Duchenne Muscular Dystrophy
Conditions
Keywords
Duchenne muscular dystrophy, Exon Skipping, DMD, Exon 53, Ambulatory, Pediatric
Brief summary
This is a first-in-human, multiple-dose 2-part study to assess the safety, tolerability, efficacy, and pharmacokinetics of SRP-4053 in Duchenne muscular dystrophy (DMD) patients with deletions amenable to exon 53 skipping.
Detailed description
Part 1: Randomized, placebo-controlled dose-titration to assess safety, tolerability and pharmacokinetics of 4 dose levels of SRP-4053 in genotypically-confirmed DMD patients with deletions amenable to exon 53 skipping. Part 2: Open-label evaluation of SRP-4053 in patients from Part 1, along with newly enrolled DMD patients with deletions amenable to exon 53 skipping and an untreated group of DMD patients with deletions not amenable to exon 53 skipping. Safety, including adverse event monitoring and routine laboratory assessments, will be followed on an ongoing basis for all patients. Clinical efficacy, including functional tests such as the six-minute walk test (6MWT), will be assessed at regularly scheduled study visits. Patients in the treated groups will undergo one baseline and one follow-up muscle biopsy. Patients in the untreated group will not undergo biopsies and will follow an abbreviated schedule of study assessments.
Interventions
DRUGPlacebo
SRP-4053 placebo-matching solution for IV infusion.
DRUGSRP-4053
SRP-4053 (golodirsen) solution for IV infusion.
Sponsors
Institut de Myologie, France
Consultants for Research in Imaging and Spectroscopy
Great Ormond Street Hospital for Children NHS Foundation Trust
Catholic University of the Sacred Heart
Royal Holloway University
SYSNAV
University College, London
University of Newcastle Upon-Tyne
Sarepta Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Masking Description: Part 1 is double-blind and randomized; Part 2 is open-label.
Eligibility
Sex/Gender
MALE
Age
6 Years to 15 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosed with DMD, genotypically confirmed. * Intact right and left biceps muscles or an alternative upper arm muscle group. * Stable pulmonary and cardiac function. * Minimum performance on 6MWT, North Star Ambulatory Assessment, and rise (Gowers) test as specified in the study protocol. * On a stable dose of corticosteroids for at least 6 months.
Exclusion criteria
* Previous treatment with the experimental agents BMN-195 (SMT C1100) or PRO053. * Current or previous treatment with any other experimental treatments within 12 weeks prior to study entry. * Major surgery within the last 3 months. * Presence of other clinically significant illness. * Major change in physical therapy regime within the last 3 months. Other inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation | Baseline up to Week 12 | Adverse event (AE) was any untoward medical occurrence in a clinical trial participant, 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: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Baseline up to Week 12 | Laboratory parameters included hematology, serum chemistry (SC), urinalysis and coagulation. Number of participants with at least one potentially clinically significant abnormal finding 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: Number of Participants With Potentially Clinically Significant Abnormalities in Vital Signs Reported as TEAEs | Baseline up to Week 12 | Vital sign parameters included systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and body temperature. Number of participants 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: Number of Participants With Potentially Clinically Significant Abnormalities in Physical Examinations | Baseline up to Week 12 | 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 participants 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: Number of Participants With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Reported as TEAEs | Baseline up to Week 12 | Twelve-lead ECGs were performed at a consistent time of day throughout the study. Electrocardiograms were performed only after the participant 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 participants 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: Number of Participants With Potentially Clinically Significant Abnormalities in Echocardiograms (ECHO) | Baseline up to Week 12 | 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 participants with potentially clinically significant abnormalities in ECHO were reported. |
| Part 2a: Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) at Week 144 in Total Golodirsen Group | Baseline and Week 144 | 6MWT was performed by standardized procedures for all participants. Participants 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. |
| Part 2b: Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) at Week 144 in Untreated Group (Non-exon 53 Amenable Participants) | Baseline and Week 144 | 6MWT was performed by standardized procedures for all participants. Participants 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 (non-exon 53 amenable participants) was calculated. |
| Part 2a: Change From Baseline in Dystrophin Protein Levels Determined by Western Blot at Week 48 in Total Golodirsen Group | Baseline, Week 48 | Change from baseline in dystrophin protein levels (in muscle biopsy samples) was determined by Western blot in total golodirsen group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2b: Percent Change From Baseline in Forced Vital Capacity Predicted (FVC%p) at Week144 in Untreated Group (Non-exon 53 Amenable Participants) | Baseline, Week 144 | FVC was the total amount of air exhaled during the forced expiratory volume test that was measured during spirometry and is the most important measurement of lung function. This test requires participant 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 participant bronchial (breathing) tubes. Percent of predicted FVC = (observed value)/ (predicted value) \* 100%. |
| Part 2a: Change From Baseline in Dystrophin Intensity Levels Determined by Immunohistochemistry (IHC) at Week 48 in Total Golodirsen Group | Baseline, Week 48 | Change from baseline in dystrophin Intensity levels (in muscle biopsy samples) was determined by Immunohistochemistry in total golodirsen group. |
| Part 1: Time to Reach Maximum Plasma Concentration (Tmax) of Golodirsen | 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) | Time to reach maximum plasma concentration (Tmax) of golodirsen was evaluated. |
| Part 2a: Percent Change From Baseline in Dystrophin Positive Fibers Determined by Immunohistochemistry (IHC) at Week 48 in Total Golodirsen Group | Baseline, Week 48 | Percent change from baseline in dystrophin positive fibers (in muscle biopsy samples) were determined by Immunohistochemistry at Week 48 in total golodirsen group. |
| 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 | Baseline, Week 48 | Percent change from baseline in Exon 53 skipping (in muscle biopsy samples) was determined by reverse transcription polymerase chain reaction in total golodirsen group. |
| Part 1: Maximum Plasma Concentration (Cmax) of Golodirsen | 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) | Maximum Concentration (Cmax) of golodirsen in plasma was evaluated. |
| Part 1: Area Under the Concentration-Time Curve From Time Zero Extrapolated to the Infinity (AUCinf) of Golodirsen in Plasma | 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) | Area under the concentration-time curve from time zero extrapolated to the infinity was evaluated. |
| Part 1: Apparent Volume of Distribution at Steady State (Vss) of Golodirsen | 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) | 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. |
| Part 1: Elimination Half-life (T1/2) of Golodirsen | 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) | T1/2 is the time measured for the plasma concentration of drug to decrease by one half. T1/2 of golodirsen was evaluated. |
| Part 1: Total Clearance (CL) of Golodirsen | 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) | Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. |
| Part 1: Mean Residence Time (MRT) of Golodirsen | 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) | 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. |
| Part 1: Renal Clearance (CLR) of Golodirsen | 0 to 1440 min after initiation of dosing on Day 1 | 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 are reported. |
| Part 2a: Percent Change From Baseline in Forced Vital Capacity Predicted (FVC%p) at Week144 in Total Golodirsen Group | Baseline, Week 144 | FVC was the total amount of air exhaled during the forced expiratory volume test that was measured during spirometry and the most important measurement of lung function. This test required participant 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 participant bronchial (breathing) tubes. Percent of predicted FVC = (observed value)/ (predicted value) \* 100%. |
Countries
France, Italy, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 5 sites in the France, Italy, United Kingdom and United States from 13 January 2015 to 25 March 2019.
Pre-assignment 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.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Placebo Participants received placebo-matched to golodirsen intravenous (IV) infusions, once weekly up to 12 weeks in Part 1. | 4 |
| Part 1: Golodirsen Participants 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. | 8 |
| Part 2a: Total Golodirsen Group All participants from Part 1 (who previously received placebo or golodirsen) and including additional new participants 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. | 25 |
| Part 2b: Untreated Group (Natural History of Non-exon 53) Untreated participants 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. Participants underwent the same study assessments as treated participants in other reporting groups (except for PK sampling and muscle biopsies), but at a reduced schedule through Week 144. Thus, the untreated participants were not considered as control group. | 14 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Part 2: Open Label Phase (168 Weeks) | Enrollment in other therapeutic study | 0 | 0 | 0 | 2 |
| Part 2: Open Label Phase (168 Weeks) | Lost to Follow-up | 0 | 0 | 0 | 1 |
| Part 2: Open Label Phase (168 Weeks) | Personal reasons | 0 | 0 | 0 | 1 |
| Part 2: Open Label Phase (168 Weeks) | Withdrawal by Subject | 0 | 0 | 2 | 4 |
Baseline characteristics
| Characteristic | Part 1: Placebo | Part 1: Golodirsen | Total | Part 2a: Total Golodirsen Group | Part 2b: Untreated Group (Natural History of Non-exon 53) |
|---|---|---|---|---|---|
| Age, Continuous Part 1 | 7.0 years STANDARD_DEVIATION 0.82 | 8.6 years STANDARD_DEVIATION 2.07 | 8.1 years STANDARD_DEVIATION 1.88 | — | — |
| Age, Continuous Part 2 | — | — | 8.4 years STANDARD_DEVIATION 2.06 | 8.4 years STANDARD_DEVIATION 2.18 | 8.5 years STANDARD_DEVIATION 1.91 |
| Ethnicity (NIH/OMB) Part 1 Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants | — | — |
| Ethnicity (NIH/OMB) Part 1 Not Hispanic or Latino | 1 Participants | 4 Participants | 5 Participants | — | — |
| Ethnicity (NIH/OMB) Part 1 Unknown or Not Reported | 2 Participants | 3 Participants | 5 Participants | — | — |
| Ethnicity (NIH/OMB) Part 2 Hispanic or Latino | — | — | 4 Participants | 4 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Part 2 Not Hispanic or Latino | — | — | 18 Participants | 9 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Part 2 Unknown or Not Reported | — | — | 17 Participants | 12 Participants | 5 Participants |
| Race (NIH/OMB) Part 1 American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Part 1 Asian | 0 Participants | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Part 1 Black or African American | 0 Participants | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Part 1 More than one race | 1 Participants | 0 Participants | 1 Participants | — | — |
| Race (NIH/OMB) Part 1 Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Part 1 Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Part 1 White | 3 Participants | 8 Participants | 11 Participants | — | — |
| Race (NIH/OMB) Part 2 American Indian or Alaska Native | — | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Part 2 Asian | — | — | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Part 2 Black or African American | — | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Part 2 More than one race | — | — | 4 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Part 2 Native Hawaiian or Other Pacific Islander | — | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Part 2 Unknown or Not Reported | — | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Part 2 White | — | — | 34 Participants | 23 Participants | 11 Participants |
| Sex: Female, Male Part 1 Female | 0 Participants | 0 Participants | 0 Participants | — | — |
| Sex: Female, Male Part 1 Male | 4 Participants | 8 Participants | 12 Participants | — | — |
| Sex: Female, Male Part 2 Female | — | — | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Part 2 Male | — | — | 39 Participants | 25 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 25 | 0 / 14 |
| other Total, other adverse events | 4 / 4 | 5 / 8 | 5 / 8 | 3 / 8 | 6 / 8 | 25 / 25 | 10 / 14 |
| serious Total, serious adverse events | 0 / 4 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 4 / 25 | 2 / 14 |
Outcome results
Primary
Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Echocardiograms (ECHO)
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 participants with potentially clinically significant abnormalities in ECHO were reported.
Time frame: Baseline up to Week 12
Population: Part 1 safety set included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Placebo | Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Echocardiograms (ECHO) | 0 Participants |
| Part 1: Golodirsen (4 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Echocardiograms (ECHO) | 0 Participants |
| Part 1: Golodirsen (10 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Echocardiograms (ECHO) | 0 Participants |
| Part 1: Golodirsen (20 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Echocardiograms (ECHO) | 0 Participants |
| Part 1: Golodirsen (30 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Echocardiograms (ECHO) | 3 Participants |
Primary
Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Reported as TEAEs
Twelve-lead ECGs were performed at a consistent time of day throughout the study. Electrocardiograms were performed only after the participant 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 participants 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.
Time frame: Baseline up to Week 12
Population: Part 1 safety set included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Placebo | Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Reported as TEAEs | 0 Participants |
| Part 1: Golodirsen (4 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Reported as TEAEs | 1 Participants |
| Part 1: Golodirsen (10 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Reported as TEAEs | 0 Participants |
| Part 1: Golodirsen (20 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Reported as TEAEs | 0 Participants |
| Part 1: Golodirsen (30 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Reported as TEAEs | 0 Participants |
Primary
Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Physical Examinations
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 participants with potentially clinically significant abnormalities in physical examinations were reported. Potentially clinically significant abnormalities in physical examinations were based on Investigator's discretion.
Time frame: Baseline up to Week 12
Population: Part 1 safety set included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Placebo | Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Physical Examinations | 0 Participants |
| Part 1: Golodirsen (4 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Physical Examinations | 0 Participants |
| Part 1: Golodirsen (10 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Physical Examinations | 2 Participants |
| Part 1: Golodirsen (20 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Physical Examinations | 0 Participants |
| Part 1: Golodirsen (30 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Physical Examinations | 3 Participants |
Primary
Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Vital Signs Reported as TEAEs
Vital sign parameters included systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and body temperature. Number of participants 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.
Time frame: Baseline up to Week 12
Population: Part 1 safety set included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Placebo | Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Vital Signs Reported as TEAEs | 1 Participants |
| Part 1: Golodirsen (4 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Vital Signs Reported as TEAEs | 3 Participants |
| Part 1: Golodirsen (10 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Vital Signs Reported as TEAEs | 1 Participants |
| Part 1: Golodirsen (20 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Vital Signs Reported as TEAEs | 1 Participants |
| Part 1: Golodirsen (30 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Vital Signs Reported as TEAEs | 4 Participants |
Primary
Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs
Laboratory parameters included hematology, serum chemistry (SC), urinalysis and coagulation. Number of participants with at least one potentially clinically significant abnormal finding 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.
Time frame: Baseline up to Week 12
Population: Part 1 safety set included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Placebo | Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Hepatic Chemistry | 0 Participants |
| Part 1: Placebo | Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Renal Chemistry | 0 Participants |
| Part 1: Placebo | Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Hematology | 2 Participants |
| Part 1: Placebo | Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Coagulation | 0 Participants |
| Part 1: Placebo | Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Urinalysis | 0 Participants |
| Part 1: Golodirsen (4 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Urinalysis | 0 Participants |
| Part 1: Golodirsen (4 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Hematology | 0 Participants |
| Part 1: Golodirsen (4 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Hepatic Chemistry | 0 Participants |
| Part 1: Golodirsen (4 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Coagulation | 0 Participants |
| Part 1: Golodirsen (4 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Renal Chemistry | 0 Participants |
| Part 1: Golodirsen (10 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Hepatic Chemistry | 0 Participants |
| Part 1: Golodirsen (10 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Coagulation | 0 Participants |
| Part 1: Golodirsen (10 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Hematology | 1 Participants |
| Part 1: Golodirsen (10 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Renal Chemistry | 0 Participants |
| Part 1: Golodirsen (10 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Urinalysis | 0 Participants |
| Part 1: Golodirsen (20 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Urinalysis | 0 Participants |
| Part 1: Golodirsen (20 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Hepatic Chemistry | 0 Participants |
| Part 1: Golodirsen (20 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Renal Chemistry | 0 Participants |
| Part 1: Golodirsen (20 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Hematology | 0 Participants |
| Part 1: Golodirsen (20 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Coagulation | 0 Participants |
| Part 1: Golodirsen (30 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Coagulation | 0 Participants |
| Part 1: Golodirsen (30 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Urinalysis | 0 Participants |
| Part 1: Golodirsen (30 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Renal Chemistry | 0 Participants |
| Part 1: Golodirsen (30 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Hepatic Chemistry | 0 Participants |
| Part 1: Golodirsen (30 mg/kg) | Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Hematology | 0 Participants |
Primary
Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation
Adverse event (AE) was any untoward medical occurrence in a clinical trial participant, 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.
Time frame: Baseline up to Week 12
Population: Part 1 safety set included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Placebo | Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation | Participants with TEAE | 4 Participants |
| Part 1: Placebo | Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation | Participants with TEAEs leading to discontinuation | 0 Participants |
| Part 1: Placebo | Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation | Participants with Serious TEAE | 0 Participants |
| Part 1: Golodirsen (4 mg/kg) | Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation | Participants with Serious TEAE | 0 Participants |
| Part 1: Golodirsen (4 mg/kg) | Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation | Participants with TEAE | 5 Participants |
| Part 1: Golodirsen (4 mg/kg) | Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation | Participants with TEAEs leading to discontinuation | 0 Participants |
| Part 1: Golodirsen (10 mg/kg) | Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation | Participants with Serious TEAE | 0 Participants |
| Part 1: Golodirsen (10 mg/kg) | Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation | Participants with TEAE | 5 Participants |
| Part 1: Golodirsen (10 mg/kg) | Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation | Participants with TEAEs leading to discontinuation | 0 Participants |
| Part 1: Golodirsen (20 mg/kg) | Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation | Participants with TEAE | 3 Participants |
| Part 1: Golodirsen (20 mg/kg) | Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation | Participants with TEAEs leading to discontinuation | 0 Participants |
| Part 1: Golodirsen (20 mg/kg) | Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation | Participants with Serious TEAE | 0 Participants |
| Part 1: Golodirsen (30 mg/kg) | Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation | Participants with Serious TEAE | 0 Participants |
| Part 1: Golodirsen (30 mg/kg) | Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation | Participants with TEAE | 6 Participants |
| Part 1: Golodirsen (30 mg/kg) | Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation | Participants with TEAEs leading to discontinuation | 0 Participants |
Primary
Part 2a: Change From Baseline in Dystrophin Protein Levels Determined by Western Blot at Week 48 in Total Golodirsen Group
Change from baseline in dystrophin protein levels (in muscle biopsy samples) was determined by Western blot in total golodirsen group.
Time frame: Baseline, Week 48
Population: Muscle biopsy set included all participants 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 was not planned to be collected and analyzed for untreated group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo | Part 2a: Change From Baseline in Dystrophin Protein Levels Determined by Western Blot at Week 48 in Total Golodirsen Group | 0.924 Percent normal dystrophin protein level | Standard Deviation 1.0129 |
Primary
Part 2a: Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) at Week 144 in Total Golodirsen Group
6MWT was performed by standardized procedures for all participants. Participants 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.
Time frame: Baseline and Week 144
Population: Efficacy set consisted of all randomized participants who had at least one post baseline functional assessment. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo | Part 2a: Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) at Week 144 in Total Golodirsen Group | -99.0 meters | Standard Deviation 123.75 |
Primary
Part 2b: Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) at Week 144 in Untreated Group (Non-exon 53 Amenable Participants)
6MWT was performed by standardized procedures for all participants. Participants 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 (non-exon 53 amenable participants) was calculated.
Time frame: Baseline and Week 144
Population: Efficacy set consisted of all randomized participants who had at least one post baseline functional assessment. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo | Part 2b: Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) at Week 144 in Untreated Group (Non-exon 53 Amenable Participants) | -160.8 Meters | Standard Deviation 162.41 |
Secondary
Part 1: Apparent Volume of Distribution at Steady State (Vss) of Golodirsen
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.
Time frame: 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)
Population: PK set: all randomized participants from Part 1 who received planned full dose of study drug, for whom there were adequate PK samples from which to estimate PK parameters. Overall number of participants analyzed= number of participants evaluable for this outcome. Data were not planned to be collected and analyzed for the placebo arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo | Part 1: Apparent Volume of Distribution at Steady State (Vss) of Golodirsen | 0.670 Liter per kilogram (L/kg) | Geometric Coefficient of Variation 38.6 |
| Part 1: Golodirsen (4 mg/kg) | Part 1: Apparent Volume of Distribution at Steady State (Vss) of Golodirsen | 0.767 Liter per kilogram (L/kg) | Geometric Coefficient of Variation 43.4 |
| Part 1: Golodirsen (10 mg/kg) | Part 1: Apparent Volume of Distribution at Steady State (Vss) of Golodirsen | 0.576 Liter per kilogram (L/kg) | Geometric Coefficient of Variation 84.5 |
| Part 1: Golodirsen (20 mg/kg) | Part 1: Apparent Volume of Distribution at Steady State (Vss) of Golodirsen | 0.668 Liter per kilogram (L/kg) | Geometric Coefficient of Variation 32.3 |
Secondary
Part 1: Area Under the Concentration-Time Curve From Time Zero Extrapolated to the Infinity (AUCinf) of Golodirsen in Plasma
Area under the concentration-time curve from time zero extrapolated to the infinity was evaluated.
Time frame: 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)
Population: PK set: all randomized participants 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. Overall number of participants analyzed= number of participants evaluable for this outcome. Data were not planned to be collected and analyzed for the placebo arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo | Part 1: Area Under the Concentration-Time Curve From Time Zero Extrapolated to the Infinity (AUCinf) of Golodirsen in Plasma | 11800 hr*ng/mL | Geometric Coefficient of Variation 35.5 |
| Part 1: Golodirsen (4 mg/kg) | Part 1: Area Under the Concentration-Time Curve From Time Zero Extrapolated to the Infinity (AUCinf) of Golodirsen in Plasma | 26400 hr*ng/mL | Geometric Coefficient of Variation 42.7 |
| Part 1: Golodirsen (10 mg/kg) | Part 1: Area Under the Concentration-Time Curve From Time Zero Extrapolated to the Infinity (AUCinf) of Golodirsen in Plasma | 62300 hr*ng/mL | Geometric Coefficient of Variation 52.6 |
| Part 1: Golodirsen (20 mg/kg) | Part 1: Area Under the Concentration-Time Curve From Time Zero Extrapolated to the Infinity (AUCinf) of Golodirsen in Plasma | 90800 hr*ng/mL | Geometric Coefficient of Variation 33.4 |
Secondary
Part 1: Elimination Half-life (T1/2) of Golodirsen
T1/2 is the time measured for the plasma concentration of drug to decrease by one half. T1/2 of golodirsen was evaluated.
Time frame: 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)
Population: PK set: all randomized participants from Part 1 who received planned full dose of study drug, for whom there were adequate PK samples from which to estimate PK parameters. Overall number of participants analyzed= number of participants evaluable for this outcome. Data were not planned to be collected and analyzed for the placebo arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo | Part 1: Elimination Half-life (T1/2) of Golodirsen | 2.36 hour | Standard Deviation 0.581 |
| Part 1: Golodirsen (4 mg/kg) | Part 1: Elimination Half-life (T1/2) of Golodirsen | 3.63 hour | Standard Deviation 2.04 |
| Part 1: Golodirsen (10 mg/kg) | Part 1: Elimination Half-life (T1/2) of Golodirsen | 3.27 hour | Standard Deviation 0.897 |
| Part 1: Golodirsen (20 mg/kg) | Part 1: Elimination Half-life (T1/2) of Golodirsen | 3.42 hour | Standard Deviation 0.628 |
Secondary
Part 1: Maximum Plasma Concentration (Cmax) of Golodirsen
Maximum Concentration (Cmax) of golodirsen in plasma was evaluated.
Time frame: 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)
Population: Pharmacokinetic (PK) set consisted of all randomized participants 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 were not planned to be collected and analyzed for the placebo arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo | Part 1: Maximum Plasma Concentration (Cmax) of Golodirsen | 7840 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 45.7 |
| Part 1: Golodirsen (4 mg/kg) | Part 1: Maximum Plasma Concentration (Cmax) of Golodirsen | 17000 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 40.9 |
| Part 1: Golodirsen (10 mg/kg) | Part 1: Maximum Plasma Concentration (Cmax) of Golodirsen | 39700 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 71.8 |
| Part 1: Golodirsen (20 mg/kg) | Part 1: Maximum Plasma Concentration (Cmax) of Golodirsen | 53300 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 37.9 |
Secondary
Part 1: Mean Residence Time (MRT) of Golodirsen
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.
Time frame: 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)
Population: PK set: all randomized participants from Part 1 who received planned full dose of study drug, for whom there were adequate PK samples from which to estimate PK parameters. Overall number of participants analyzed= number of participants evaluable for this outcome. Data were not planned to be collected and analyzed for the placebo arm
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo | Part 1: Mean Residence Time (MRT) of Golodirsen | 1.79 hour | Standard Deviation 0.325 |
| Part 1: Golodirsen (4 mg/kg) | Part 1: Mean Residence Time (MRT) of Golodirsen | 1.92 hour | Standard Deviation 0.338 |
| Part 1: Golodirsen (10 mg/kg) | Part 1: Mean Residence Time (MRT) of Golodirsen | 1.77 hour | Standard Deviation 0.495 |
| Part 1: Golodirsen (20 mg/kg) | Part 1: Mean Residence Time (MRT) of Golodirsen | 1.95 hour | Standard Deviation 0.312 |
Secondary
Part 1: Renal Clearance (CLR) of Golodirsen
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 are reported.
Time frame: 0 to 1440 min after initiation of dosing on Day 1
Population: PK set: all randomized participants from Part 1 who received planned full dose of study drug, for whom there were adequate PK samples from which to estimate PK parameters. Overall number of participants analyzed= number of participants evaluable for this outcome. Data were not planned to be collected and analyzed for the placebo arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo | Part 1: Renal Clearance (CLR) of Golodirsen | 0.345 L/h/kg | Geometric Coefficient of Variation 31.9 |
| Part 1: Golodirsen (4 mg/kg) | Part 1: Renal Clearance (CLR) of Golodirsen | 0.370 L/h/kg | Geometric Coefficient of Variation 50.6 |
| Part 1: Golodirsen (10 mg/kg) | Part 1: Renal Clearance (CLR) of Golodirsen | 0.355 L/h/kg | Geometric Coefficient of Variation 42.1 |
| Part 1: Golodirsen (20 mg/kg) | Part 1: Renal Clearance (CLR) of Golodirsen | 0.374 L/h/kg | Geometric Coefficient of Variation 26.8 |
Secondary
Part 1: Time to Reach Maximum Plasma Concentration (Tmax) of Golodirsen
Time to reach maximum plasma concentration (Tmax) of golodirsen was evaluated.
Time frame: 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)
Population: PK set consisted of all randomized participants 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 were not planned to be collected and analyzed for the placebo arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Placebo | Part 1: Time to Reach Maximum Plasma Concentration (Tmax) of Golodirsen | 1.11 hour |
| Part 1: Golodirsen (4 mg/kg) | Part 1: Time to Reach Maximum Plasma Concentration (Tmax) of Golodirsen | 1.09 hour |
| Part 1: Golodirsen (10 mg/kg) | Part 1: Time to Reach Maximum Plasma Concentration (Tmax) of Golodirsen | 1.12 hour |
| Part 1: Golodirsen (20 mg/kg) | Part 1: Time to Reach Maximum Plasma Concentration (Tmax) of Golodirsen | 1.12 hour |
Secondary
Part 1: Total Clearance (CL) of Golodirsen
Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Time frame: 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)
Population: PK set: all randomized participants from Part 1 who received planned full dose of study drug, for whom there were adequate PK samples from which to estimate PK parameters. Overall number of participants analyzed= number of participants evaluable for this outcome. Data were not planned to be collected and analyzed for the placebo arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo | Part 1: Total Clearance (CL) of Golodirsen | 0.381 Liters per hour per kilogram (L/h/kg) | Standard Deviation 36 |
| Part 1: Golodirsen (4 mg/kg) | Part 1: Total Clearance (CL) of Golodirsen | 0.405 Liters per hour per kilogram (L/h/kg) | Standard Deviation 46.2 |
| Part 1: Golodirsen (10 mg/kg) | Part 1: Total Clearance (CL) of Golodirsen | 0.338 Liters per hour per kilogram (L/h/kg) | Standard Deviation 52.2 |
| Part 1: Golodirsen (20 mg/kg) | Part 1: Total Clearance (CL) of Golodirsen | 0.346 Liters per hour per kilogram (L/h/kg) | Standard Deviation 34.3 |
Secondary
Part 2a: Change From Baseline in Dystrophin Intensity Levels Determined by Immunohistochemistry (IHC) at Week 48 in Total Golodirsen Group
Change from baseline in dystrophin Intensity levels (in muscle biopsy samples) was determined by Immunohistochemistry in total golodirsen group.
Time frame: Baseline, Week 48
Population: Muscle biopsy set included all participants 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 were not planned to be collected and analyzed for the untreated group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo | Part 2a: Change From Baseline in Dystrophin Intensity Levels Determined by Immunohistochemistry (IHC) at Week 48 in Total Golodirsen Group | 0.023 Percent dystrophin positive fibers | Standard Deviation 0.0243 |
Secondary
Part 2a: Percent Change From Baseline in Dystrophin Positive Fibers Determined by Immunohistochemistry (IHC) at Week 48 in Total Golodirsen Group
Percent change from baseline in dystrophin positive fibers (in muscle biopsy samples) were determined by Immunohistochemistry at Week 48 in total golodirsen group.
Time frame: Baseline, Week 48
Population: Muscle biopsy set included all participants 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 were not planned to be collected and analyzed for the untreated group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo | Part 2a: Percent Change From Baseline in Dystrophin Positive Fibers Determined by Immunohistochemistry (IHC) at Week 48 in Total Golodirsen Group | 12.508 Percent change | Standard Deviation 14.6012 |
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
Percent change from baseline in Exon 53 skipping (in muscle biopsy samples) was determined by reverse transcription polymerase chain reaction in total golodirsen group.
Time frame: Baseline, Week 48
Population: Muscle biopsy set included all participants 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 were not planned to be collected and analyzed for the untreated group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo | 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 | 16.363 Percent change | Standard Deviation 10.6223 |
Secondary
Part 2a: Percent Change From Baseline in Forced Vital Capacity Predicted (FVC%p) at Week144 in Total Golodirsen Group
FVC was the total amount of air exhaled during the forced expiratory volume test that was measured during spirometry and the most important measurement of lung function. This test required participant 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 participant bronchial (breathing) tubes. Percent of predicted FVC = (observed value)/ (predicted value) \* 100%.
Time frame: Baseline, Week 144
Population: Efficacy set consisted of all randomized participants who had at least 1 post-baseline functional assessment. Here, overall number of participants analyzed = number of participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo | Part 2a: Percent Change From Baseline in Forced Vital Capacity Predicted (FVC%p) at Week144 in Total Golodirsen Group | -8.382 Percent change | Standard Deviation 29.4566 |
Secondary
Part 2b: Percent Change From Baseline in Forced Vital Capacity Predicted (FVC%p) at Week144 in Untreated Group (Non-exon 53 Amenable Participants)
FVC was the total amount of air exhaled during the forced expiratory volume test that was measured during spirometry and is the most important measurement of lung function. This test requires participant 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 participant bronchial (breathing) tubes. Percent of predicted FVC = (observed value)/ (predicted value) \* 100%.
Time frame: Baseline, Week 144
Population: Efficacy set consisted of all randomized participants who had at least 1 post-baseline functional assessment. Here, overall number of participants analyzed = number of participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo | Part 2b: Percent Change From Baseline in Forced Vital Capacity Predicted (FVC%p) at Week144 in Untreated Group (Non-exon 53 Amenable Participants) | -6.739 Percent change | Standard Deviation 17.5278 |