search
Back to results

Safety and Dose Finding Study of NS-065/NCNP-01 in Boys With Duchenne Muscular Dystrophy (DMD)

Primary Purpose

Duchenne Muscular Dystrophy

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
NS-065/NCNP-01
Placebo
Sponsored by
NS Pharma, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Duchenne Muscular Dystrophy

Eligibility Criteria

4 Years - 9 Years (Child)MaleDoes not accept healthy volunteers

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.

Sites / Locations

  • UC Davis
  • University of Florida Health
  • Lurie Children's Hospital
  • Washington University
  • Duke University Medical Center
  • Children's Hospital of Richmond at VCU
  • Alberta Children's Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Placebo Comparator

Arm Label

NS-065/NCNP-01 40mg/kg

NS-065/NCNP-01 80mg/kg

Placebo

Arm Description

Six 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 dose once a week for 24 weeks

Six 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

Two patients in each of the dose groups will be administered placebo as an intravenous infusion once a week for 4 weeks followed by 20 weeks of open label treatment

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

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.
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.
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.
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).
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).
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).
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).
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).
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).
Change From Baseline in Time to Stand (TTSTAND)
A secondary efficacy endpoint was compared to Pre-Infusion Visit: Time to Stand (TTSTAND)
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).
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.

Full Information

First Posted
March 23, 2016
Last Updated
November 12, 2021
Sponsor
NS Pharma, Inc.
Collaborators
Nippon Shinyaku Co., Ltd., Cooperative International Neuromuscular Research Group, Therapeutic Research in Neuromuscular Disorders Solutions
search

1. Study Identification

Unique Protocol Identification Number
NCT02740972
Brief Title
Safety and Dose Finding Study of NS-065/NCNP-01 in Boys With Duchenne Muscular Dystrophy (DMD)
Official Title
A Phase II, Dose Finding Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of NS-065/NCNP-01 in Boys With Duchenne Muscular Dystrophy (DMD)
Study Type
Interventional

2. Study Status

Record Verification Date
November 2021
Overall Recruitment Status
Completed
Study Start Date
December 2016 (Actual)
Primary Completion Date
March 2018 (Actual)
Study Completion Date
April 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
NS Pharma, Inc.
Collaborators
Nippon Shinyaku Co., Ltd., Cooperative International Neuromuscular Research Group, Therapeutic Research in Neuromuscular Disorders Solutions

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Duchenne Muscular Dystrophy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
16 (Actual)

8. Arms, Groups, and Interventions

Arm Title
NS-065/NCNP-01 40mg/kg
Arm Type
Experimental
Arm Description
Six 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 dose once a week for 24 weeks
Arm Title
NS-065/NCNP-01 80mg/kg
Arm Type
Experimental
Arm Description
Six 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
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Two patients in each of the dose groups will be administered placebo as an intravenous infusion once a week for 4 weeks followed by 20 weeks of open label treatment
Intervention Type
Drug
Intervention Name(s)
NS-065/NCNP-01
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Incidence of Adverse Events as Assessed by CTCAE v4.0.
Description
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
Title
Dystrophin Production by Western Blot
Description
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
Secondary Outcome Measure Information:
Title
Dystrophin Production by RT-PCR for mRNA - Percentage of Exons Skipped - Molarity
Description
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
Title
Dystrophin Production by Mass Spectrometry
Description
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
Title
Dystrophin Production by Immunofluorescence
Description
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
Title
Change From Baseline in Muscle Strength as Measured by Quantitative Muscle Testing (QMT).
Description
A secondary efficacy endpoint was compared to Pre-Infusion Visit: quantitative muscle testing (QMT).
Time Frame
Baseline and 24 weeks of treatment
Title
Change From Baseline in Distance Traveled in the Six-Minute Walk Test (6MWT).
Description
A secondary efficacy endpoint was compared to Pre-Infusion Visit: Six-Minute Walk Test (6MWT).
Time Frame
Baseline and 24 weeks of treatment
Title
Change From Baseline in Time to Climb 4 Stairs (TTCLIMB).
Description
A secondary efficacy endpoint was compared to Pre-Infusion Visit: Time to Climb 4 Stairs (TTCLIMB).
Time Frame
Baseline and 24 weeks of treatment
Title
Change From Baseline in Time to Climb 4 Stairs (TTCLIMB) Velocity
Description
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
Title
Change From Baseline in Time to Run/Walk 10 Meters (TTRW).
Description
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
Title
Change From Baseline in Time to Run/Walk 10 Meters (TTRW) Velocity.
Description
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
Title
Change From Baseline in Time to Stand (TTSTAND)
Description
A secondary efficacy endpoint was compared to Pre-Infusion Visit: Time to Stand (TTSTAND)
Time Frame
Baseline and 24 weeks of treatment
Title
Change From Baseline in Time to Stand (TTSTAND) Velocity
Description
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
Title
Change From Baseline in North Star Ambulatory Assessment (NSAA) Score.
Description
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

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
4 Years
Maximum Age & Unit of Time
9 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Paula R. Clemens, MD
Organizational Affiliation
University of Pittsburgh
Official's Role
Study Chair
Facility Information:
Facility Name
UC Davis
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
Facility Name
University of Florida Health
City
Gainesville
State/Province
Florida
Country
United States
Facility Name
Lurie Children's Hospital
City
Chicago
State/Province
Illinois
Country
United States
Facility Name
Washington University
City
Saint Louis
State/Province
Missouri
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
Country
United States
Facility Name
Children's Hospital of Richmond at VCU
City
Richmond
State/Province
Virginia
Country
United States
Facility Name
Alberta Children's Hospital
City
Calgary
State/Province
Alberta
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
32453377
Citation
Clemens PR, Rao VK, Connolly AM, Harper AD, Mah JK, Smith EC, McDonald CM, Zaidman CM, Morgenroth LP, Osaki H, Satou Y, Yamashita T, Hoffman EP; CINRG DNHS Investigators. Safety, Tolerability, and Efficacy of Viltolarsen in Boys With Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping: A Phase 2 Randomized Clinical Trial. JAMA Neurol. 2020 Aug 1;77(8):982-991. doi: 10.1001/jamaneurol.2020.1264. Erratum In: JAMA Neurol. 2020 Aug 1;77(8):1040.
Results Reference
derived

Learn more about this trial

Safety and Dose Finding Study of NS-065/NCNP-01 in Boys With Duchenne Muscular Dystrophy (DMD)

We'll reach out to this number within 24 hrs