Phase II Study of NPC-14 (Arbekacin Sulfate) to Explore Safety, Tolerability, and Efficacy in Duchenne Muscular Dystrophy (NORTH POLE DMD)

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2013 by Kobe University
Sponsor:
Collaborators:
Japan Medical Association
Nobelpharma
Information provided by (Responsible Party):
Yasuhiro Takeshima, Kobe University
ClinicalTrials.gov Identifier:
NCT01918384
First received: August 1, 2013
Last updated: September 11, 2013
Last verified: September 2013
  Purpose

Duchenne Muscular Dystrophy (DMD) is inherited neuromuscular disorders due to mutation in the gene that encodes critical muscle protein called dystrophin. Currently, there is no effective treatment option for the disease. A pharmacological approach by promoting mRNA translation regardless of the presence of premature stop codons by nonsense mutation, called the readthrough strategy, has been developing recently for DMD with nonsense mutation. NPC-14 is a candidate compound for the readthrough strategy, since effective readthrough activities were demonstrated in nonclinical studies. This study is a phase II study designed to assess safety, tolerability, and efficacy of NPC-14 in ambulant DMD patients with nonsense mutation that were confirmed by whole genome analysis. These goals will be accomplished by monitoring adverse events by physical examination, cardiac, pulmonary, auditory, balance, and laboratory tests as safety endpoints, and dystrophin expression in muscle biopsy as primary efficacy endpoint, muscle function (NSAA, timed test, muscle strength (QMT, MMT) , dairy activities by lifecorder), and biomarkers as secondary efficacy endpoints. The study is a randomized, double blind, placebo-controlled study in 21 DMD patients. After screening, eligible patients are allocated dynamically to weekly NPC-14 or a placebo (saline) in a 2:1 ratio and will receive study drugs for 36 weeks.


Condition Intervention Phase
Muscular Dystrophy, Duchenne
Drug: NPC-14
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Phase II Study of Nonsense Readthrough Compound NPC-14 (Arbekacin Sulfate) to Explore Safety, Tolerability, and Efficacy in Duchenne Muscular Dystrophy Patients (NORTH POLE DMD Study)

Resource links provided by NLM:


Further study details as provided by Kobe University:

Primary Outcome Measures:
  • Safety and tolerability (Adverse events) [ Time Frame: Up to 38 weeks (36 weeks treatment period and 2 weeks follow up period) ] [ Designated as safety issue: Yes ]
  • Change of dystrophin expression rate in muscle tissues from the baseline assessment [ Time Frame: At 37 weeks (1 week after from 36 weeks treatment period) ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • North Star Ambulatory Assessment [ Time Frame: At 36 weeks ] [ Designated as safety issue: No ]
  • Timed test (6MWT, time to walk/run 10 meters, time to climb/descent four steps, time to rise from the floor) [ Time Frame: At 36 weeks ] [ Designated as safety issue: No ]
  • Muscle strength (MMT, QMT) [ Time Frame: At 36 weeks ] [ Designated as safety issue: No ]
  • Dairy activities [ Time Frame: At 36 weeks ] [ Designated as safety issue: No ]
  • Biomarkers (CK, ALD) [ Time Frame: At 36 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 21
Study Start Date: August 2013
Estimated Study Completion Date: October 2014
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: NPC-14
Intravenous drip, QW, 36 weeks, Dose will be adjusted and maintained by therapeutic drug monitoring of peak serum levels of NPC-14
Drug: NPC-14

NPC-14 will be administrated as following steps. The dose of NPC-14 will be calculated and adjusted by a non-blinded medical doctor and/or a non-blinded pharmacist.

  • An initial dose of NPC-14 will be half of that calculated by distribution volume:Vd based on patient age for safety reason.
  • After the initial administration, the dose of NPC-14 will be adjusted and maintained by actual Vd, therapeutic drug monitoring of peak serum levels of NPC-14
Other Name: Arbekacin
Placebo Comparator: Placebo
Dose will be adjusted by volume of distribution (Vd) of patients in accordance with the NPC-14 dose regimen
Drug: Placebo
Dose will be adjusted by volume of distribution (Vd) of patients in accordance with the NPC-14 dose regimen

  Eligibility

Ages Eligible for Study:   4 Years and older
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Diagnosis of DMD resulting from a nonsense mutation by whole genome sequencing of the dystrophin gene
  2. To have intact right or left biceps muscles, or an alternative muscle group that is able to be underwent for appropriate evaluation of efficacy
  3. To meet the following criteria at screening (baseline visit), within 30 days prior to the first dose of study drug

    • Ambulant and able to walk at least 75 meters during the 6MWT
    • Able to comply with and complete all protocol requirements, and judged by the investigator to be appropriate to participate in the study from the screening results
  4. Aged at least 4 years at the time of giving informed consent
  5. Male
  6. Able to be hospitalized for the study requirement
  7. Signed Informed consent by parents/legal guardian and/or signed assent by the subject (age of assent to be determined by IRB)

Exclusion Criteria:

  1. Prior exposure to investigational medicines that have a potential of restoring dystrophin or other functional protein (readthrough, exon skipping, utrophin upregulation therapy etc.)
  2. Known mutation at nucleotide 1555 in 12S rRNA gene of mitochondrial DNA, and/or personally or families have been treated or have a history of eight cranial nerve disorder (hearing loss、vertigo、tinnitus etc.)as a result of aminoglycoside use
  3. Inability to hear within the range of 0 to 25 dB by pure tone audiometry, abnormalities on auditory brainstem response audiometry, and/or loss of frequency by distortion product oto acoustic emissions at screening
  4. Poor oral intake or enable to oral intake, and/or bad general status
  5. Known allergies to NPC-14, other aminoglycosides, and/or bacitracin
  6. Presence of anti-dystrophin antibody at the baseline assessments
  7. Cys-C ≥1.2 mg/L and/or creatinine concentration >1.5 times the upper limit of age corrected normal range
  8. Left ventricular ejection fraction (EF) <40% or left ventricular fractional shortening (FS) <25%, and/or ≥480 msec QTc (corrected QT interval by Fridericia's method)
  9. Need of mechanical ventilation
  10. Forced vital capacity (FVC) <50% predicted
  11. Clinically significant concomitant diseases (hematology, psychoneurotic, hepatic, pulmonary, endocrine, immune, renal, and gastroenterological diseases), and/or cancer
  12. Impairment of intellectual functions, and/or expressive language ability which might interfere with study assessments
  13. Treatment with other systemic aminoglycoside within 6 months prior to the first administration of study drug
  14. Initiation of systemic glucocorticosteroids treatment, and/or start exercise cure, physical therapy, or occupational therapy which might interfere with study assessments. Changing of dose and schedule of systemic glucocorticosteroids within 6 months prior to the first administration of study drug
  15. History of any surgical procedure within months prior to the first administration of study drug or have a plan during study
  16. History of sever allergy from food and medicine like an anaphylaxis shock or generalized rash
  17. Participation in any other clinical trial and intake of any investigational drug within 6month of study entry
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01918384

Contacts
Contact: Manabu Kume +81-78-382-6667 npc14dmd@med.kobe-u.ac.jp

Locations
Japan
Kobe university hospital, department of pediatrics Recruiting
Kobe, Hyogo prefecture, Japan, 650-0017
Contact: Manabu Kume    +81-78-382-6667    npc14dmd@med.kobe-u.ac.jp   
Principal Investigator: Yasuhiro Takeshima, MD, PhD         
Sub-Investigator: Tomoko Lee, MD         
Sub-Investigator: Tomoko Kusunoki, MD         
National center of neurology and psychiatry Recruiting
Kodaira, Tokyo, Japan, 187-8551
Contact: Akemi Tamaura    +81-42-341-2712 ext 7289    tamaura@ncnp.go.jp   
Principal Investigator: Hirofumi Komaki, MD, PhD         
Sponsors and Collaborators
Kobe University
Japan Medical Association
Nobelpharma
Investigators
Principal Investigator: Yasuhiro Takeshima, MD, PhD Kobe university hospital, department of pediatrics
Study Director: Hirofumi Komaki, MD, PhD National center of neurology and psychiatry, department of child neurology, Muscular disease center
  More Information

No publications provided

Responsible Party: Yasuhiro Takeshima, MD, PhD, Kobe University
ClinicalTrials.gov Identifier: NCT01918384     History of Changes
Other Study ID Numbers: NPC-14-1, JMA-IIA00134
Study First Received: August 1, 2013
Last Updated: September 11, 2013
Health Authority: Japan: Ministry of Health, Labor and Welfare
Japan: Pharmaceuticals and Medical Devices Agency

Keywords provided by Kobe University:
Duchenne muscular dystrophy
NPC-14
Arbekacin
nonsense
readthrough

Additional relevant MeSH terms:
Muscular Dystrophy, Duchenne
Muscular Dystrophies
Muscular Disorders, Atrophic
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Genetic Diseases, Inborn
Genetic Diseases, X-Linked
Habekacin
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 18, 2014