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This is a first-in-human dose-titration and open-label extension study to assess safety, tolerability, and pharmacokinetics of SRP-4045 in advanced-stage Duchenne muscular dystrophy (DMD) patients with deletions amenable to exon 45 skipping.
This is a randomized, placebo-controlled dose-titration study to assess safety, tolerability, and pharmacokinetics of 4 dose levels of SRP-4045 in genotypically confirmed advanced-stage DMD patients with deletions amenable to exon 45 skipping.
After completion of the dose-titration portion of the study and SRP-4045 is determined to be safe, all patients will be evaluated on open-label SRP-4045 for the duration of the study.
Safety, including adverse event monitoring, routine laboratory assessments, and cardiac testing will be monitored through the duration of the dose-titration and open-label portions of the study.
Clinical efficacy will be assessed at regularly scheduled study visits via quality of life questionnaires and tests of pulmonary and upper extremity function through the duration of the dose-titration and open-label portions of the trial.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo (double-blind dose titration) | Placebo Comparator | Participants with genotypically confirmed Duchenne muscular dystrophy (DMD) characterized by deletions amenable to exon 45 skipping will receive placebo-matching to casimersen intravenous (IV) infusions, once weekly over approximately 12 weeks in the double-blind period. |
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| SRP-4045 (double-blind dose titration) | Experimental | Participants with genotypically confirmed DMD characterized by deletions amenable to exon 45 skipping will receive weekly IV infusions of casimersen at four escalating dose levels, each for at least 2 weeks: 4 milligrams per kilograms (mg/kg) during Week 1 to Week 2, followed by 10 mg/kg during Week 3 to Week 4, followed by 20 mg/kg during Week 5 to Week 6, followed by 30 mg/kg beginning at Week 7 and continue over approximately Week 12 in the double-blind period. |
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| SRP-4045 (open label extension period) | Experimental | All participants who completed double blind period will be enrolled to receive casimersen 30 mg/kg once weekly, for up to Week 144 in the open label extension period. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| SRP-4045 | Drug | SRP-4045 solution for IV infusion. |
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| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 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. AEs also included abnormal physical examination findings (Physical examination were conducted per protocol and any clinically significant abnormal findings were recorded in medical history if pre-existing or addressed as an AE if new or worsening). TEAEs was defined as AEs that started, worsened, or became serious on or after the start of first infusion through 148 weeks. Number of participants with TEAEs were reported. | Baseline up to Week 148 |
| Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Laboratory parameters included serum chemistry (hepatic chemistry and renal chemistry), hematology, coagulation, and urinalysis. Number of participants with 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. | Baseline up to Week 148 |
| 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. | Baseline up to Week 148 |
| Number of Participants With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Reported as TEAEs |
| Measure | Description | Time Frame |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of Casimersen | Maximum Concentration (Cmax) of casimersen in plasma was evaluated. | Pre-infusion, 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 ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 (for 30 mg/kg arm) in DBP and Week 60 (for 30 mg/kg arm) in OLEP |
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Inclusion Criteria:
Exclusion Criteria:
Other inclusion/exclusion criteria apply.
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| Name | Affiliation | Role |
|---|---|---|
| Medical Director | Sarepta Therapeutics, Inc. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| David Geffen School of Medicine at UCLA | Los Angeles | California | 90095 | United States | ||
| Ann & Robert H. Lurie Children's Hospital of Chicago |
Study conducted in 2 parts: Part 1 (Double-Blind Period [DBP]) and Part 2 (Open Label Extension Period [OLEP]). When Part 1 was completed and cumulative safety data was reviewed by an independent Data Safety Monitoring Board (DSMB), Part 2 was conducted.
The study was conducted at 3 sites in United States.
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| ID | Title | Description |
|---|---|---|
| FG000 | Double-Blind Period: Placebo | Participants with genotypically confirmed Duchenne muscular dystrophy (DMD) characterized by deletions amenable to exon 45 skipping received placebo-matched to casimersen intravenous (IV) infusions, once weekly over approximately 12 weeks in the double-blind period. |
| FG001 | Double-Blind Period: Casimersen | Participants with genotypically confirmed DMD characterized by deletions amenable to exon 45 skipping received weekly IV infusions of casimersen at four escalating dose levels, each for at least 2 weeks: 4 milligrams per kilograms (mg/kg) during Week 1 to Week 2, followed by 10 mg/kg during Week 3 to Week 4, followed by 20 mg/kg during Week 5 to Week 6, followed by 30 mg/kg beginning at Week 7 and continued over approximately Week 12 in the double-blind period. |
| FG002 | Open Label Extension Period: Casimersen | All participants who completed double blind period were enrolled to receive casimersen 30 mg/kg once weekly, for up to Week 144 in the open label extension period. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Double-Blind Period (12 Weeks) |
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| Open Label Extension Period (132 Weeks) |
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Safety set included all randomized participants who received at least 1 dose of study drug (casimersen or placebo) in double-blind period.
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| ID | Title | Description |
|---|---|---|
| BG000 | Double-Blind Period: Placebo | Participants with genotypically confirmed DMD characterized by deletions amenable to exon 45 skipping received placebo-matched to casimersen IV infusions, once weekly over approximately 12 weeks in the double-blind period. |
| BG001 | Double-Blind Period: Casimersen |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 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. AEs also included abnormal physical examination findings (Physical examination were conducted per protocol and any clinically significant abnormal findings were recorded in medical history if pre-existing or addressed as an AE if new or worsening). TEAEs was defined as AEs that started, worsened, or became serious on or after the start of first infusion through 148 weeks. Number of participants with TEAEs were reported. | Safety set included all randomized participants who received at least 1 dose of study drug (casimersen or placebo) in both double-blind and open-label extension periods. | Posted | Count of Participants | Participants | Baseline up to Week 148 |
|
From start of study drug administration up to Week 148
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Double-Blind Period: Placebo | Participants with genotypically confirmed DMD characterized by deletions amenable to exon 45 skipping received placebo-matched to casimersen IV infusions, once weekly over approximately 12 weeks in the double-blind period. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Septic embolus | Infections and infestations | MedDRA (17.1) | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vomiting | Gastrointestinal disorders | MedDRA (17.1) | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Medical Director | Sarepta Therapeutics, Inc. | 1-800-690-2003 | clinicaltrials@sarepta.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Mar 29, 2018 | Apr 23, 2021 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Dec 5, 2018 | Apr 23, 2021 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D020388 | Muscular Dystrophy, Duchenne |
| ID | Term |
|---|---|
| D009136 | Muscular Dystrophies |
| D020966 | Muscular Disorders, Atrophic |
| D009135 | Muscular Diseases |
| D009140 | Musculoskeletal Diseases |
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| ID | Term |
|---|---|
| C000718147 | casimersen |
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| Placebo | Drug | SRP-4045 placebo-matching solution for IV infusion. |
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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 were presented here. The Investigator determined whether abnormal assessment results were potentially clinically significant or not. |
| Baseline up to Week 148 |
| 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.The ECHO was reviewed and interpreted by medically qualified personnel. Number of participants with potentially clinically significant abnormalities in ECHO were reported. | Baseline up to Week 148 |
| Time to Reach Maximum Plasma Concentration (Tmax) of Casimersen |
Time to reach maximum plasma concentration (Tmax) of casimersen was evaluated. |
| Pre-infusion, 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 ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 (for 30 mg/kg arm) in DBP and Week 60 (for 30 mg/kg arm) in OLEP |
| Area Under Concentration-time Curve From Time of Dosing to the Last Measurable Concentration (AUClast) of Casimersen in Plasma | Area under the concentration-time curve from time zero to the last quantifiable concentration of casimersen in plasma were evaluated. | Pre-infusion, 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 ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 (for 30 mg/kg arm) in DBP and Week 60 (for 30 mg/kg arm) in OLEP |
| Area Under Concentration-Time Curve From Time Zero Pre-dose to Twenty-Four Hours Post-dose (AUC0-24) of Casimersen in Plasma | Area under concentration-time curve from time zero pre-dose to twenty-four hours post-dos of casimersen in plasma were evaluated. | Pre-infusion, 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 ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 (for 30 mg/kg arm) in DBP and Week 60 (for 30 mg/kg arm) in OLEP |
| Area Under the Concentration-Time Curve From Time Zero Extrapolated to the Infinity (AUCinf) of Casimersen in Plasma | Area under the concentration-time curve from time zero extrapolated to the infinity of casimersen in plasma was evaluated. | Pre-infusion, 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 ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 (for 30 mg/kg arm) in DBP and Week 60 (for 30 mg/kg arm) in OLEP |
| Apparent Volume of Distribution at Steady State (Vss) of Casimersen | 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 casimersen was evaluated. | Pre-infusion, 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 ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 (for 30 mg/kg arm) in DBP and Week 60 (for 30 mg/kg arm) in OLEP |
| Elimination Half-life (T1/2) of Casimersen | T1/2 is the time measured for the plasma concentration of drug to decrease by one half. T1/2 of casimersen was evaluated. | Pre-infusion, 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 ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 (for 30 mg/kg arm) in DBP and Week 60 (for 30 mg/kg arm) in OLEP |
| Total Clearance (CL) of Casimersen | Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. CL of casimersen was evaluated. | Pre-infusion, 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 ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 (for 30 mg/kg arm) in DBP and Week 60 (for 30 mg/kg arm) in OLEP |
| Mean Residence Time Extrapolated to Infinity (MRTinf) of Casimersen | MRTinf = AUMCinf/AUCinf - T/2, where T was the infusion duration, and AUMCinf was the area under the first moment curve from time 0 extrapolated to infinite time, calculated using the linear/log trapezoidal method. MRTinf of casimersen was evaluated. | Pre-infusion, 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 ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 (for 30 mg/kg arm) in DBP and Week 60 (for 30 mg/kg arm) in OLEP |
| Double-Blind Period: Renal Clearance (CLR) of Casimersen | 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. | 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hours post-dose at Weeks 1 (for 4 mg/kg ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 and 12 (for 30 mg/kg arm) in double-blind period |
| Chicago |
| Illinois |
| 60611 |
| United States |
| Kennedy Krieger Institute | Baltimore | Maryland | 21205 | United States |
| NOT COMPLETED |
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Participants with genotypically confirmed DMD characterized by deletions amenable to exon 45 skipping received weekly IV infusions of casimersen at four escalating dose levels, each for at least 2 weeks: 4 mg/kg during Week 1 to Week 2, followed by 10 mg/kg during Week 3 to Week 4, followed by 20 mg/kg during Week 5 to Week 6, followed by 30 mg/kg beginning at Week 7 and continued over approximately Week 12 in the double-blind period. |
| BG002 | Total | Total of all reporting groups |
| Years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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Participants with genotypically confirmed DMD characterized by deletions amenable to exon 45 skipping received placebo-matched to casimersen IV infusions, once weekly over approximately 12 weeks in the double-blind period. |
| OG001 | Double-Blind Period: Casimersen 4 mg/kg | Participants with genotypically confirmed DMD characterized by deletions amenable to exon 45 skipping received casimersen IV infusions, at a dose level of 4 mg/kg once weekly for 2 weeks (i.e. Week 1 to Week 2) in the double-blind period. |
| OG002 | Double-Blind Period: Casimersen 10 mg/kg | Participants with genotypically confirmed DMD characterized by deletions amenable to exon 45 skipping received casimersen IV infusions, at a dose level of 10 mg/kg once weekly for 2 weeks (i.e. Week 3 to Week 4) in the double-blind period. |
| OG003 | Double-Blind Period: Casimersen 20 mg/kg | Participants with genotypically confirmed DMD characterized by deletions amenable to exon 45 skipping received casimersen IV infusions, at a dose level of 20 mg/kg once weekly for 2 weeks (i.e. Week 5 to Week 6) in the double-blind period. |
| OG004 | Double-Blind Period: Casimersen 30 mg/kg | Participants with genotypically confirmed DMD characterized by deletions amenable to exon 45 skipping received casimersen IV infusions, at a dose level of 30 mg/kg once weekly from Week 7 to Week 12 in the double-blind period. |
| OG005 | Open Label Extension Period: Casimersen 30 mg/kg | All participants who completed double blind period were enrolled to receive casimersen 30 mg/kg once weekly, for up to Week 144 in the open label extension period. |
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| Primary | Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs | Laboratory parameters included serum chemistry (hepatic chemistry and renal chemistry), hematology, coagulation, and urinalysis. Number of participants with 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. | Safety set included all randomized participants who received at least 1 dose of study drug (casimersen or placebo) in both double-blind and open-label extension periods. | Posted | Count of Participants | Participants | Baseline up to Week 148 |
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| Primary | 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. | Safety set included all randomized participants who received at least 1 dose of study drug (casimersen or placebo) in both double-blind and open-label extension periods. | Posted | Count of Participants | Participants | Baseline up to Week 148 |
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| Primary | 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 were presented here. The Investigator determined whether abnormal assessment results were potentially clinically significant or not. | Safety set included all randomized participants who received at least 1 dose of study drug (casimersen or placebo) in both double-blind and open-label extension periods. | Posted | Count of Participants | Participants | Baseline up to Week 148 |
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| Primary | 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.The ECHO was reviewed and interpreted by medically qualified personnel. Number of participants with potentially clinically significant abnormalities in ECHO were reported. | Safety set included all randomized participants who received at least 1 dose of study drug (casimersen or placebo) in both double-blind and open-label extension periods. | Posted | Count of Participants | Participants | Baseline up to Week 148 |
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| Secondary | Maximum Plasma Concentration (Cmax) of Casimersen | Maximum Concentration (Cmax) of casimersen in plasma was evaluated. | Pharmacokinetic (PK) set included all randomized participants who received the planned full dose of study drug (casimersen) and for whom there are adequate PK samples from which to estimate PK parameters. Data was not planned to be collected and analyzed for placebo arm. | Posted | Geometric Mean | Geometric Coefficient of Variation | Nanogram per milliliter (ng/mL) | Pre-infusion, 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 ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 (for 30 mg/kg arm) in DBP and Week 60 (for 30 mg/kg arm) in OLEP |
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| Secondary | Time to Reach Maximum Plasma Concentration (Tmax) of Casimersen | Time to reach maximum plasma concentration (Tmax) of casimersen was evaluated. | PK set included all randomized participants who received the planned full dose of study drug (casimersen or placebo) and for whom there are adequate PK samples from which to estimate PK parameters. Data was not planned to be collected and analyzed for placebo arm. | Posted | Median | Full Range | Hour | Pre-infusion, 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 ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 (for 30 mg/kg arm) in DBP and Week 60 (for 30 mg/kg arm) in OLEP |
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| Secondary | Area Under Concentration-time Curve From Time of Dosing to the Last Measurable Concentration (AUClast) of Casimersen in Plasma | Area under the concentration-time curve from time zero to the last quantifiable concentration of casimersen in plasma were evaluated. | PK set included all randomized participants who received the planned full dose of study drug (casimersen or placebo) and for whom there are adequate PK samples from which to estimate PK parameters. Data was not planned to be collected and analyzed for placebo arm. | Posted | Geometric Mean | Geometric Coefficient of Variation | Hour*nanogram per milliliter (hr*ng/mL) | Pre-infusion, 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 ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 (for 30 mg/kg arm) in DBP and Week 60 (for 30 mg/kg arm) in OLEP |
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| Secondary | Area Under Concentration-Time Curve From Time Zero Pre-dose to Twenty-Four Hours Post-dose (AUC0-24) of Casimersen in Plasma | Area under concentration-time curve from time zero pre-dose to twenty-four hours post-dos of casimersen in plasma were evaluated. | PK set included all randomized participants who received the planned full dose of study drug (casimersen or placebo) and for whom there are adequate PK samples from which to estimate PK parameters. Data was not planned to be collected and analyzed for placebo arm. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Pre-infusion, 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 ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 (for 30 mg/kg arm) in DBP and Week 60 (for 30 mg/kg arm) in OLEP |
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| Secondary | Area Under the Concentration-Time Curve From Time Zero Extrapolated to the Infinity (AUCinf) of Casimersen in Plasma | Area under the concentration-time curve from time zero extrapolated to the infinity of casimersen in plasma was evaluated. | PK set included all randomized participants who received the planned full dose of study drug (casimersen or placebo) and for whom there are adequate PK samples from which to estimate PK parameters. Here, "Overall number of participants analyzed" = number of participants evaluable for this outcome. Data was not planned to be collected and analyzed for placebo arm. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Pre-infusion, 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 ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 (for 30 mg/kg arm) in DBP and Week 60 (for 30 mg/kg arm) in OLEP |
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| Secondary | Apparent Volume of Distribution at Steady State (Vss) of Casimersen | 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 casimersen was evaluated. | PK set included all randomized participants who received the planned full dose of study drug (casimersen or placebo) and for whom there are adequate PK samples from which to estimate PK parameters. Here, "Overall number of participants analyzed" = number of participants evaluable for this outcome. Data was not planned to be collected and analyzed for placebo arm. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liter per kilogram (L/kg) | Pre-infusion, 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 ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 (for 30 mg/kg arm) in DBP and Week 60 (for 30 mg/kg arm) in OLEP |
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| Secondary | Elimination Half-life (T1/2) of Casimersen | T1/2 is the time measured for the plasma concentration of drug to decrease by one half. T1/2 of casimersen was evaluated. | PK set included all randomized participants who received the planned full dose of study drug (casimersen or placebo) and for whom there are adequate PK samples from which to estimate PK parameters. Here, "Overall number of participants analyzed" = number of participants evaluable for this outcome. Data was not planned to be collected and analyzed for placebo arm. | Posted | Mean | Standard Deviation | Hour | Pre-infusion, 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 ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 (for 30 mg/kg arm) in DBP and Week 60 (for 30 mg/kg arm) in OLEP |
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| Secondary | Total Clearance (CL) of Casimersen | Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. CL of casimersen was evaluated. | PK set included all randomized participants who received the planned full dose of study drug (casimersen or placebo) and for whom there are adequate PK samples from which to estimate PK parameters. Here, "Overall number of participants analyzed" = number of participants evaluable for this outcome. Data was not planned to be collected and analyzed for placebo arm. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liters per hour per kilogram (L/h/kg) | Pre-infusion, 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 ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 (for 30 mg/kg arm) in DBP and Week 60 (for 30 mg/kg arm) in OLEP |
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| Secondary | Mean Residence Time Extrapolated to Infinity (MRTinf) of Casimersen | MRTinf = AUMCinf/AUCinf - T/2, where T was the infusion duration, and AUMCinf was the area under the first moment curve from time 0 extrapolated to infinite time, calculated using the linear/log trapezoidal method. MRTinf of casimersen was evaluated. | PK set included all randomized participants who received the planned full dose of study drug (casimersen or placebo) and for whom there are adequate PK samples from which to estimate PK parameters. Here, "Overall number of participants analyzed" = number of participants evaluable for this outcome. Data was not planned to be collected and analyzed for placebo arm. | Posted | Geometric Mean | Geometric Coefficient of Variation | Hour | Pre-infusion, 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 ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 (for 30 mg/kg arm) in DBP and Week 60 (for 30 mg/kg arm) in OLEP |
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| Secondary | Double-Blind Period: Renal Clearance (CLR) of Casimersen | 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. | PK set included all randomized participants who received the planned full dose of study drug (casimersen or placebo) and for whom there are adequate PK samples from which to estimate PK parameters. Here, "Overall number of participants analyzed"= number of participants evaluable for this outcome. Data was not planned to be collected and analyzed for placebo and open-label extension period arm. | Posted | Geometric Mean | Geometric Coefficient of Variation | L/h/kg | 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hours post-dose at Weeks 1 (for 4 mg/kg ), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm), 7 and 12 (for 30 mg/kg arm) in double-blind period |
|
|
|
| 0 |
| 4 |
| 0 |
| 4 |
| 4 |
| 4 |
| EG001 | Double-Blind Period: Casimersen 4 mg/kg | Participants with genotypically confirmed DMD characterized by deletions amenable to exon 45 skipping received casimersen IV infusions, at a dose level of 4 mg/kg once weekly for 2 weeks (i.e. Week 1 to Week 2) in the double-blind period. | 0 | 8 | 0 | 8 | 5 | 8 |
| EG002 | Double-Blind Period: Casimersen 10 mg/kg | Participants with genotypically confirmed DMD characterized by deletions amenable to exon 45 skipping received casimersen IV infusions, at a dose level of 10 mg/kg once weekly for 2 weeks (i.e. Week 3 to Week 4) in the double-blind period. | 0 | 8 | 0 | 8 | 3 | 8 |
| EG003 | Double-Blind Period: Casimersen 20 mg/kg | Participants with genotypically confirmed DMD characterized by deletions amenable to exon 45 skipping received casimersen IV infusions, at a dose level of 20 mg/kg once weekly for 2 weeks (i.e. Week 5 to Week 6) in the double-blind period. | 0 | 8 | 0 | 8 | 3 | 8 |
| EG004 | Double-Blind Period: Casimersen 30 mg/kg | Participants with genotypically confirmed DMD characterized by deletions amenable to exon 45 skipping received casimersen IV infusions, at a dose level of 30 mg/kg once weekly from Week 7 to Week 12 in the double-blind period. | 0 | 8 | 1 | 8 | 7 | 8 |
| EG005 | Open Label Extension Period: Casimersen 30 mg/kg | All participants who completed double blind period were enrolled to receive casimersen 30 mg/kg once weekly, for up to Week 144 in the open label extension period. | 0 | 12 | 3 | 12 | 12 | 12 |
| vena cava thrombosis | Vascular disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| bacteraemia | Infections and infestations | MedDRA (17.1) | Non-systematic Assessment |
|
| Femur fracture | Injury, poisoning and procedural complications | MedDRA (17.1) | Non-systematic Assessment |
|
| Tibia fracture | Injury, poisoning and procedural complications | MedDRA (17.1) | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Abdominal rigidity | Gastrointestinal disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Dental caries | Gastrointestinal disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Gingival pain | Gastrointestinal disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Bronchitis | Infections and infestations | MedDRA (17.1) | Non-systematic Assessment |
|
| Candida infection | Infections and infestations | MedDRA (17.1) | Non-systematic Assessment |
|
| Ear infection | Infections and infestations | MedDRA (17.1) | Non-systematic Assessment |
|
| Gastroenteritis viral | Infections and infestations | MedDRA (17.1) | Non-systematic Assessment |
|
| Influenza | Infections and infestations | MedDRA (17.1) | Non-systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA (17.1) | Non-systematic Assessment |
|
| Tinea versicolour | Infections and infestations | MedDRA (17.1) | Non-systematic Assessment |
|
| Procedural pain | Injury, poisoning and procedural complications | MedDRA (17.1) | Non-systematic Assessment |
|
| Incision site pain | Injury, poisoning and procedural complications | MedDRA (17.1) | Non-systematic Assessment |
|
| Infusion related reaction | Injury, poisoning and procedural complications | MedDRA (17.1) | Non-systematic Assessment |
|
| Limb injury | Injury, poisoning and procedural complications | MedDRA (17.1) | Non-systematic Assessment |
|
| Ligament sprain | Injury, poisoning and procedural complications | MedDRA (17.1) | Non-systematic Assessment |
|
| Blood calcium decreased | Investigations | MedDRA (17.1) | Non-systematic Assessment |
|
| Blood potassium decreased | Investigations | MedDRA (17.1) | Non-systematic Assessment |
|
| Neutrophil count increased | Investigations | MedDRA (17.1) | Non-systematic Assessment |
|
| Urine calcium | Investigations | MedDRA (17.1) | Non-systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Drug withdrawal headache | Nervous system disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Migraine | Nervous system disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Device dislocation | General disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Pyrexia | General disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Thrombosis in device | General disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Neck pain | Musculoskeletal and connective tissue disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Iron deficiency | Metabolism and nutrition disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Skin papilloma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (17.1) | Non-systematic Assessment |
|
| Upper respiratory tract congestion | Respiratory, thoracic and mediastinal disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Flushing | Vascular disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Dermatitis contact | Skin and subcutaneous tissue disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA (17.1) | Non-systematic Assessment |
|
| Hordeolum | Infections and infestations | MedDRA (17.1) | Non-systematic Assessment |
|
| Acarodermatitis | Infections and infestations | MedDRA (17.1) | Non-systematic Assessment |
|
| Eye infection | Infections and infestations | MedDRA (17.1) | Non-systematic Assessment |
|
| Labyrinthitis | Infections and infestations | MedDRA (17.1) | Non-systematic Assessment |
|
| Otitis externa | Infections and infestations | MedDRA (17.1) | Non-systematic Assessment |
|
| Pharyngitis | Infections and infestations | MedDRA (17.1) | Non-systematic Assessment |
|
| Sinusitis | Infections and infestations | MedDRA (17.1) | Non-systematic Assessment |
|
| Staphylococcal infection | Infections and infestations | MedDRA (17.1) | Non-systematic Assessment |
|
| Tinea pedis | Infections and infestations | MedDRA (17.1) | Non-systematic Assessment |
|
| Abdominal pain upper | Gastrointestinal disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Haemorrhoids | Gastrointestinal disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Acne | Skin and subcutaneous tissue disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Eczema | Skin and subcutaneous tissue disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Erythema | Skin and subcutaneous tissue disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Psoriasis | Skin and subcutaneous tissue disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Skin hyperpigmentation | Skin and subcutaneous tissue disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Vitiligo | Skin and subcutaneous tissue disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Tibia fracture | Injury, poisoning and procedural complications | MedDRA (17.1) | Non-systematic Assessment |
|
| Ankle fracture | Injury, poisoning and procedural complications | MedDRA (17.1) | Non-systematic Assessment |
|
| Concussion | Injury, poisoning and procedural complications | MedDRA (17.1) | Non-systematic Assessment |
|
| Fibula fracture | Injury, poisoning and procedural complications | MedDRA (17.1) | Non-systematic Assessment |
|
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Application site bruise | General disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Application site dermatitis | General disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Application site erythema | General disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Catheter site bruise | General disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Catheter site inflammation | General disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Catheter site pain | General disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Fatigue | General disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Injection site bruising | General disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Non-cardiac chest pain | General disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Blood pressure increased | Investigations | MedDRA (17.1) | Non-systematic Assessment |
|
| Weight increased | Investigations | MedDRA (17.1) | Non-systematic Assessment |
|
| Paraesthesia | Nervous system disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Presyncope | Nervous system disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Atrial thrombosis | Cardiac disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Left ventricular dysfunction | Cardiac disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Ventricular tachycardia | Cardiac disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Delayed puberty | Endocrine disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Cataract | Eye disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Seasonal allergy | Immune system disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Anxiety | Psychiatric disorders | MedDRA (17.1) | Non-systematic Assessment |
|
| Nephrolithiasis | Renal and urinary disorders | MedDRA (17.1) | Non-systematic Assessment |
|
The most restrictive relevant agreement provides that the PI can only publish the study results with the approval of Sponsor.
| D009468 | Neuromuscular Diseases |
| D009422 | Nervous System Diseases |
| D040181 | Genetic Diseases, X-Linked |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| Serum chemistry: Renal chemistry |
|
| Hematolgy: Leukocytes |
|
| Hematolgy: Neutrophils |
|
| Coagulation: Platelet count |
|
| Urinalysis |
|