Duchenne Muscular Dystrophy
Conditions
Brief summary
The main objective of this study is to evaluate the safety of a high (80mg/kg) and low (40mg/kg) dose of NS-065/NCNP-01 delivered as an intravenous infusion in patients with Duchenne Muscular Dystrophy (DMD) amendable to exon 53 skipping. Additional objectives include tolerability, muscle function and strength, pharmacokinetics and pharmacodynamics.
Detailed description
This is a Phase II, multiple center, 2-period, randomized, placebo-controlled, dose finding study of NS-065/NCNP-01 administered by infusion once weekly for 24 weeks to ambulant boys ages 4-\<10 years with DMD. Two dose level cohorts will be enrolled. Period 1 of this study will be conducted in a double-blind fashion. Randomized patients will receive weekly IV infusions of NS-065/NCNP-01 or placebo for the first 4 weeks of their participation (Period 1) and NS-065/NCNP-01 by IV infusion for weeks 5-24 (20 weeks of active treatment - Period 2). Analysis of safety data from Period 1 of the 40mg/kg dose cohort will be completed prior to enrolling patients in the 80mg/kg dose cohort. Patients completing the 24-week study will be eligible for an open-label extension study. Clinical efficacy will be assessed at regularly scheduled study visits, including functional tests such as the six-minute walk test (6MWT), time to stand (TTSTAND), time to run/walk 10 meters (TTRW), time to climb 4 stairs (TTCLIMB) and quantitative muscle testing (QMT). All patients will undergo a muscle biopsy of the bicep at baseline and a second muscle biopsy at Week 24. Safety will be assessed through the collection of adverse events (AEs), blood and urine laboratory tests, electrocardiograms (ECGs), vital signs, and physical examinations throughout the study. Serial blood samples will be taken at four of the study visits to assess the pharmacokinetics of the study drug.
Interventions
DRUGNS-065/NCNP-01
DRUGPlacebo
Sponsors
Nippon Shinyaku Co., Ltd.
Cooperative International Neuromuscular Research Group
Therapeutic Research in Neuromuscular Disorders Solutions
NS Pharma, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
4 Years to 9 Years
Healthy volunteers
No
Inclusion criteria
* Male ≥ 4 years and \<10 years of age * Confirmed DMD mutation(s) in the dystrophin gene that is amenable to skipping of exon 53 to restore the dystrophin mRNA reading frame; * Able to walk independently without assistive devices; * Ability to complete the time to stand, time to run/walk and time to climb assessments; * Stable dose of glucocorticoid for at least 3 months
Exclusion criteria
* Acute illness within 4 weeks prior to the first dose of study medication; * Evidence of symptomatic cardiomyopathy. \[Note: Asymptomatic cardiac abnormality on investigation would not be exclusionary\]; * Severe allergy or hypersensitivity to medications; * Severe behavioral or cognitive problems that preclude participation in the study, in the opinion of the Investigator; * Previous or ongoing medical condition, medical history, physical findings or laboratory abnormalities that could affect safety, make it unlikely that treatment and follow-up will be correctly completed or impair the assessment of study results, in the opinion of the Investigator; * Patient is taking any other investigational drug currently or within 3 months prior to the start of study treatment; or * Patient has had surgery within the 3 months prior to the first anticipated administration of study medication or surgery is planned for anytime during the duration of the study; * Patient has previously participated in this study or any other study during which NS-065/NCNP-01 was administered.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events as Assessed by CTCAE v4.0. | 24 weeks of treatment | Treatment emergent adverse events (TEAEs) were summarized for Period 1 by comparing low dose to high dose to placebo and for Period 2 between the low dose cohort and the high dose cohort. TEAEs were summarized both at the patient level for number of TEAEs, highest severity, relationship, action and outcome and at the TEAE level (summarizing events) by organ system and preferred term TEAE as well as severity, relationship, action and outcome. The Medical Dictionary for Regulatory Activities (MedDRA) version 20.1 was used and the Common Terminology Criteria for Adverse Events (CTCAE) grading. |
| Dystrophin Production by Western Blot | Baseline and 24 weeks of treatment | Percentage normal dystrophin production in muscle biopsies from study participants at baseline and after 24 weeks treatment was measured by Western blot. To analyze dystrophin induction, biopsies were taken from a biceps muscle at baseline and the other biceps muscle after 24 weeks of treatment. Muscle samples were snap frozen and delivered to a central laboratory. All laboratory researchers remained blinded to sample identity. Dystrophin protein levels were assessed using standard curves on each gel (range from 0-25% of normal levels) generated by mixing 5 normal control samples with one DMD sample. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Dystrophin Production by Immunofluorescence | Baseline and 24 weeks of treatment | The production of dystrophin protein was measured by immunofluorescence staining methods from a patient muscle biopsy at baseline and after 24 weeks treatment. To analyze dystrophin induction, biopsies were taken from a biceps muscle at baseline and the other biceps muscle after 24 weeks of treatment. Muscle samples were snap frozen and delivered to a central laboratory. All laboratory researchers remained blinded to sample identity. Immunofluorescence staining for dystrophin was performed on serial muscle biopsy sections in duplicate. |
| Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Baseline and 24 weeks of treatment | A secondary efficacy endpoint was compared to Pre-Infusion Visit: quantitative muscle testing (QMT). |
| Change From Baseline in Distance Traveled in the Six-Minute Walk Test (6MWT). | Baseline and 24 weeks of treatment | A secondary efficacy endpoint was compared to Pre-Infusion Visit: Six-Minute Walk Test (6MWT). |
| Change From Baseline in Time to Climb 4 Stairs (TTCLIMB). | Baseline and 24 weeks of treatment | A secondary efficacy endpoint was compared to Pre-Infusion Visit: Time to Climb 4 Stairs (TTCLIMB). |
| Change From Baseline in Time to Climb 4 Stairs (TTCLIMB) Velocity | Baseline and 24 weeks of treatment | A secondary efficacy endpoint was compared to Pre-Infusion Visit: Time to Run/Walk 10 meters (TTRW). The results were converted into velocity (meter/time). |
| Dystrophin Production by RT-PCR for mRNA - Percentage of Exons Skipped - Molarity | Baseline and 24 weeks of treatment | The alteration of mRNA splicing was measured by RT-PCR of dystrophin mRNA transcripts from a patient muscle biopsy at baseline and after 24 weeks treatment. To analyze dystrophin induction, biopsies were taken from a biceps muscle at baseline and the other biceps muscle after 24 weeks of treatment. Muscle samples were snap frozen and delivered to a central laboratory. All laboratory researchers remained blinded to sample identity. For RT-PCR, bands corresponding to specific versions of the spliced dystrophin mRNA were visualized by gel electrophoresis, and the amounts of different mRNA isoforms were compared. |
| Change From Baseline in Time to Run/Walk 10 Meters (TTRW) Velocity. | Baseline and 24 weeks of treatment | A secondary efficacy endpoint was compared to Pre-Infusion Visit: Time to Run/Walk 10 meters (TTRW). The results were converted into velocity (meter/time). |
| Change From Baseline in Time to Stand (TTSTAND) | Baseline and 24 weeks of treatment | A secondary efficacy endpoint was compared to Pre-Infusion Visit: Time to Stand (TTSTAND) |
| Change From Baseline in Time to Stand (TTSTAND) Velocity | Baseline and 24 weeks of treatment | A secondary efficacy endpoint was compared to Pre-Infusion Visit: Time to Stand (TTSTAND).The results were converted into velocity (rise/time). |
| Change From Baseline in North Star Ambulatory Assessment (NSAA) Score. | Baseline and 24 weeks of treatment | The NSAA is a functional scale devised for use in ambulant children with Duchenne muscular dystrophy (DMD). It consists of 17 activities graded 0 (unable to perform), 1 (performs with modifications), 2 (normal movement). It assesses abilities necessary to remain ambulant that have been found to progressively deteriorate in untreated DMD patients, as well as in other muscular dystrophies such as Becker Muscular Dystrophy. NSAA Total Score ranges from 0 to 34, with a score of 34 implying normal function. |
| Change From Baseline in Time to Run/Walk 10 Meters (TTRW). | Baseline and 24 weeks of treatment | A secondary efficacy endpoint was compared to Pre-Infusion Visit: Time to Run/Walk 10 meters (TTRW). |
| Dystrophin Production by Mass Spectrometry | Baseline and 24 weeks of treatment | The production of dystrophin protein was measured by stable isotope mass spectrometry methods from a patient muscle biopsy at baseline and after 24 weeks treatment. To analyze dystrophin induction, biopsies were taken from a biceps muscle at baseline and the other biceps muscle after 24 weeks of treatment. Muscle samples were snap frozen and delivered to a central laboratory. All laboratory researchers remained blinded to sample identity. Dystrophin peptides were identified and quantified using reversed-phase nanoflow high-performance liquid chromatography with high resolution Mass Spectrometry. |
Countries
Canada, United States
Participant flow
Recruitment details
Study enrollment occurred between December 16, 2016, and August 17, 2017, at 6 sites in the US and Canada.
Pre-assignment details
A total of 17 patients were screened at 6 sites in the United States and Canada. Of the 17 patients screened, 1 failed to meet an inclusion criterion.
Participants by arm
| Arm | Count |
|---|---|
| NS-065/NCNP-01 40mg/kg Patients with confirmed DMD with genetic deletions amenable to exon 53 skipping will be administered an intravenous infusion of NS-065/NCNP-01 40mg/kg once a week for 24 weeks | 8 |
| NS-065/NCNP-01 80mg/kg Patients with confirmed DMD with genetic deletions amenable to exon 53 skipping will be administered an intravenous infusion of NS-065/NCNP-01 80mg/kg once a week for 24 weeks | 8 |
| Total | 16 |
Baseline characteristics
| Characteristic | NS-065/NCNP-01 40mg/kg | NS-065/NCNP-01 80mg/kg | Total |
|---|---|---|---|
| 6-Minute walk test | 391.4 m STANDARD_DEVIATION 33.3 | 353.4 m STANDARD_DEVIATION 106.3 | 372.4 m STANDARD_DEVIATION 78.6 |
| Age, Continuous | 7.5 years STANDARD_DEVIATION 1.8 | 7.2 years STANDARD_DEVIATION 2 | 7.4 years STANDARD_DEVIATION 1.8 |
| Body Mass Index(BMI) | 17.9 kg/m^2 STANDARD_DEVIATION 2.3 | 17.4 kg/m^2 STANDARD_DEVIATION 2 | 17.7 kg/m^2 STANDARD_DEVIATION 2.1 |
| Dystrophin Production by Immunofluorescence | 1.5 % of normal control levels STANDARD_DEVIATION 0.98 | 1.8 % of normal control levels STANDARD_DEVIATION 2.36 | 1.7 % of normal control levels STANDARD_DEVIATION 1.75 |
| Dystrophin Production by Mass Spectrometry | 0.5 % of normal control levels STANDARD_DEVIATION 0.15 | 0.6 % of normal control levels STANDARD_DEVIATION 0.19 | 0.6 % of normal control levels STANDARD_DEVIATION 0.17 |
| Dystrophin Production by RT-PCR for mRNA - Percentage of Exons Skipped - Molarity | 0.0 % of normal control levels STANDARD_DEVIATION 0 | 0.0 % of normal control levels STANDARD_DEVIATION 0 | 0.0 % of normal control levels STANDARD_DEVIATION 0 |
| Dystrophin Production by Western Blot Normalized to Alpha-Actinin | 0.2 % of normal control levels STANDARD_DEVIATION 0.22 | 0.4 % of normal control levels STANDARD_DEVIATION 0.67 | 0.3 % of normal control levels STANDARD_DEVIATION 0.5 |
| Dystrophin Production by Western Blot Normalized to Myosin | 0.3 % of normal control levels STANDARD_DEVIATION 0.1 | 0.6 % of normal control levels STANDARD_DEVIATION 0.82 | 0.4 % of normal control levels STANDARD_DEVIATION 0.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 6 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Height | 114.6 cm STANDARD_DEVIATION 6.5 | 112.2 cm STANDARD_DEVIATION 10 | 113.4 cm STANDARD_DEVIATION 8.2 |
| NSAA score | 24.8 scores on a scale STANDARD_DEVIATION 5.9 | 23.8 scores on a scale STANDARD_DEVIATION 5.1 | 24.3 scores on a scale STANDARD_DEVIATION 5.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 7 Participants | 15 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 16 Participants |
| Time to climb 4 stairs | 3.90 second STANDARD_DEVIATION 0.93 | 3.33 second STANDARD_DEVIATION 0.94 | 3.61 second STANDARD_DEVIATION 0.95 |
| Time to climb 4 stairs velocity | 0.27 m/s STANDARD_DEVIATION 0.08 | 0.32 m/s STANDARD_DEVIATION 0.08 | 0.30 m/s STANDARD_DEVIATION 0.08 |
| Time to run/walk 10m | 6.30 second STANDARD_DEVIATION 1.59 | 5.55 second STANDARD_DEVIATION 1.34 | 5.93 second STANDARD_DEVIATION 1.47 |
| Time to run/walk 10m velocity | 1.67 m/s STANDARD_DEVIATION 0.39 | 1.88 m/s STANDARD_DEVIATION 0.36 | 1.77 m/s STANDARD_DEVIATION 0.37 |
| Time to stand from supine | 4.17 second STANDARD_DEVIATION 1.15 | 4.76 second STANDARD_DEVIATION 2.58 | 4.44 second STANDARD_DEVIATION 1.96 |
| Time to stand from supine velocity | 0.26 rise/s STANDARD_DEVIATION 0.06 | 0.25 rise/s STANDARD_DEVIATION 0.09 | 0.25 rise/s STANDARD_DEVIATION 0.07 |
| Weight | 23.7 kg STANDARD_DEVIATION 4.7 | 22.3 kg STANDARD_DEVIATION 6.2 | 23.0 kg STANDARD_DEVIATION 5.3 |
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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 6 | 0 / 5 | 0 / 8 | 0 / 8 | 0 / 16 |
| other Total, other adverse events | 3 / 5 | 4 / 6 | 4 / 5 | 5 / 8 | 7 / 8 | 15 / 16 |
| serious Total, serious adverse events | 0 / 5 | 0 / 6 | 0 / 5 | 0 / 8 | 0 / 8 | 0 / 16 |
Outcome results
Primary
Dystrophin Production by Western Blot
Percentage normal dystrophin production in muscle biopsies from study participants at baseline and after 24 weeks treatment was measured by Western blot. To analyze dystrophin induction, biopsies were taken from a biceps muscle at baseline and the other biceps muscle after 24 weeks of treatment. Muscle samples were snap frozen and delivered to a central laboratory. All laboratory researchers remained blinded to sample identity. Dystrophin protein levels were assessed using standard curves on each gel (range from 0-25% of normal levels) generated by mixing 5 normal control samples with one DMD sample.
Time frame: Baseline and 24 weeks of treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Period 1) | Dystrophin Production by Western Blot | Normalized to Myosin | 5.7 % of normal control levels | Standard Deviation 2.37 |
| Placebo (Period 1) | Dystrophin Production by Western Blot | Normalized to Alpha-Actinin | 5.4 % of normal control levels | Standard Deviation 2.79 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Dystrophin Production by Western Blot | Normalized to Myosin | 5.9 % of normal control levels | Standard Deviation 4.5 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Dystrophin Production by Western Blot | Normalized to Alpha-Actinin | 3.7 % of normal control levels | Standard Deviation 2.37 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Dystrophin Production by Western Blot | Normalized to Myosin | 5.8 % of normal control levels | Standard Deviation 3.47 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Dystrophin Production by Western Blot | Normalized to Alpha-Actinin | 4.5 % of normal control levels | Standard Deviation 2.64 |
Primary
Incidence of Adverse Events as Assessed by CTCAE v4.0.
Treatment emergent adverse events (TEAEs) were summarized for Period 1 by comparing low dose to high dose to placebo and for Period 2 between the low dose cohort and the high dose cohort. TEAEs were summarized both at the patient level for number of TEAEs, highest severity, relationship, action and outcome and at the TEAE level (summarizing events) by organ system and preferred term TEAE as well as severity, relationship, action and outcome. The Medical Dictionary for Regulatory Activities (MedDRA) version 20.1 was used and the Common Terminology Criteria for Adverse Events (CTCAE) grading.
Time frame: 24 weeks of treatment
Population: Within each category, patients were counted only once if they had \>1 event reported during the treatment period.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo (Period 1) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Death | 0 Participants |
| Placebo (Period 1) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with CTCAE ≥ Grade 3 | 0 Participants |
| Placebo (Period 1) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with drug-related TEAE | 0 Participants |
| Placebo (Period 1) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with serious TEAE | 0 Participants |
| Placebo (Period 1) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with TEAEs leading to discontinuation | 0 Participants |
| Placebo (Period 1) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with TEAE | 3 Participants |
| NS-065/NCNP-01 40mg/kg (Period 1) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with CTCAE ≥ Grade 3 | 0 Participants |
| NS-065/NCNP-01 40mg/kg (Period 1) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with TEAE | 4 Participants |
| NS-065/NCNP-01 40mg/kg (Period 1) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with TEAEs leading to discontinuation | 0 Participants |
| NS-065/NCNP-01 40mg/kg (Period 1) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with drug-related TEAE | 0 Participants |
| NS-065/NCNP-01 40mg/kg (Period 1) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with serious TEAE | 0 Participants |
| NS-065/NCNP-01 40mg/kg (Period 1) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Death | 0 Participants |
| NS-065/NCNP-01 80mg/kg (Period 1) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with TEAE | 4 Participants |
| NS-065/NCNP-01 80mg/kg (Period 1) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with CTCAE ≥ Grade 3 | 0 Participants |
| NS-065/NCNP-01 80mg/kg (Period 1) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with drug-related TEAE | 0 Participants |
| NS-065/NCNP-01 80mg/kg (Period 1) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with serious TEAE | 0 Participants |
| NS-065/NCNP-01 80mg/kg (Period 1) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Death | 0 Participants |
| NS-065/NCNP-01 80mg/kg (Period 1) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with TEAEs leading to discontinuation | 0 Participants |
| NS-065/NCNP-01 40mg/kg (Period 2) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with TEAEs leading to discontinuation | 0 Participants |
| NS-065/NCNP-01 40mg/kg (Period 2) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Death | 0 Participants |
| NS-065/NCNP-01 40mg/kg (Period 2) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with drug-related TEAE | 0 Participants |
| NS-065/NCNP-01 40mg/kg (Period 2) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with CTCAE ≥ Grade 3 | 0 Participants |
| NS-065/NCNP-01 40mg/kg (Period 2) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with serious TEAE | 0 Participants |
| NS-065/NCNP-01 40mg/kg (Period 2) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with TEAE | 5 Participants |
| NS-065/NCNP-01 80mg/kg (Period 2) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Death | 0 Participants |
| NS-065/NCNP-01 80mg/kg (Period 2) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with CTCAE ≥ Grade 3 | 0 Participants |
| NS-065/NCNP-01 80mg/kg (Period 2) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with drug-related TEAE | 0 Participants |
| NS-065/NCNP-01 80mg/kg (Period 2) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with serious TEAE | 0 Participants |
| NS-065/NCNP-01 80mg/kg (Period 2) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with TEAE | 7 Participants |
| NS-065/NCNP-01 80mg/kg (Period 2) | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with TEAEs leading to discontinuation | 0 Participants |
| Total | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with TEAE | 15 Participants |
| Total | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with TEAEs leading to discontinuation | 0 Participants |
| Total | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with serious TEAE | 0 Participants |
| Total | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with drug-related TEAE | 0 Participants |
| Total | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Death | 0 Participants |
| Total | Incidence of Adverse Events as Assessed by CTCAE v4.0. | Participants with CTCAE ≥ Grade 3 | 0 Participants |
Secondary
Change From Baseline in Distance Traveled in the Six-Minute Walk Test (6MWT).
A secondary efficacy endpoint was compared to Pre-Infusion Visit: Six-Minute Walk Test (6MWT).
Time frame: Baseline and 24 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Period 1) | Change From Baseline in Distance Traveled in the Six-Minute Walk Test (6MWT). | 15.6 m | Standard Deviation 26.4 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Change From Baseline in Distance Traveled in the Six-Minute Walk Test (6MWT). | 44.0 m | Standard Deviation 41.98 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Change From Baseline in Distance Traveled in the Six-Minute Walk Test (6MWT). | 28.9 m | Standard Deviation 36.31 |
Secondary
Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT).
A secondary efficacy endpoint was compared to Pre-Infusion Visit: quantitative muscle testing (QMT).
Time frame: Baseline and 24 weeks of treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Handgrip | -0.2029 lb | Standard Deviation 2.98334 |
| Placebo (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Non-Dominant Side Knee Flexors (hamstrings) | -1.7373 lb | Standard Deviation 3.10626 |
| Placebo (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Dominant Side Knee Extensors (quadriceps) | -2.1524 lb | Standard Deviation 4.58595 |
| Placebo (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Dominant Side Handgrip | -0.4173 lb | Standard Deviation 2.46596 |
| Placebo (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Non-Dominant Side Handgrip | -0.2280 lb | Standard Deviation 3.39211 |
| Placebo (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Elbow Flexors (biceps) | 0.3190 lb | Standard Deviation 1.9988 |
| Placebo (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Dominant Side Elbow Flexors (biceps) | 0.5111 lb | Standard Deviation 2.57829 |
| Placebo (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Non-Dominant Side Elbow Flexors (biceps) | 0.2067 lb | Standard Deviation 2.71502 |
| Placebo (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Elbow Extensors (triceps) | 0.6777 lb | Standard Deviation 2.65006 |
| Placebo (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Dominant Side Elbow Extensors (triceps) | 0.7046 lb | Standard Deviation 2.78271 |
| Placebo (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Non-Dominant Side Elbow Extensors (triceps) | 0.0001 lb | Standard Deviation 2.34657 |
| Placebo (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Knee Flexors (hamstrings) | -1.2209 lb | Standard Deviation 3.37401 |
| Placebo (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Dominant Side Knee Flexors (hamstrings) | -1.8985 lb | Standard Deviation 4.01798 |
| Placebo (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Knee Extensors (quadriceps) | -2.2261 lb | Standard Deviation 4.82146 |
| Placebo (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Non-Dominant Side Knee Extensors (quadriceps) | -0.5994 lb | Standard Deviation 4.3815 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Elbow Flexors (biceps) | -0.7110 lb | Standard Deviation 1.61528 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Handgrip | -0.8513 lb | Standard Deviation 1.85797 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Non-Dominant Side Elbow Flexors (biceps) | -0.3732 lb | Standard Deviation 2.50228 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Dominant Side Elbow Flexors (biceps) | -0.4468 lb | Standard Deviation 1.49138 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Dominant Side Knee Extensors (quadriceps) | 2.0867 lb | Standard Deviation 2.96796 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Non-Dominant Side Knee Flexors (hamstrings) | 0.6377 lb | Standard Deviation 2.03566 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Dominant Side Knee Flexors (hamstrings) | -0.7175 lb | Standard Deviation 3.64572 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Knee Extensors (quadriceps) | 1.5798 lb | Standard Deviation 3.33316 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Elbow Extensors (triceps) | 0.6895 lb | Standard Deviation 1.0099 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Non-Dominant Side Elbow Extensors (triceps) | 0.5168 lb | Standard Deviation 1.44498 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Knee Flexors (hamstrings) | -0.0283 lb | Standard Deviation 3.4324 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Dominant Side Handgrip | -1.0867 lb | Standard Deviation 1.75915 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Non-Dominant Side Knee Extensors (quadriceps) | 1.3308 lb | Standard Deviation 4.44474 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Dominant Side Elbow Extensors (triceps) | 0.6502 lb | Standard Deviation 0.81291 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Non-Dominant Side Handgrip | -0.1780 lb | Standard Deviation 2.27428 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Dominant Side Elbow Extensors (triceps) | 0.6813 lb | Standard Deviation 2.10345 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Elbow Flexors (biceps) | -0.1224 lb | Standard Deviation 1.85326 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Knee Flexors (hamstrings) | -0.7098 lb | Standard Deviation 3.32207 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Dominant Side Elbow Flexors (biceps) | 0.1006 lb | Standard Deviation 2.16263 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Non-Dominant Side Knee Extensors (quadriceps) | 0.2279 lb | Standard Deviation 4.3495 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Non-Dominant Side Elbow Flexors (biceps) | -0.0163 lb | Standard Deviation 2.54427 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Elbow Extensors (triceps) | 0.6828 lb | Standard Deviation 2.04299 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Non-Dominant Side Handgrip | -0.2066 lb | Standard Deviation 2.86108 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Handgrip | -0.4808 lb | Standard Deviation 2.49621 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Dominant Side Knee Flexors (hamstrings) | -1.3924 lb | Standard Deviation 3.76469 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Non-Dominant Side Knee Flexors (hamstrings) | -0.7194 lb | Standard Deviation 2.87696 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Knee Extensors (quadriceps) | -0.5950 lb | Standard Deviation 4.5399 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Non-Dominant Side Elbow Extensors (triceps) | 0.2216 lb | Standard Deviation 1.9592 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Dominant Side Handgrip | -0.7041 lb | Standard Deviation 2.14074 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT). | Dominant Side Knee Extensors (quadriceps) | -0.3356 lb | Standard Deviation 4.41039 |
Secondary
Change From Baseline in North Star Ambulatory Assessment (NSAA) Score.
The NSAA is a functional scale devised for use in ambulant children with Duchenne muscular dystrophy (DMD). It consists of 17 activities graded 0 (unable to perform), 1 (performs with modifications), 2 (normal movement). It assesses abilities necessary to remain ambulant that have been found to progressively deteriorate in untreated DMD patients, as well as in other muscular dystrophies such as Becker Muscular Dystrophy. NSAA Total Score ranges from 0 to 34, with a score of 34 implying normal function.
Time frame: Baseline and 24 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Period 1) | Change From Baseline in North Star Ambulatory Assessment (NSAA) Score. | 0.5 score on a scale | Standard Deviation 3.07 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Change From Baseline in North Star Ambulatory Assessment (NSAA) Score. | 1.1 score on a scale | Standard Deviation 2.8 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Change From Baseline in North Star Ambulatory Assessment (NSAA) Score. | 0.8 score on a scale | Standard Deviation 2.86 |
Secondary
Change From Baseline in Time to Climb 4 Stairs (TTCLIMB).
A secondary efficacy endpoint was compared to Pre-Infusion Visit: Time to Climb 4 Stairs (TTCLIMB).
Time frame: Baseline and 24 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Period 1) | Change From Baseline in Time to Climb 4 Stairs (TTCLIMB). | -0.34 second | Standard Deviation 1.14 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Change From Baseline in Time to Climb 4 Stairs (TTCLIMB). | 0.00 second | Standard Deviation 0.6 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Change From Baseline in Time to Climb 4 Stairs (TTCLIMB). | -0.17 second | Standard Deviation 0.897 |
Secondary
Change From Baseline in Time to Climb 4 Stairs (TTCLIMB) Velocity
A secondary efficacy endpoint was compared to Pre-Infusion Visit: Time to Run/Walk 10 meters (TTRW). The results were converted into velocity (meter/time).
Time frame: Baseline and 24 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Period 1) | Change From Baseline in Time to Climb 4 Stairs (TTCLIMB) Velocity | 0.07 m/s | Standard Deviation 0.105 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Change From Baseline in Time to Climb 4 Stairs (TTCLIMB) Velocity | -0.00 m/s | Standard Deviation 0.054 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Change From Baseline in Time to Climb 4 Stairs (TTCLIMB) Velocity | 0.32 m/s | Standard Deviation 0.088 |
Secondary
Change From Baseline in Time to Run/Walk 10 Meters (TTRW).
A secondary efficacy endpoint was compared to Pre-Infusion Visit: Time to Run/Walk 10 meters (TTRW).
Time frame: Baseline and 24 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Period 1) | Change From Baseline in Time to Run/Walk 10 Meters (TTRW). | -0.65 second | Standard Deviation 1.225 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Change From Baseline in Time to Run/Walk 10 Meters (TTRW). | -0.66 second | Standard Deviation 0.921 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Change From Baseline in Time to Run/Walk 10 Meters (TTRW). | -0.66 second | Standard Deviation 1.047 |
Secondary
Change From Baseline in Time to Run/Walk 10 Meters (TTRW) Velocity.
A secondary efficacy endpoint was compared to Pre-Infusion Visit: Time to Run/Walk 10 meters (TTRW). The results were converted into velocity (meter/time).
Time frame: Baseline and 24 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Period 1) | Change From Baseline in Time to Run/Walk 10 Meters (TTRW) Velocity. | 0.21 m/s | Standard Deviation 0.291 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Change From Baseline in Time to Run/Walk 10 Meters (TTRW) Velocity. | 0.24 m/s | Standard Deviation 0.222 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Change From Baseline in Time to Run/Walk 10 Meters (TTRW) Velocity. | 0.23 m/s | Standard Deviation 0.251 |
Secondary
Change From Baseline in Time to Stand (TTSTAND)
A secondary efficacy endpoint was compared to Pre-Infusion Visit: Time to Stand (TTSTAND)
Time frame: Baseline and 24 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Period 1) | Change From Baseline in Time to Stand (TTSTAND) | 0.05 second | Standard Deviation 1.446 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Change From Baseline in Time to Stand (TTSTAND) | -0.44 second | Standard Deviation 0.75 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Change From Baseline in Time to Stand (TTSTAND) | -0.19 second | Standard Deviation 1.141 |
Secondary
Change From Baseline in Time to Stand (TTSTAND) Velocity
A secondary efficacy endpoint was compared to Pre-Infusion Visit: Time to Stand (TTSTAND).The results were converted into velocity (rise/time).
Time frame: Baseline and 24 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Period 1) | Change From Baseline in Time to Stand (TTSTAND) Velocity | 0.02 rise/time | Standard Deviation 0.093 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Change From Baseline in Time to Stand (TTSTAND) Velocity | 0.02 rise/time | Standard Deviation 0.06 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Change From Baseline in Time to Stand (TTSTAND) Velocity | 0.02 rise/time | Standard Deviation 0.075 |
Secondary
Dystrophin Production by Immunofluorescence
The production of dystrophin protein was measured by immunofluorescence staining methods from a patient muscle biopsy at baseline and after 24 weeks treatment. To analyze dystrophin induction, biopsies were taken from a biceps muscle at baseline and the other biceps muscle after 24 weeks of treatment. Muscle samples were snap frozen and delivered to a central laboratory. All laboratory researchers remained blinded to sample identity. Immunofluorescence staining for dystrophin was performed on serial muscle biopsy sections in duplicate.
Time frame: Baseline and 24 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Period 1) | Dystrophin Production by Immunofluorescence | 14.2 % dystrophin-positive fibers | Standard Deviation 7.77 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Dystrophin Production by Immunofluorescence | 34.8 % dystrophin-positive fibers | Standard Deviation 20.42 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Dystrophin Production by Immunofluorescence | 24.5 % dystrophin-positive fibers | Standard Deviation 18.32 |
Secondary
Dystrophin Production by Mass Spectrometry
The production of dystrophin protein was measured by stable isotope mass spectrometry methods from a patient muscle biopsy at baseline and after 24 weeks treatment. To analyze dystrophin induction, biopsies were taken from a biceps muscle at baseline and the other biceps muscle after 24 weeks of treatment. Muscle samples were snap frozen and delivered to a central laboratory. All laboratory researchers remained blinded to sample identity. Dystrophin peptides were identified and quantified using reversed-phase nanoflow high-performance liquid chromatography with high resolution Mass Spectrometry.
Time frame: Baseline and 24 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Period 1) | Dystrophin Production by Mass Spectrometry | 2.1 % of normal control levels | Standard Deviation 1.09 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Dystrophin Production by Mass Spectrometry | 4.2 % of normal control levels | Standard Deviation 3.73 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Dystrophin Production by Mass Spectrometry | 3.1 % of normal control levels | Standard Deviation 2.88 |
Secondary
Dystrophin Production by RT-PCR for mRNA - Percentage of Exons Skipped - Molarity
The alteration of mRNA splicing was measured by RT-PCR of dystrophin mRNA transcripts from a patient muscle biopsy at baseline and after 24 weeks treatment. To analyze dystrophin induction, biopsies were taken from a biceps muscle at baseline and the other biceps muscle after 24 weeks of treatment. Muscle samples were snap frozen and delivered to a central laboratory. All laboratory researchers remained blinded to sample identity. For RT-PCR, bands corresponding to specific versions of the spliced dystrophin mRNA were visualized by gel electrophoresis, and the amounts of different mRNA isoforms were compared.
Time frame: Baseline and 24 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Period 1) | Dystrophin Production by RT-PCR for mRNA - Percentage of Exons Skipped - Molarity | 17.4 % of normal control levels | Standard Deviation 7.17 |
| NS-065/NCNP-01 40mg/kg (Period 1) | Dystrophin Production by RT-PCR for mRNA - Percentage of Exons Skipped - Molarity | 43.9 % of normal control levels | Standard Deviation 16.68 |
| NS-065/NCNP-01 80mg/kg (Period 1) | Dystrophin Production by RT-PCR for mRNA - Percentage of Exons Skipped - Molarity | 30.6 % of normal control levels | Standard Deviation 18.45 |