A Multi-center, Randomized, Double-blind, Placebo-controlled, Phase 1/2 Trial to Evaluate the Efficacy and Safety of EN001 in Patients With Duchenne Muscular Dystrophy
Overview
- Phase
- Phase 1
- Intervention
- EN001
- Conditions
- Duchenne Muscular Dystrophy
- Sponsor
- ENCell
- Enrollment
- 88
- Locations
- 2
- Primary Endpoint
- <Phase 2> Change in time to stand test (TTSTAND)
- Status
- Not yet recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
A Multi-center, Randomized, Double-blind, Placebo-controlled, Phase 1/2 Trial to Evaluate the Efficacy and Safety of EN001 in Patients with Duchenne Muscular Dystrophy
Detailed Description
This clinical trial is a multi-center study conducted in two phases: Phase 1 and Phase 2. Phase 1 follows a 3+3 dose-escalation design to assess the safety, efficacy, and tolerability of EN001, an investigational product. Phase 2 evaluates the efficacy and safety of EN001 at the recommended phase 2 dose (RP2D), as determined in Phase 1, compared to a placebo. Phase 1 is designed using the traditional 3+3 dose-escalation method to determine the maximum tolerated dose (MTD) and establish the RP2D. Dose escalation continues until the MTD is identified, which must be within the maximum planned dose (MPD) of 2.5 x 10\^6 cells/kg (Cohort 2) or lower. The MTD is defined as the highest dose at which the incidence rate of dose-limiting toxicity (DLT) is less than 33%. To determine the MTD, 3-6 subjects are enrolled in each dose cohort. They receive EN001 every 6 weeks for 3 cycles, with DLTs evaluated up to the 2-week time point (Visit 7). The Safety Review Committee (SRC) consists of the coordinating Investigator, the responsible trial monitor for subjects enrolled in cohorts requiring safety review, and the sponsor. These members participate as committee members. At the conclusion of each cohort-defined as the endpoint of the DLT assessment for the last subject in that cohort-they comprehensively review the safety data for EN001. The committee makes decisions related to dose adjustments, whether to increase or decrease the dose, and ultimately determines the RP2D. Phase 2 clinical trials are randomized, double-blind, placebo-controlled clinical trials. In phase 2, eligible subjects will be randomly assigned to the test group (recommended phase 2 dose (RP2D) of EN001) or the control group (placebo of EN001) in a 1:1 ratio. Efficacy and safety will be evaluated up to 48 weeks after EN001 administration compared to placebo. In addition, test subjects participating in phase 1 and phase 2 will be followed up for safety and effectiveness for 5 years from the time of EN001 administration according to the long-term follow-up protocol.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Males aged between 6 and 11 years at the time of providing written consent.
- •Individuals exhibiting phenotypic signs of Duchenne Muscular Dystrophy (DMD), such as lower limb muscle weakness, a duck walk, or Gower's sign, and who are diagnosed with DMD following confirmation of a dystrophin gene mutation through genetic testing.
- •Participants who meet the Time to Stand Test (TTSTAND) criteria without the use of assistive devices or help from others during screening and baseline assessments:
- •Phase 1: Capable of completing the TTSTAND evaluation.
- •Phase 2: TTSTAND time of 10 seconds or less.
- •Participants with a 6-Minute Walk Test (6MWT) result of 75 meters or more at screening and baseline.
- •Individuals who meet the following laboratory test criteria at the time of screening and baseline:
- •Hemoglobin ≥10 g/dL
- •Platelet ≥50,000/μL
- •Serum albumin ≥2.5 g/dL
Exclusion Criteria
- •Individuals with confirmed comorbidities at the time of screening:
- •Left ventricular ejection fraction (LVEF) below 50%, as determined by echocardiography
- •Percent predicted forced vital capacity (FVC%) less than 35%
- •Positive for Hepatitis B surface antigen (HBsAg). However, individuals undergoing interferon or antiviral treatment can register
- •Positive for Hepatitis C virus antibody (HCV Ab). Registration is possible if the HCV ribonucleic acid (RNA) test result is negative
- •Positive for Human immunodeficiency virus (HIV) antibody
- •Comorbidities that are uncontrollable or require treatment that could affect the safety and efficacy evaluation of this clinical trial, based on the investigator's judgment
- •Individuals with confirmed treatment history at the time of screening:
- •Administration of cell therapy or gene therapy throughout life
- •Administer antisense oligonucleotide (e.g., exon skipping treatment) or stop- codon readthrough treatment (e.g., aminoglycoside, ataluren) within 24 weeks before screening.
Arms & Interventions
Phase 1 - Cohort 1
EN001 5.0x10\^5 cells/kg
Intervention: EN001
Phase 1 - Cohort 2
EN001 2.5x10\^6 cells/kg
Intervention: EN001
Phase 2 - Experimental Group
The recommended phase 2 dose (RP2D) of EN001
Intervention: EN001
Phase 2 - Control Group
EN001 placebo
Intervention: EN001
Outcomes
Primary Outcomes
<Phase 2> Change in time to stand test (TTSTAND)
Time Frame: At 48 weeks compared to baseline (Visit 2)
Present the changes in time to stand test (TTSTAND) at the 48-week time point compared to baseline (Visit 2). Provide the subject count, mean, standard deviation, median, minimum, and maximum for the change in each treatment group. Analyze the change as the dependent variable using a repeated measures mixed model (MMRM) with treatment group, visit (6, 12, 18, 24, 36, 48 weeks), and the interaction between treatment group and visit as factors. Include baseline TTSTAND values and age as fixed effects in the analysis.
<Phase 1> Adverse drug reactions related to discontinuation of clinical trial drug administration
Time Frame: Up to 14 weeks
Present the frequency and percentage of dose-limiting toxicity (DLT) occurrence across dose cohorts, along with detailed information on the types of DLTs.
<Phase 1> Adverse drug reactions related to dose limiting toxicity (DLT)
Time Frame: Up to 14 weeks
Present the frequency and percentage of dose-limiting toxicity (DLT) occurrence across dose cohorts, along with detailed information on the types of DLTs.
Secondary Outcomes
- <Phase 1> Changes amount in muscle strength by region(At 6, 12, 18, 24, 36, and 48 weeks compared to baseline (Visit 2))
- <Phase 1> Time to stand test (TTSTAND) change amount(At 6, 12, 18, 24, 36, and 48 weeks compared to baseline (Visit 2))
- <Phase 1> TTRW velocity (1/TTRW) change amount(At 6, 12, 18, 24, 36, and 48 weeks compared to baseline (Visit 2))
- <Phase 1> Adverse Event(Up to 48weeks. However, adverse drug reactions that persist at the end of the clinical trial will be followed up until the possible adverse reactions are resolved or it is determined that further follow-up is not meaningful.)
- <Phase 1> TTSTAND velocity (1/TTSTAND) change amount(At 6, 12, 18, 24, 36, and 48 weeks compared to baseline (Visit 2))
- <Phase 1> Time to climb 4 steps test (TTCLIMB) change amount(At 6, 12, 18, 24, 36, and 48 weeks compared to baseline (Visit 2))
- <Phase 1> TTCLIMB velocity (1/TTCLIMB) change amount(At 6, 12, 18, 24, 36, and 48 weeks compared to baseline (Visit 2))
- <Phase 1> North Star Ambulatory Assessment (NSAA) change amount(At 6, 12, 18, 24, 36, and 48 weeks compared to baseline (Visit 2))
- <Phase 2> Time to stand test (TTSTAND) change amount(At 6, 12, 18, 24, and 36 weeks compared to baseline (Visit 2))
- <Phase 2> TTSTAND velocity (1/TTSTAND) change amount(At 6, 12, 18, 24, 36, and 48 weeks compared to baseline (Visit 2))
- <Phase 2> TTRW velocity (1/TTRW) change amount(At 6, 12, 18, 24, 36, and 48 weeks compared to baseline (Visit 2))
- <Phase 2> Time to climb 4 steps test (TTCLIMB) change(At 6, 12, 18, 24, 36, and 48 weeks compared to baseline (Visit 2))
- <Phase 2> 6-minute walk test (6MWT) change amount(At 6, 12, 18, 24, 36, and 48 weeks compared to baseline (Visit 2))
- <Phase 2> Pediatric Outcomes Data Collection Instrument (PODCI) item score and total score change(At 24 and 48 weeks compared to baseline (Visit 2))
- <Phase 2> Adverse Event(Up to 48weeks. However, adverse drug reactions that persist at the end of the clinical trial will be followed up until the possible adverse reactions are resolved or it is determined that further follow-up is not meaningful.)
- <Phase 2> Vital sign(Up to 48weeks.)
- <Phase 1> Time to run/walk 10 meters test (TTRW) change amount(At 6, 12, 18, 24, 36,, and 48 weeks compared to baseline (Visit 2))
- <Phase 1> 6-minute walk test (6MWT) change amount(At 6, 12, 18, 24, 36, and 48 weeks compared to baseline (Visit 2))
- <Phase 2> North Star Ambulatory Assessment (NSAA) change amount(At 6, 12, 18, 24, 36, and 48 weeks compared to baseline (Visit 2))
- <Phase 2> Changes amount and rate of change in whole thigh muscle volume and index assessed by MRI(At 48 weeks compared to screening (Visit 1))
- <Phase 1> Changes amount in parameters related to pulmonary function(At 12, 24, and 48 weeks compared to baseline (Visit 2))
- <Phase 1> Changes amount in parameters related to cardiac function(At 48 weeks compared to screening (Visit 1))
- <Phase 1> Change rate of creatine kinase (CK) at each visit after administration of investigational product compared to baseline (Visit 2)(From baseline)
- <Phase 2> Time to run/walk 10 meters test (TTRW) change amount(At 6, 12, 18, 24, 36, and 48 weeks compared to baseline (Visit 2))
- <Phase 2> TTCLIMB velocity (1/TTCLIMB) change amount(At 6, 12, 18, 24, 36, and 48 weeks compared to baseline (Visit 2))
- <Phase 2> Changes amount in muscle strength by region(At 6, 12, 18, 24, 36, and 48 weeks compared to baseline (Visit 2))
- <Phase 2> Changes amount in parameters related to pulmonary function(At 12, 24, and 48 weeks compared to baseline (Visit 2))
- <Phase 2> Changes amount in parameters related to cardiac function(At 48 weeks compared to screening (Visit 1))
- <Phase 2> Change rate of creatine kinase (CK) at each visit after administration of investigational product compared to baseline (Visit 2)(From baseline)
- <Phase 2> Pediatric Quality of Life inventory™ (PedsQL™) item scores and total score change(At 24 and 48 weeks compared to baseline (Visit 2))
- <Phase 1> Laboratory examination(Up to 48weeks. At Baseline and Week 4, tests are conducted before and within 4 hours after administration of the investigational drug, and PT INR and aPTT are performed only at the screening visit.)
- <Phase 1> Vital sign(Up to 48weeks.)
- <Phase 2> Laboratory examination(Up to 48weeks. At Baseline and Week 4, tests are conducted before and within 4 hours after administration of the investigational drug, and PT INR and aPTT are performed only at the screening visit.)