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

NCT01918384 | Unknown Phase 2 DMC

• 2 other identifiers: NPC-14-1JMA-IIA00134
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 4

Brief Summary

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.

Conditions

Muscular Dystrophy, Duchenne

Keywords

Duchenne muscular dystrophy; NPC-14; Arbekacin; nonsense; readthrough

Outcome Measures

Primary Outcomes (2)

• Safety and tolerability (Adverse events)

  Up to 38 weeks (36 weeks treatment period and 2 weeks follow up period)

• Change of dystrophin expression rate in muscle tissues from the baseline assessment

  At 37 weeks (1 week after from 36 weeks treatment period)

Secondary Outcomes (5)

• North Star Ambulatory Assessment

  At 36 weeks

• Timed test (6MWT, time to walk/run 10 meters, time to climb/descent four steps, time to rise from the floor)

  At 36 weeks

• Muscle strength (MMT, QMT)

  At 36 weeks

• Dairy activities

  At 36 weeks

• Biomarkers (CK, ALD)

  At 36 weeks

Study Arms (2)

NPC-14

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

Dose will be adjusted by volume of distribution (Vd) of patients in accordance with the NPC-14 dose regimen

Drug: Placebo

Interventions

NPC-14 DRUG

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

Also known as: Arbekacin

NPC-14

Placebo DRUG

Dose will be adjusted by volume of distribution (Vd) of patients in accordance with the NPC-14 dose regimen

Placebo

Eligibility Criteria

• Age: 4 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of DMD resulting from a nonsense mutation by whole genome sequencing of the dystrophin gene
• To have intact right or left biceps muscles, or an alternative muscle group that is able to be underwent for appropriate evaluation of efficacy
• 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
• Aged at least 4 years at the time of giving informed consent
• Male
• Able to be hospitalized for the study requirement
• Signed Informed consent by parents/legal guardian and/or signed assent by the subject (age of assent to be determined by IRB)

You may not qualify if:

• Prior exposure to investigational medicines that have a potential of restoring dystrophin or other functional protein (readthrough, exon skipping, utrophin upregulation therapy etc.)
• 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
• 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
• Poor oral intake or enable to oral intake, and/or bad general status
• Known allergies to NPC-14, other aminoglycosides, and/or bacitracin
• Presence of anti-dystrophin antibody at the baseline assessments
• Cys-C ≥1.2 mg/L and/or creatinine concentration \>1.5 times the upper limit of age corrected normal range
• 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)
• Need of mechanical ventilation
• Forced vital capacity (FVC) \<50% predicted
• Clinically significant concomitant diseases (hematology, psychoneurotic, hepatic, pulmonary, endocrine, immune, renal, and gastroenterological diseases), and/or cancer
• Impairment of intellectual functions, and/or expressive language ability which might interfere with study assessments
• Treatment with other systemic aminoglycoside within 6 months prior to the first administration of study drug
• 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
• History of any surgical procedure within months prior to the first administration of study drug or have a plan during study

Sponsors & Collaborators

• Kobe University: lead
• Japan Medical Association: collaborator
• Nobelpharma: collaborator

Study Sites (4)

Kobe university hospital, department of pediatrics

Kobe, Hyōgo, 650-0017, Japan

Location

Hyogo College of Medicine

Nishinomiya, Hyōgo, 663-8501, Japan

Location

National center of neurology and psychiatry

Kodaira, Tokyo, 187-8551, Japan

Location

Tokyo Women's Medical University

Shinjuku-ku, Tokyo, 162-8666, Japan

Location

MeSH Terms

Conditions

Muscular Dystrophy, Duchenne

Interventions

arbekacin

Condition Hierarchy (Ancestors)

Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Yasuhiro Takeshima, MD, PhD

  Hyogo Medical University

  PRINCIPAL INVESTIGATOR

• Hirofumi Komaki, MD, PhD

  National center of neurology and psychiatry, department of child neurology, Muscular disease center

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD

Study Record Dates

• First Submitted: August 1, 2013
• First Posted: August 7, 2013
• Study Start: August 1, 2013
• Primary Completion: October 1, 2015
• Study Completion: October 1, 2015
• Last Updated: September 3, 2015

Record last verified: 2015-09

Locations

JP (4)