopping criteria was met or if warranted at the discretion of the Sponsor or Investigator.

Arm type

Experimental

Investigational medicinal product name

Golodirsen

Investigational medicinal product code

SRP-4053

Other name

SRP-4053

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received golodirsen IV infusions, 30 mg/kg weekly, for up to 168 weeks in Part 2.

Part 2b: Untreated Group (Natural History of Non-exon 53)

Arm description

Untreated subjects intended to evaluate the natural history of the disease with DMD and various genetic mutations (not amenable to exon 53 skipping) were included in this group and did not received any treatment. Subjects underwent the same study assessments as treated subjects in other reporting groups (except for pharmacokinetic [PK] sampling and muscle biopsies), but at a reduced schedule through Week 144. Thus, the untreated subjects are not considered a control group.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Notes
[5] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
Justification: 12 subjects of part 1 were involved in the part 2 of the study (Total Golodirsen Group). Hence, the part 2 of the study was considered as the baseline period.

Number of subjects in period 2	Part 2a: Total Golodirsen Group	Part 2b: Untreated Group (Natural History of Non-exon 53)
Started	25	14
Completed	23	6
Not completed	2	8
Consent withdrawn by subject	2	4
Personal reasons	-	1
Lost to follow-up	-	1
Due to enrollment in therapeutic study	-	2

Baseline characteristics

Top of page

Reporting group title

Part 2a: Total Golodirsen Group

Reporting group description

Reporting group title

Part 2b: Untreated Group (Natural History of Non-exon 53)

Reporting group description

Reporting group values	Part 2a: Total Golodirsen Group	Part 2b: Untreated Group (Natural History of Non-exon 53)	Total
Number of subjects	25	14
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	8.4 ( 2.18 )	8.5 ( 1.91 )	-
Gender categorical
Units: Subjects
Female	0	0	0
Male	25	14	39
Race
Units: Subjects
American Indian or Alaska Native	0	0	0
Asian	0	1	1
Black	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0
White	23	11	34
Other	2	2	4
Ethnicity
Units: Subjects
Hispanic or Latino	4	0	4
Not Hispanic or Latino	9	9	18
Unknown or Not Reported	12	5	17

End points

Top of page

Reporting group title

Part 1: Placebo

Reporting group description

Participants received placebo-matched to golodirsen intravenous (IV) infusions, once weekly up to 12 weeks in Part 1.

Reporting group title

Part 1: Golodirsen

Reporting group description

Reporting group title

Part 2a: Total Golodirsen Group

Reporting group description

Reporting group title

Part 2b: Untreated Group (Natural History of Non-exon 53)

Reporting group description

Subject analysis set title

Part 1: Placebo

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects received placebo-matched to golodirsen IV infusions, once weekly for up to 12 weeks in Part 1

Subject analysis set title

Part 1: Golodirsen (4 mg/kg)

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects received golodirsen IV infusions, at dose level of 4 mg/kg, once weekly for 2 weeks in Part 1.

Subject analysis set title

Part 1: Golodirsen (10 mg/kg)

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects received golodirsen IV infusions, at a dose level of 10 mg/kg, once weekly for the next 2 weeks (i.e., up to Week 4) in Part 1.

Subject analysis set title

Part 1: Golodirsen (20 mg/kg)

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects received golodirsen IV infusions, at a dose level of 20 mg/kg, once weekly for the next 2 weeks (i.e., up to Week 6) in Part 1.

Subject analysis set title

Part 1: Golodirsen (30 mg/kg)

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects received golodirsen IV infusions, at a dose level of 30 mg/kg, once weekly from Week 7 to Week 12 in Part 1.

Primary: Part 1: Number of Subjects with Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation

Top of page

End point title

Part 1: Number of Subjects with Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation ^[1]

End point description

Adverse event (AE) was any untoward medical occurrence in a clinical trial subject, which does not necessarily have a causal relationship with the investigational drug. A Serious adverse event (SAE) was an AE resulting in any of the following outcomes: death; Life-threatening event; Required or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly. TEAEs were defined as AEs that were reported or worsened on or after the start of study drug dosing through 12 weeks. TEAEs included both Serious TEAEs and non-serious TEAEs. Part 1 safety set included all randomised subjects who received at least one dose of study drug.

End point type

Primary

End point timeframe

Baseline up to Week 12

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 testing was performed for the primary end point.

End point values	Part 1: Placebo	Part 1: Golodirsen (4 mg/kg)	Part 1: Golodirsen (10 mg/kg)	Part 1: Golodirsen (20 mg/kg)	Part 1: Golodirsen (30 mg/kg)
Number of subjects analysed	4	8	8	8	8
Units: Subjects
Subjects with TEAEs	4	5	5	3	6
Subjects with Serious TEAEs	0	0	0	0	0
Subjects with TEAEs leading to discontinuation	0	0	0	0	0

No statistical analyses for this end point

Primary: Part 1: Number of Subjects With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs

Top of page

End point title

Part 1: Number of Subjects With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs ^[2]

End point description

Laboratory parameters included hematology, serum chemistry (SC), urinalysis and coagulation. Number of subjects with at least one potentially clinically significant abnormal findings were reported as TEAEs. The Investigator determined whether abnormal assessment results were potentially clinically significant or not. Potentially clinical significance was defined as any variation in assessment results that had medical relevance resulting in an alteration in medical care. Part 1 safety set included all randomised subjects who received at least one dose of study drug.

End point type

Primary

End point timeframe

Baseline up to Week 12

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical testing was performed for the primary end point.

End point values	Part 1: Placebo	Part 1: Golodirsen (4 mg/kg)	Part 1: Golodirsen (10 mg/kg)	Part 1: Golodirsen (20 mg/kg)	Part 1: Golodirsen (30 mg/kg)
Number of subjects analysed	4	8	8	8	8
Units: Subjects
Hepatic Chemistry	0	0	0	0	0
Renal Chemistry	0	0	0	0	0
Hematology	2	0	1	0	0
Coagulation	0	0	0	0	0
Urinalysis	0	0	0	0	0

No statistical analyses for this end point

Primary: Part 1: Number of Subjects With Potentially Clinically Significant Abnormalities in Vital Signs Reported as TEAEs

Top of page

End point title

Part 1: Number of Subjects With Potentially Clinically Significant Abnormalities in Vital Signs Reported as TEAEs ^[3]

End point description

Vital sign parameters included systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and body temperature. Number of subjects with at least one potentially clinically significant abnormal vital signs findings were reported as TEAEs. The Investigator determined whether abnormal assessment results were potentially clinically significant or not. Potential clinical significance was defined as any variation in assessment results that had medical relevance resulting in an alteration in medical care. Part 1 safety set included all randomised subjects who received at least one dose of study drug.

End point type

Primary

End point timeframe

Baseline up to Week 12

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 testing was performed for the primary end point.

End point values	Part 1: Placebo	Part 1: Golodirsen (4 mg/kg)	Part 1: Golodirsen (10 mg/kg)	Part 1: Golodirsen (20 mg/kg)	Part 1: Golodirsen (30 mg/kg)
Number of subjects analysed	4	8	8	8	8
Units: Subjects	1	3	1	1	4

No statistical analyses for this end point

Primary: Part 1: Number of Subjects With Potentially Clinically Significant Abnormalities in Physical Examinations

Top of page

End point title

Part 1: Number of Subjects With Potentially Clinically Significant Abnormalities in Physical Examinations ^[4]

End point description

Physical examinations were performed by the Investigator, or qualified study staff. A full physical examination included a review of general appearance, head, eyes, ears, nose and throat, heart, lungs, abdomen, extremities, skin, lymph nodes, musculoskeletal, and neurological systems. Number of subjects with potentially clinically significant abnormalities in physical examinations were reported. Potentially clinically significant abnormalities in physical examinations were based on Investigator’s discretion. Part 1 safety set included all randomised subjects who received at least one dose of study drug.

End point type

Primary

End point timeframe

Baseline up to Week 12

Notes
[4] - 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 testing was performed for the primary end point.

End point values	Part 1: Placebo	Part 1: Golodirsen (4 mg/kg)	Part 1: Golodirsen (10 mg/kg)	Part 1: Golodirsen (20 mg/kg)	Part 1: Golodirsen (30 mg/kg)
Number of subjects analysed	4	8	8	8	8
Units: Subjects	0	0	2	0	3

No statistical analyses for this end point

Primary: Part 1: Number of Subjects With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Reported as TEAEs

Top of page

End point title

Part 1: Number of Subjects With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Reported as TEAEs ^[5]

End point description

Twelve-lead ECGs were performed at a consistent time of day throughout the study. Electrocardiograms were performed only after the subject was in the supine position, resting, and quiet for a minimum of 15 minutes. The ECG was manually reviewed and interpreted by medically qualified personnel. Number of subjects with potentially clinically significant abnormalities in ECG reported as TEAEs presented here. The Investigator determined whether abnormal assessment results were potentially clinically significant or not. Part 1 safety set included all randomised subjects who received at least one dose of study drug.

End point type

Primary

End point timeframe

Baseline up to Week 12

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 testing was performed for the primary end point.

End point values	Part 1: Placebo	Part 1: Golodirsen (4 mg/kg)	Part 1: Golodirsen (10 mg/kg)	Part 1: Golodirsen (20 mg/kg)	Part 1: Golodirsen (30 mg/kg)
Number of subjects analysed	4	8	8	8	8
Units: Subjects	0	1	0	0	0

No statistical analyses for this end point

Primary: Part 1: Number of Subjects With Potentially Clinically Significant Abnormalities in Echocardiograms (ECHO)

Top of page

End point title

Part 1: Number of Subjects With Potentially Clinically Significant Abnormalities in Echocardiograms (ECHO) ^[6]

End point description

Standard, 2-dimensional ECHOs were performed at a consistent time of day throughout the study. Cardiac function events included cardiomegaly, tachycardia, and dyspnoea. The ECHO was reviewed and interpreted by medically qualified personnel. Number of subjects with potentially clinically significant abnormalities in ECHO were reported. Part 1 safety set included all randomised subjects who received at least one dose of study drug.

End point type

Primary

End point timeframe

Baseline up to Week 12

Notes
[6] - 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 testing was performed for the primary end point.

End point values	Part 1: Placebo	Part 1: Golodirsen (4 mg/kg)	Part 1: Golodirsen (10 mg/kg)	Part 1: Golodirsen (20 mg/kg)	Part 1: Golodirsen (30 mg/kg)
Number of subjects analysed	4	8	8	8	8
Units: Subjects	0	0	0	0	3

No statistical analyses for this end point

Primary: Part 2a: Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) at Week 144 in Total Golodirsen Group

Top of page

End point title

Part 2a: Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) at Week 144 in Total Golodirsen Group ^[7] ^[8]

End point description

6MWT was performed by standardized procedures for all subjects. Subjects were asked to walk a set course of 25 meters for 6 minutes (timed), and the distance walked (in meters) was recorded. Change from baseline in 6MWT distance at Week 144 in total golodirsen group was reported. Efficacy Set consisted of all randomized subjects who had at least one post-baseline functional assessment. Here "number of subjects analysed" signifies number of subjects who were evaluable for this endpoint.

End point type

Primary

End point timeframe

Baseline, Week 144

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 testing was performed for the primary end point.
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for Total Golodirsen Group.

End point values	Part 2a: Total Golodirsen Group
Number of subjects analysed	22
Units: meters
arithmetic mean (standard deviation)	-99.0 ( 123.75 )

No statistical analyses for this end point

Primary: Part 2a: Change from Baseline in Dystrophin Protein Levels Determined by Western Blot at Week 48 in Total Golodirsen Group

Top of page

End point title

Part 2a: Change from Baseline in Dystrophin Protein Levels Determined by Western Blot at Week 48 in Total Golodirsen Group ^[9] ^[10]

End point description

Change from baseline in dystrophin protein levels (in muscle biopsy samples) were determined by Western blot in total golodirsen group. Muscle biopsy set included all subjects who received at least one dose of study drug and who had data from both baseline (pre-treatment) and Part 2 Week 48 (on-treatment) muscle biopsy samples. Data for this endpoint was not planned to be collected and analysed for untreated group (Natural History of Non-exon 53).

End point type

Primary

End point timeframe

Baseline, Week 48

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 testing was performed for the primary end point.
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for Total Golodirsen Group.

End point values	Part 2a: Total Golodirsen Group
Number of subjects analysed	25
Units: Percent normal dystrophin protein level
arithmetic mean (standard deviation)	0.924 ( 1.0129 )

No statistical analyses for this end point

Primary: Part 2b: Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) at Week 144 in Untreated Group (Natural History of Non-exon 53)

Top of page

End point title

Part 2b: Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) at Week 144 in Untreated Group (Natural History of Non-exon 53) ^[11] ^[12]

End point description

6MWT was performed by standardized procedures for all subjects. Subjects were asked to walk a set course of 25 meters for 6 minutes (timed), and the distance walked (in meters) was recorded. Change from baseline in 6MWT distance at Week 144 in untreated group (Natural History of Non-exon 53) was reported. Efficacy Set consisted of all randomized subjects who had at least one post-baseline functional assessment. Here "number of subjects analysed" signifies number of subjects who were evaluable for this endpoint.

End point type

Primary

End point timeframe

Baseline, Week 144

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 testing was performed for the primary end point.
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for Untreated Group (Natural History of Non-exon 53).

End point values	Part 2b: Untreated Group (Natural History of Non-exon 53)
Number of subjects analysed	6
Units: meters
arithmetic mean (standard deviation)	-160.8 ( 162.41 )

No statistical analyses for this end point

Secondary: Part 1: Maximum Plasma Concentration (Cmax) of Golodirsen

Top of page

End point title

Part 1: Maximum Plasma Concentration (Cmax) of Golodirsen

End point description

Maximum Concentration (Cmax) of golodirsen in plasma was evaluated. Pharmacokinetic (PK) set consisted of all randomised subjects from Part 1 who received the planned full dose of study drug and for whom there were adequate PK samples from which to estimate PK parameters. Data for this endpoint was not planned to be collected and analysed for placebo arm.

End point type

Secondary

End point timeframe

Pre-dose, 5 to 10 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose at Weeks 1 (for 4 mg/kg arm), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm) and 7 (for 30 mg/kg arm)

End point values	Part 1: Golodirsen (4 mg/kg)	Part 1: Golodirsen (10 mg/kg)	Part 1: Golodirsen (20 mg/kg)	Part 1: Golodirsen (30 mg/kg)
Number of subjects analysed	8	8	8	8
Units: nanogram per milliliter (ng/mL)
geometric mean (geometric coefficient of variation)	7840 ( 45.7 )	17000 ( 40.9 )	39700 ( 71.8 )	53300 ( 37.9 )

No statistical analyses for this end point

Secondary: Part 1: Time to Reach Maximum Plasma Concentration (Tmax) of Golodirsen

Top of page

End point title

Part 1: Time to Reach Maximum Plasma Concentration (Tmax) of Golodirsen

End point description

Time to reach maximum plasma concentration (Tmax) of golodirsen was evaluated. PK set consisted of all randomised subjects from Part 1 who received the planned full dose of study drug and for whom there were adequate PK samples from which to estimate PK parameters. Data for this endpoint was not planned to be collected and analysed for placebo arm.

End point type

Secondary

End point timeframe

Pre-dose, 5 to 10 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose at Weeks 1 (for 4 mg/kg arm), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm) and 7 (for 30 mg/kg arm)

End point values	Part 1: Golodirsen (4 mg/kg)	Part 1: Golodirsen (10 mg/kg)	Part 1: Golodirsen (20 mg/kg)	Part 1: Golodirsen (30 mg/kg)
Number of subjects analysed	8	8	8	8
Units: hour
median (full range (min-max))	1.11 (0.77 to 1.67)	1.09 (0.12 to 1.62)	1.12 (0.80 to 1.58)	1.12 (0.68 to 1.50)

No statistical analyses for this end point

Secondary: Part 1: Area Under the Concentration-Time Curve From Time Zero Extrapolated to the Infinity (AUCinf) of Golodirsen in Plasma

Top of page

End point title

Part 1: Area Under the Concentration-Time Curve From Time Zero Extrapolated to the Infinity (AUCinf) of Golodirsen in Plasma

End point description

Area under the concentration-time curve from time zero extrapolated to the infinity was evaluated. PK set consisted of all randomised subjects from Part 1 who received the planned full dose of study drug and for whom there were adequate PK samples from which to estimate PK parameters. Here, "number of subjects" analysed signifies number of subjects who were evaluable for this endpoint. Data for this endpoint was not planned to be collected and analysed for placebo arm.

End point type

Secondary

End point timeframe

Pre-dose, 5 to 10 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose at Weeks 1 (for 4 mg/kg arm), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm) and 7 (for 30 mg/kg arm)

End point values	Part 1: Golodirsen (4 mg/kg)	Part 1: Golodirsen (10 mg/kg)	Part 1: Golodirsen (20 mg/kg)	Part 1: Golodirsen (30 mg/kg)
Number of subjects analysed	8	8	6	8
Units: hr*ng/mL
geometric mean (geometric coefficient of variation)	11800 ( 35.5 )	26400 ( 42.7 )	62300 ( 52.6 )	90800 ( 33.4 )

No statistical analyses for this end point

Secondary: Part 1: Apparent Volume of Distribution at Steady State (Vss) of Golodirsen

Top of page

End point title

Part 1: Apparent Volume of Distribution at Steady State (Vss) of Golodirsen

End point description

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution at steady state of golodirsen was evaluated. PK set consisted of all randomised subjects from Part 1 who received the planned full dose of study drug and for whom there were adequate PK samples from which to estimate PK parameters. Here, "number of subjects" analysed signifies number of subjects who were evaluable for this endpoint. Data for this endpoint was not planned to be collected and analysed for placebo arm.

End point type

Secondary

End point timeframe

Pre-dose, 5 to 10 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose at Weeks 1 (for 4 mg/kg arm), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm) and 7 (for 30 mg/kg arm)

End point values	Part 1: Golodirsen (4 mg/kg)	Part 1: Golodirsen (10 mg/kg)	Part 1: Golodirsen (20 mg/kg)	Part 1: Golodirsen (30 mg/kg)
Number of subjects analysed	8	8	6	8
Units: liter per kilogram (L/kg)
geometric mean (geometric coefficient of variation)	0.670 ( 38.6 )	0.767 ( 43.4 )	0.576 ( 84.5 )	0.668 ( 32.3 )

No statistical analyses for this end point

Secondary: Part 1: Elimination Half-life (T1/2) of Golodirsen

Top of page

End point title

Part 1: Elimination Half-life (T1/2) of Golodirsen

End point description

T1/2 is the time measured for the plasma concentration of drug to decrease by one half. T1/2 of golodirsen was evaluated. PK set consisted of all randomised subjects from Part 1 who received the planned full dose of study drug and for whom there were adequate PK samples from which to estimate PK parameters. Here, "number of subjects" analysed signifies number of subjects who were evaluable for this endpoint. Data for this endpoint was not planned to be collected and analysed for placebo arm.

End point type

Secondary

End point timeframe

Pre-dose, 5 to 10 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose at Weeks 1 (for 4 mg/kg arm), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm) and 7 (for 30 mg/kg arm)

End point values	Part 1: Golodirsen (4 mg/kg)	Part 1: Golodirsen (10 mg/kg)	Part 1: Golodirsen (20 mg/kg)	Part 1: Golodirsen (30 mg/kg)
Number of subjects analysed	8	8	6	8
Units: hour
arithmetic mean (standard deviation)	2.36 ( 0.581 )	3.63 ( 2.04 )	3.27 ( 0.897 )	3.42 ( 0.628 )

No statistical analyses for this end point

Secondary: Part 1: Total Clearance (CL) of Golodirsen

Top of page

End point title

Part 1: Total Clearance (CL) of Golodirsen

End point description

Drug clearance is a quantitative measure of the rate at which a drug substance was removed from the blood. PK set consisted of all randomised subjects from Part 1 who received the planned full dose of study drug and for whom there were adequate PK samples from which to estimate PK parameters. Here, "number of subjects" analysed signifies number of subjects who were evaluable for this endpoint. Data for this endpoint was not planned to be collected and analysed for placebo arm.

End point type

Secondary

End point timeframe

Pre-dose, 5 to 10 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose at Weeks 1 (for 4 mg/kg arm), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm) and 7 (for 30 mg/kg arm)

End point values	Part 1: Golodirsen (4 mg/kg)	Part 1: Golodirsen (10 mg/kg)	Part 1: Golodirsen (20 mg/kg)	Part 1: Golodirsen (30 mg/kg)
Number of subjects analysed	8	8	6	8
Units: liters per hour per kilogram (L/hr/kg)
arithmetic mean (standard deviation)	0.381 ( 36.0 )	0.405 ( 46.2 )	0.338 ( 52.2 )	0.346 ( 34.3 )

No statistical analyses for this end point

Secondary: Part 1: Mean Residence Time (MRT) of Golodirsen

Top of page

End point title

Part 1: Mean Residence Time (MRT) of Golodirsen

End point description

MRT= AUMCinf/AUCinf, where AUMCinf is the area under the first moment curve from time 0 extrapolated to infinite time, calculated using the linear/log trapezoidal method. Mean residence time of golodirsen was evaluated. PK set consisted of all randomised subjects from Part 1 who received the planned full dose of study drug and for whom there were adequate PK samples from which to estimate PK parameters. Here, "number of subjects" analysed signifies number of subjects who were evaluable for this endpoint. Data for this endpoint was not planned to be collected and analysed for placebo arm.

End point type

Secondary

End point timeframe

Pre-dose, 5 to 10 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose at Weeks 1 (for 4 mg/kg arm), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm) and 7 (for 30 mg/kg arm)

End point values	Part 1: Golodirsen (4 mg/kg)	Part 1: Golodirsen (10 mg/kg)	Part 1: Golodirsen (20 mg/kg)	Part 1: Golodirsen (30 mg/kg)
Number of subjects analysed	8	8	6	8
Units: hour
arithmetic mean (standard deviation)	1.79 ( 0.325 )	1.92 ( 0.338 )	1.77 ( 0.495 )	1.95 ( 0.312 )

No statistical analyses for this end point

Secondary: Part 1: Renal Clearance (CLR) of Golodirsen

Top of page

End point title

Part 1: Renal Clearance (CLR) of Golodirsen

End point description

Renal clearance was calculated using the partial AUC0-24 from the non-compartmental analysis in plasma and AE0-24. AUC0-24 was defined as area under the plasma concentration-time curve, from time 0 to 24 hours after completion of dosing. AE0-24 was defined as total cumulative amount excreted from 0 to 24 hours. Summarized data of all urine collection intervals were reported. PK set consisted of all randomised subjects from Part 1 who received the planned full dose of study drug and for whom there were adequate PK samples from which to estimate PK parameters. Here, "number of subjects analysed" signifies number of subjects who were evaluable for this endpoint. Data for this endpoint was not planned to be collected and analysed for placebo arm.

End point type

Secondary

End point timeframe

0 to 1440 min after initiation of dosing on Day 1

End point values	Part 1: Golodirsen (4 mg/kg)	Part 1: Golodirsen (10 mg/kg)	Part 1: Golodirsen (20 mg/kg)	Part 1: Golodirsen (30 mg/kg)
Number of subjects analysed	8	8	7	8
Units: L/hr/kg
geometric mean (geometric coefficient of variation)	0.345 ( 31.9 )	0.370 ( 50.6 )	0.355 ( 42.1 )	0.374 ( 26.8 )

No statistical analyses for this end point

Secondary: Part 2a: Percent Change from Baseline in Forced Vital Capacity Predicted (FVC %p) to Week144 in Total Golodirsen Group

Top of page

End point title

Part 2a: Percent Change from Baseline in Forced Vital Capacity Predicted (FVC %p) to Week144 in Total Golodirsen Group ^[13]

End point description

FVC is the total amount of air exhaled during the forced expiratory volume test that was measured during spirometry; and was the most important measurement of lung function. This test requires subject to breath into a tube connected to a machine that measures the amount of air that can be moved in and out of the lungs after taking an inhaled bronchodilator medicine, which was used to dilate subjects bronchial (breathing) tubes. Percent of predicted FVC = (observed value)/ (predicted value) * 100%. Efficacy set consisted of all randomised subjects from Part 1 and all Part 2 subjects who had at least 1 post-baseline functional assessment. Here, "number of subjects analysed" signifies number of subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 144

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for Total Golodirsen Group.

End point values	Part 2a: Total Golodirsen Group
Number of subjects analysed	23
Units: percent change
arithmetic mean (standard deviation)	-8.382 ( 29.4566 )

No statistical analyses for this end point

Secondary: Part 2a: Change from Baseline in Dystrophin Intensity Levels Determined by Immunohistochemistry (IHC) at Week 48 in Total Golodirsen Group

Top of page

End point title

Part 2a: Change from Baseline in Dystrophin Intensity Levels Determined by Immunohistochemistry (IHC) at Week 48 in Total Golodirsen Group ^[14]

End point description

Change from baseline in dystrophin Intensity levels (in muscle biopsy samples) was determined by Immunohistochemistry in total golodirsen group. Muscle biopsy set included all subjects who received at least 1 dose of study drug and who had data from both baseline (pre-treatment) and Part 2 Week 48 (on-treatment) muscle biopsy samples. Data for this endpoint was not planned to be collected and analysed for untreated group (Natural History of Non-exon 53).

End point type

Secondary

End point timeframe

Baseline, Week 48

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for Total Golodirsen Group.

End point values	Part 2a: Total Golodirsen Group
Number of subjects analysed	25
Units: Percent dystrophin positive fibers
arithmetic mean (standard deviation)	0.023 ( 0.0243 )

No statistical analyses for this end point

Secondary: Part 2a: Percent Change from Baseline in Exon 53 Skipping Determined by Reverse Transcription Polymerase Chain Reaction (PCR) at Week 48 in Total Golodirsen Group

Top of page

End point title

Part 2a: Percent Change from Baseline in Exon 53 Skipping Determined by Reverse Transcription Polymerase Chain Reaction (PCR) at Week 48 in Total Golodirsen Group ^[15]

End point description

Percent change from baseline in Exon 53 skipping (in muscle biopsy samples) was determined by reverse transcription polymerase chain reaction in total golodirsen group. Muscle biopsy set included all subjects who received at least 1 dose of study drug and who had data from both baseline (pre-treatment) and Part 2 Week 48 (on-treatment) muscle biopsy samples. Data for this endpoint was not planned to be collected and analysed for untreated group (Natural History of Non-exon 53).

End point type

Secondary

End point timeframe

Baseline, Week 48

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for Total Golodirsen Group.

End point values	Part 2a: Total Golodirsen Group
Number of subjects analysed	25
Units: Percent change
arithmetic mean (standard deviation)	16.363 ( 10.6223 )

No statistical analyses for this end point

Secondary: Part 2a: Percent Change from Baseline in Dystrophin Positive Fibers Determined by Immunohistochemistry (IHC) at Week 48 in Total Golodirsen Group

Top of page

End point title

Part 2a: Percent Change from Baseline in Dystrophin Positive Fibers Determined by Immunohistochemistry (IHC) at Week 48 in Total Golodirsen Group ^[16]

End point description

Percent change from baseline in dystrophin positive fibers (in muscle biopsy samples) were determined by Immunohistochemistry at Week 48 in total golodirsen group. Muscle biopsy set included all subjects who received at least 1 dose of study drug and who had data from both baseline (pre-treatment) and Part 2 Week 48 (on-treatment) muscle biopsy samples. Data for this endpoint was not planned to be collected and analysed for untreated group (Natural History of Non-exon 53).

End point type

Secondary

End point timeframe

Baseline, Week 48

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for Total Golodirsen Group.

End point values	Part 2a: Total Golodirsen Group
Number of subjects analysed	25
Units: Percent change
arithmetic mean (standard deviation)	12.508 ( 14.6012 )

No statistical analyses for this end point

Secondary: Part 2b: Percent Change From Baseline in Forced Vital Capacity Predicted (FVC%p) at Week144 in Untreated Group (Natural History of Non-exon 53)

Top of page

End point title

Part 2b: Percent Change From Baseline in Forced Vital Capacity Predicted (FVC%p) at Week144 in Untreated Group (Natural History of Non-exon 53) ^[17]

End point description

FVC is the total amount of air exhaled during the forced expiratory volume test that is measured during spirometry; and is the most important measurement of lung function. This test required subject to breath into a tube connected to a machine that measures the amount of air that can be moved in and out of the lungs after taking an inhaled bronchodilator medicine which is used to dilate subject’s bronchial (breathing) tubes. Percent of predicted FVC = (observed value)/ (predicted value) * 100%. Efficacy set consisted of all randomised subjects from Part 1 and all Part 2 subjects who had at least 1 post-baseline functional assessment. Here, "number of subjects analysed" signifies number of subjects who were evaluable for this end point.

End point type

Secondary

End point timeframe

Baseline, Week 144

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analysed only for Untreated Group (Natural History of Non-exon 53).

End point values	Part 2b: Untreated Group (Natural History of Non-exon 53)
Number of subjects analysed	5
Units: percent change
arithmetic mean (standard deviation)	-6.739 ( 17.5278 )

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

From start of study drug administration up to 189 weeks

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

Part 1: Placebo

Reporting group description

Subjects received placebo-matched to golodirsen IV infusions, once weekly for up to 12 weeks in Part 1.

Reporting group title

Part 1: Golodirsen (4 mg/kg)

Reporting group description

Subjects received golodirsen IV infusions, at dose level of 4 mg/kg, once weekly for 2 weeks in Part 1.

Reporting group title

Part 1: Golodirsen (30 mg/kg)

Reporting group description

Subjects received golodirsen IV infusions, at a dose level of 30 mg/kg, once weekly from Week 7 to Week 12 in Part 1.

Reporting group title

Part 1: Golodirsen (10 mg/kg)

Reporting group description

Subjects received golodirsen IV infusions, at a dose level of 10 mg/kg, once weekly for the next 2 weeks (i.e., up to Week 4) in Part 1.

Reporting group title

Part 1: Golodirsen (20 mg/kg)

Reporting group description

Subjects received golodirsen IV infusions, at a dose level of 20 mg/kg, once weekly for the next 2 weeks (i.e., up to Week 6) in Part 1.

Reporting group title

Part 2a: Total Golodirsen Group

Reporting group description

All subjects from Part 1 (who previously received placebo or golodirsen) and including additional new subjects received golodirsen 30 milligram (mg)/kilogram (kg) once weekly, for up to 168 weeks in Part 2. Dosing was interrupted or halted when any specific predefined stopping criteria was met or if warranted at the discretion of the Sponsor or Investigator.

Reporting group title

Part 2b: Untreated Group (Natural History of Non-exon 53)

Reporting group description

Serious adverse events	Part 1: Placebo	Part 1: Golodirsen (4 mg/kg)	Part 1: Golodirsen (30 mg/kg)	Part 1: Golodirsen (10 mg/kg)	Part 1: Golodirsen (20 mg/kg)	Part 2a: Total Golodirsen Group	Part 2b: Untreated Group (Natural History of Non-exon 53)
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	4 / 25 (16.00%)	2 / 14 (14.29%)
number of deaths (all causes)	0	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0
Nervous system disorders
Convulsion
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 25 (4.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 25 (4.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Haematemesis
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 25 (4.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 25 (4.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tooth development disorder
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 25 (0.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Tonsillar hypertrophy
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 25 (4.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Rhabdomyolysis
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 25 (0.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Gastroenteritis viral
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 25 (4.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypocalcaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 25 (4.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Part 1: Placebo	Part 1: Golodirsen (4 mg/kg)	Part 1: Golodirsen (30 mg/kg)	Part 1: Golodirsen (10 mg/kg)	Part 1: Golodirsen (20 mg/kg)	Part 2a: Total Golodirsen Group	Part 2b: Untreated Group (Natural History of Non-exon 53)
Total subjects affected by non serious adverse events
subjects affected / exposed	4 / 4 (100.00%)	5 / 8 (62.50%)	6 / 8 (75.00%)	5 / 8 (62.50%)	3 / 8 (37.50%)	25 / 25 (100.00%)	10 / 14 (71.43%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	3 / 25 (12.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	6	0
Haemangioma of skin
subjects affected / exposed	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 25 (0.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	0	0
Vascular disorders
Haematoma
subjects affected / exposed	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 25 (4.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	1	0
Flushing
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 25 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	0	1
Surgical and medical procedures
Tooth extraction
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	4 / 25 (16.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	5	0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 4 (25.00%)	2 / 8 (25.00%)	4 / 8 (50.00%)	1 / 8 (12.50%)	1 / 8 (12.50%)	13 / 25 (52.00%)	1 / 14 (7.14%)
occurrences all number	6	2	16	1	1	33	1
Abasia
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	4 / 25 (16.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	4	1
Catheter site bruise
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	3 / 25 (12.00%)	0 / 14 (0.00%)
occurrences all number	0	0	2	0	0	4	0
Catheter site pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	3 / 25 (12.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	5	0
Fatigue
subjects affected / exposed	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	3 / 25 (12.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	7	0
Infusion site pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	3 / 25 (12.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	4	0
Gait disturbance
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Malaise
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Peripheral swelling
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Catheter site related reaction
subjects affected / exposed	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 25 (0.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	0	0
Immune system disorders
Seasonal allergy
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	3 / 8 (37.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	16 / 25 (64.00%)	3 / 14 (21.43%)
occurrences all number	0	0	12	0	0	57	3
Rhinorrhoea
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	2 / 8 (25.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	12 / 25 (48.00%)	0 / 14 (0.00%)
occurrences all number	0	0	6	0	0	43	0
Oropharyngeal pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	6 / 25 (24.00%)	0 / 14 (0.00%)
occurrences all number	0	0	2	0	0	11	0
Choking
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	3 / 25 (12.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	3	0
Dyspnoea
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	2	0
Epistaxis
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	4	0	0	3	0
Nasal congestion
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Pharyngeal erythema
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Productive cough
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	3	0
Psychiatric disorders
Initial insomnia
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Insomnia
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Stress
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Aggression
subjects affected / exposed	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 25 (0.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	0	0
Panic attack
subjects affected / exposed	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 25 (0.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	0	0
Investigations
Vitamin D decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Platelet count increased
subjects affected / exposed	2 / 4 (50.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 25 (0.00%)	0 / 14 (0.00%)
occurrences all number	12	0	0	0	0	0	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 4 (25.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	9 / 25 (36.00%)	1 / 14 (7.14%)
occurrences all number	3	0	2	0	0	13	1
Fall
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	6 / 25 (24.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	18	0
Limb injury
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	6 / 25 (24.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	7	0
Scratch
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	6 / 25 (24.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	9	0
Arthropod bite
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	4 / 25 (16.00%)	0 / 14 (0.00%)
occurrences all number	0	0	2	0	0	5	0
Back injury
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	4 / 25 (16.00%)	0 / 14 (0.00%)
occurrences all number	0	0	2	0	0	7	0
Ligament sprain
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	4 / 25 (16.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	6	0
Procedural pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	4 / 25 (16.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	5	0
Head injury
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	3 / 25 (12.00%)	0 / 14 (0.00%)
occurrences all number	0	0	2	0	0	4	0
Joint injury
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	3 / 25 (12.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	4	0
Muscle strain
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Spinal compression fracture
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	3	0
Hand fracture
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 25 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	0	1
Cardiac disorders
Sinus tachycardia
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	1 / 25 (4.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	1	0
Tachycardia
subjects affected / exposed	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 25 (4.00%)	0 / 14 (0.00%)
occurrences all number	0	1	0	0	0	1	0
Ventricular dysfunction
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 25 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	0	1
Nervous system disorders
Headache
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	3 / 8 (37.50%)	0 / 8 (0.00%)	1 / 8 (12.50%)	11 / 25 (44.00%)	0 / 14 (0.00%)
occurrences all number	0	0	12	0	1	51	0
Lethargy
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	3	1
Dizziness
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	1 / 25 (4.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	3	0
Syncope
subjects affected / exposed	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 25 (4.00%)	0 / 14 (0.00%)
occurrences all number	0	1	0	0	0	1	0
Blood and lymphatic system disorders
Lymphadenopathy
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	3 / 25 (12.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	4	0
Anaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	2	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	7 / 25 (28.00%)	0 / 14 (0.00%)
occurrences all number	0	0	4	0	0	21	0
Eye disorders
Eye pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	2	0	0	4	0
Gastrointestinal disorders
Vomiting
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 8 (12.50%)	15 / 25 (60.00%)	1 / 14 (7.14%)
occurrences all number	0	0	2	0	1	38	2
Diarrhoea
subjects affected / exposed	0 / 4 (0.00%)	1 / 8 (12.50%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	14 / 25 (56.00%)	0 / 14 (0.00%)
occurrences all number	0	1	2	0	0	29	0
Abdominal pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	9 / 25 (36.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	19	2
Abdominal pain upper
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	2 / 8 (25.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	9 / 25 (36.00%)	2 / 14 (14.29%)
occurrences all number	0	0	4	0	1	25	2
Nausea
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	5 / 25 (20.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	10	0
Constipation
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	4 / 25 (16.00%)	2 / 14 (14.29%)
occurrences all number	0	0	0	0	0	6	2
Dyspepsia
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Rectal haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Toothache
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	3	0
Gingival pain
subjects affected / exposed	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 25 (0.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	0	0
Glossitis
subjects affected / exposed	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 25 (0.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	0	0
Tooth discolouration
subjects affected / exposed	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 25 (0.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	0	0
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 25 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	0	1
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	6 / 25 (24.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	8	0
Ecchymosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	3 / 25 (12.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	8	0
Dry skin
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Eczema
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	4	0
Erythema
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Pruritus
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Urticaria
subjects affected / exposed	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	1 / 14 (7.14%)
occurrences all number	3	0	0	0	0	2	1
Petechiae
subjects affected / exposed	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 25 (4.00%)	0 / 14 (0.00%)
occurrences all number	0	1	0	0	0	1	0
Rash papular
subjects affected / exposed	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 25 (0.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	0	0
Renal and urinary disorders
Proteinuria
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	11 / 25 (44.00%)	0 / 14 (0.00%)
occurrences all number	0	0	4	0	0	16	0
Back pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	2 / 8 (25.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	10 / 25 (40.00%)	1 / 14 (7.14%)
occurrences all number	0	0	4	0	0	38	1
Pain in extremity
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	9 / 25 (36.00%)	0 / 14 (0.00%)
occurrences all number	0	0	2	0	0	26	0
Infections and infestations
Rhinitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	2 / 8 (25.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	16 / 25 (64.00%)	0 / 14 (0.00%)
occurrences all number	0	0	4	0	0	31	0
Nasopharyngitis
subjects affected / exposed	1 / 4 (25.00%)	1 / 8 (12.50%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	13 / 25 (52.00%)	4 / 14 (28.57%)
occurrences all number	3	1	2	0	0	39	4
Gastroenteritis
subjects affected / exposed	1 / 4 (25.00%)	1 / 8 (12.50%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	8 / 25 (32.00%)	0 / 14 (0.00%)
occurrences all number	3	1	2	0	0	14	0
Influenza
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	5 / 25 (20.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	7	0
Ear infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	3 / 25 (12.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	1	0	3	1
Viral upper respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	3 / 25 (12.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	4	0
Conjunctivitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Gastroenteritis viral
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	4	0
Lower respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	4	0
Oral herpes
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Otitis media
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	2 / 14 (14.29%)
occurrences all number	0	0	0	0	0	3	2
Tonsillitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 25 (8.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Bronchitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 25 (4.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	1	1
Device related infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 25 (4.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	1	0
Hordeolum
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 25 (4.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	1	1
Upper respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 25 (4.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	3	1
Viral infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 25 (4.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	1	1
Bronchiolitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 25 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	0	1
Scarlet fever
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 25 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	0	1
Cystitis
subjects affected / exposed	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 25 (0.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	0	0
Metabolism and nutrition disorders
Iron deficiency
subjects affected / exposed	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 25 (4.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	1	0
Decreased appetite
subjects affected / exposed	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 25 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	0	1

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

07 Aug 2014

Amendment 1: Added the occurrence of greater than or equal to (>=) 2 severe AEs to the stopping rules. Added that if interruption of dosing was warranted at the discretion of Sarepta or Investigation, re-initiation of dosing was permitted, if deemed appropriate following safety data review by Sarepta.

19 Nov 2014

Amendment 2: Changed magnetic resonance imagings (MRIs) to optional at 12 weeks and 24 weeks for the untreated control group in Part 2. Removed the Week 36 leg muscle MRI for both treated and untreated groups in Part 2. Removed the untreated control group Part 2 Week 1 functional assessments for North Star Ambulatory Assessment (NSAA), 6MWT, pulmonary function tests, and the timed 4-step. Removed the assessment of vital signs for the untreated control group from Weeks 5 to 7, 9 to 11, 13 to 15, 17 to 19, 21 to 23, 25 to 35, and 37 to 47. Updated language for the untreated control group functional assessments in Study Assessments. Clarified that subjects in the untreated control group could have been enrolled concurrently in an observational study, unless it interfered with assessments in this study. Corrected the concentration of the human equivalent dose in Rationale for Initial Dose.

07 Apr 2015

Amendment 3: Changed the stopping rule regarding increases in serum creatinine to take into account the natural variability of serum creatinine levels observed in DMD subjects and to reflect the standard practice of requiring a confirmatory laboratory test for changes in test results. Reduced the frequency of assessments for the untreated control group in Part 2 of the study in order to reduce the burden on subjects and parents in this group. Separated the informed consent from the inclusion/exclusion criteria assessments. Removed the assessment of anti-PMO antibodies from the study.

09 Oct 2015

Amendment 4: Added an Extension Phase to Part 2, which extended the Part 2 treatment period by 96 weeks and defined the end of study as Week 148 (144 weeks of treatment and a follow-up safety visit 4 weeks after the last on-study dose). This included adding a schedule of assessments for the safety extension phase in Part 2.

20 Apr 2016

Amendment 5: Part 2 and the Part 2 Extension Phase, which was added in Amendment 4, were combined. In addition, the comparison period between treated subjects and untreated control subjects was extended from Week 48 (original end of Part 2) to Week 144 (end of Extension Phase of Part 2). Clarified that new subjects in Part 2 were treatment-naïve. Added specific information on requirements for muscle biopsies at Week 48. Clarified that modifications to dose based on weight was acceptable, provided the dose was equivalent. Included immunogenicity in safety endpoints. Clarified strategy for interim review of safety and efficacy data by the DSMB. Changed that magnetic resonance scans were to be performed at Baseline and Week 12 of Part 1, not at Week 1. Added the collection of blood samples at Week 1 prior to the first infusion to provide a baseline for biomarkers and immunogenicity. Clarified that control subjects were to undergo all procedures at Screening and Baseline except for skin/muscle biopsies. Added MoviPlate to Screening/Baseline assessments. Added language regarding an interim analysis and specified that safety data were to be reviewed in an ongoing basis by the DSMB.

20 Oct 2016

Amendment 6: Removed actimetry as an endpoint due to problems with the measurement device (ActiMyo).

21 Apr 2017

Amendment 7: Added text to distinguish the difference between efficacy and biological (ie, pharmacodynamics) endpoints. Switched the primary biological endpoint (percentage of dystrophin-positive fibers) with a secondary biological endpoint (dystrophin protein levels by Western blot).

08 Nov 2017

Amendment 8: Extended the treatment period for golodirsen-treated subjects from 144 weeks to 168 weeks, thereby also extending the total study duration for golodirsen-treated subjects from 166 weeks to 190 weeks. Added the option of actimetry assessment at Week 144 (±2 weeks) using a newly available version of the ActiMyo device. Specified that forced vital capacity% was the key respiratory function endpoint. Added an interim analysis to permit muscle biopsy analysis after the last biopsy was collected (i.e, after all golodirsen-treated subjects from Part 1 and Part 2 had completed the Week 48 muscle biopsy in Part 2).

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

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

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

Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part 1: Number of Subjects with Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation

Primary: Part 1: Number of Subjects with Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation

Primary: Part 1: Number of Subjects With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs

Primary: Part 1: Number of Subjects With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs

Primary: Part 1: Number of Subjects With Potentially Clinically Significant Abnormalities in Vital Signs Reported as TEAEs

Primary: Part 1: Number of Subjects With Potentially Clinically Significant Abnormalities in Vital Signs Reported as TEAEs

Primary: Part 1: Number of Subjects With Potentially Clinically Significant Abnormalities in Physical Examinations

Primary: Part 1: Number of Subjects With Potentially Clinically Significant Abnormalities in Physical Examinations

Primary: Part 1: Number of Subjects With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Reported as TEAEs

Primary: Part 1: Number of Subjects With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Reported as TEAEs

Primary: Part 1: Number of Subjects With Potentially Clinically Significant Abnormalities in Echocardiograms (ECHO)

Primary: Part 1: Number of Subjects With Potentially Clinically Significant Abnormalities in Echocardiograms (ECHO)

Primary: Part 2a: Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) at Week 144 in Total Golodirsen Group

Primary: Part 2a: Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) at Week 144 in Total Golodirsen Group

Primary: Part 2a: Change from Baseline in Dystrophin Protein Levels Determined by Western Blot at Week 48 in Total Golodirsen Group

Primary: Part 2a: Change from Baseline in Dystrophin Protein Levels Determined by Western Blot at Week 48 in Total Golodirsen Group

Primary: Part 2b: Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) at Week 144 in Untreated Group (Natural History of Non-exon 53)

Primary: Part 2b: Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) at Week 144 in Untreated Group (Natural History of Non-exon 53)

Secondary: Part 1: Maximum Plasma Concentration (Cmax) of Golodirsen

Secondary: Part 1: Maximum Plasma Concentration (Cmax) of Golodirsen

Secondary: Part 1: Time to Reach Maximum Plasma Concentration (Tmax) of Golodirsen

Secondary: Part 1: Time to Reach Maximum Plasma Concentration (Tmax) of Golodirsen

Secondary: Part 1: Area Under the Concentration-Time Curve From Time Zero Extrapolated to the Infinity (AUCinf) of Golodirsen in Plasma

Secondary: Part 1: Area Under the Concentration-Time Curve From Time Zero Extrapolated to the Infinity (AUCinf) of Golodirsen in Plasma

Secondary: Part 1: Apparent Volume of Distribution at Steady State (Vss) of Golodirsen

Secondary: Part 1: Apparent Volume of Distribution at Steady State (Vss) of Golodirsen

Secondary: Part 1: Elimination Half-life (T1/2) of Golodirsen

Secondary: Part 1: Elimination Half-life (T1/2) of Golodirsen

Secondary: Part 1: Total Clearance (CL) of Golodirsen

Secondary: Part 1: Total Clearance (CL) of Golodirsen

Secondary: Part 1: Mean Residence Time (MRT) of Golodirsen

Secondary: Part 1: Mean Residence Time (MRT) of Golodirsen

Secondary: Part 1: Renal Clearance (CLR) of Golodirsen

Secondary: Part 1: Renal Clearance (CLR) of Golodirsen

Secondary: Part 2a: Percent Change from Baseline in Forced Vital Capacity Predicted (FVC %p) to Week144 in Total Golodirsen Group

Secondary: Part 2a: Percent Change from Baseline in Forced Vital Capacity Predicted (FVC %p) to Week144 in Total Golodirsen Group

Secondary: Part 2a: Change from Baseline in Dystrophin Intensity Levels Determined by Immunohistochemistry (IHC) at Week 48 in Total Golodirsen Group

Secondary: Part 2a: Change from Baseline in Dystrophin Intensity Levels Determined by Immunohistochemistry (IHC) at Week 48 in Total Golodirsen Group

Secondary: Part 2a: Percent Change from Baseline in Exon 53 Skipping Determined by Reverse Transcription Polymerase Chain Reaction (PCR) at Week 48 in Total Golodirsen Group

Secondary: Part 2a: Percent Change from Baseline in Exon 53 Skipping Determined by Reverse Transcription Polymerase Chain Reaction (PCR) at Week 48 in Total Golodirsen Group

Secondary: Part 2a: Percent Change from Baseline in Dystrophin Positive Fibers Determined by Immunohistochemistry (IHC) at Week 48 in Total Golodirsen Group

Secondary: Part 2a: Percent Change from Baseline in Dystrophin Positive Fibers Determined by Immunohistochemistry (IHC) at Week 48 in Total Golodirsen Group

Secondary: Part 2b: Percent Change From Baseline in Forced Vital Capacity Predicted (FVC%p) at Week144 in Untreated Group (Natural History of Non-exon 53)

Secondary: Part 2b: Percent Change From Baseline in Forced Vital Capacity Predicted (FVC%p) at Week144 in Untreated Group (Natural History of Non-exon 53)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information