A 2-Part, Randomized, Double-Blind, Placebo-Controlled, Dose-Titration, Safety, Tolerability, and Pharmacokinetics Study (Part 1) Followed by an Open-Label Efficacy and Safety Evaluation (Part 2) of SRP-4053 in Patients With Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 39
- 试验地点
- 5
- 主要终点
- Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Masking Description: Part 1 is double-blind and randomized; Part 2 is open-label.
入排标准
- 年龄范围
- 6 Years 至 15 Years（Child）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •Previous treatment with the experimental agents BMN-195 (SMT C1100) or PRO
- •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 exclusion criteria may apply.
研究组 & 干预措施
Part 1: SRP-4053
Patients will receive SRP-4053 (golodirsen) intravenous (IV) infusions, weekly, at escalating dose levels as follows: Weeks 1-2, 4 mg/kg/week; Weeks 3-4, 10 mg/kg/week; Weeks 5-6, 20 mg/kg/week; Weeks 7-12, 30 mg/kg/week. Dosing will be interrupted or halted if specific predefined stopping criteria are met or if warranted at the discretion of the Sponsor or Investigator.
干预措施: SRP-4053 (Drug)
Part 1: Placebo
Patients will receive SRP-4053 placebo-matching IV infusions, weekly, for 12 weeks. Dosing will be interrupted or halted if specific predefined stopping criteria are met or if warranted at the discretion of the Sponsor or Investigator.
干预措施: Placebo (Drug)
Part 2: SRP-4053
All eligible patients from Part 1, as well as new patients, will receive SRP-4053 (golodirsen) 30 mg/kg/week IV infusions, weekly, for up to 168 weeks.
干预措施: SRP-4053 (Drug)
结局指标
主要结局
Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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)
时间窗: 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
时间窗: 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)
时间窗: 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
时间窗: Baseline, Week 48
Change from baseline in dystrophin protein levels (in muscle biopsy samples) was determined by Western blot in total golodirsen group.
次要结局
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- Part 1: Renal Clearance (CLR) of Golodirsen(0 to 1440 min after initiation of dosing on Day 1)
- Part 2a: Percent Change From Baseline in Forced Vital Capacity Predicted (FVC%p) at Week144 in Total Golodirsen Group(Baseline, Week 144)
- 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)
- Part 2a: Change From Baseline in Dystrophin Intensity Levels Determined by Immunohistochemistry (IHC) at Week 48 in Total Golodirsen Group(Baseline, Week 48)
- 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)
- Part 2a: Percent Change From Baseline in Dystrophin Positive Fibers Determined by Immunohistochemistry (IHC) at Week 48 in Total Golodirsen Group(Baseline, Week 48)