Clinical trial NCT01254019: A Clinical Study to Assess the Efficacy and Safety of GSK2402968 in Subjects With Duchenne Muscular Dystrophy
Official title: A Phase III, Randomized, Double Blind, Placebo-controlled Clinical Study to Assess the Efficacy and Safety of GSK2402968 in Subjects With Duchenne Muscular Dystrophy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Muscular Dystrophies
Keywords: Duchenne Muscular Dystrophy
DMD
968
GSK
Duchenne
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2010-12-06
Enrollment: 186
Sex: MALE
Minimum age (years): 5
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether GSK2402968 is effective in the treatment of ambulant boys with Duchenne muscular dystrophy resulting from a mutation thought to be corrected by exon 51 skipping.


Eligibility criteria: Inclusion Criteria:

* Ambulant subjects with Duchenne muscular dystrophy resulting from a mutation/deletion within the DMD gene, confirmed by a state-of-the-art DNA diagnostic technique covering all DMD gene exons, including but not limited to MLPA (Multiplex Ligation-dependent Probe Amplification), CGH (Comparative Genomic Hybridisation), SCAIP (Single Condition Amplification/Internal Primer) or H-RMCA (High-Resolution Melting Curve Analysis), and correctable by GSK2402968-induced DMD exon 51 skipping.
* Males, aged at least 5 years, and with life expectancy of at least 1 year
* Able to complete 6MWD test with minimal distance of at least 75m at each predrug visit. In addition, results of 6MWD must be within 20% of each other at each pre-drug visit
* Receiving glucocorticoids for a minimum of 6 months immediately prior to screening, with no significant change in total daily dosage or dosing regimen for a minimum of 3 months immediately prior to screening and a reasonable expectation that total daily dosage and dosing regimen will not change significantly for the duration of the study
* QTc \<450msec (based on single or average QTc value of triplicate ECGs obtained over a brief recording period), or \<480 msec for subjects with Bundle Branch Block. Note: QTc may be either QTcB or QTcF, and machine read or manual overread.
* Subjects, where appropriate, must be willing to use adequate contraception (condoms or abstinence) for the duration of the study and for at least 5 months after the last dose of study drug.
* Willing and able to comply with all protocol requirements and procedures,
* Able to give informed assent and/or consent in writing signed by the subject and/or parent(s)/legal guardian (according to local regulations).
* French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

Exclusion Criteria:

* Any additional missing exon for DMD that cannot be treated with GSK2402968
* Current or history of liver or renal disease or impairment
* Acute illness within 4 weeks of the first anticipated administration of study medication which may interfere with study assessments
* Use of anticoagulants, antithrombotics or antiplatelet agents, previous treatment with investigational drugs, within 6 months of the first administration of study medication; and idebenone or other forms of Coenzyme Q10 within 1 month of the first administration of study medication.
* Current or anticipated participation in any investigational clinical studies
* Positive hepatitis B surface antigen, hepatitis C antibody test (if verified via RIBA or PCA testing), or human immunodeficiency virus (HIV) test at screening,
* Symptomatic cardiomyopathy. If subject has a left ventricular ejection fraction \<45% at Screening, the investigator should discuss inclusion of subject in the study with the medical monitor,
* Children in Care. The definition of a Child in Care is a child who has been placed under the control or protection of an agency, organisation, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation. The definition of a child in care can include a child cared for by foster parents or living in a care home or institution, provided that the arrangement falls within the definition above. The definition of a child in care does not include a child who is adopted or has an appointed legal guardian.

Primary outcomes:
measure: Change From Baseline in Muscle Function Using the 6 Minute Walking Distance (6MWD) Test Assessed at Week 48
timeFrame: Baseline (Day 0) and Week 48
Secondary outcomes:
measure: Change From Baseline in the Linearized North Star Ambulatory Assessment (NSAA) Total Score at Week 48
timeFrame: Baseline (Day 0) and Week 48
measure: Change From Baseline in the 4 Stair Climb (Ascent) Velocity at Week 48
timeFrame: Baseline (Day 0) and Week 48
measure: Change From Baseline in the 10-meter Walk/Run Velocity at Week 48
timeFrame: Baseline (Day 0) and Week 48
measure: Change From Baseline in the Timed Function Test Rise From Floor at Week 48
timeFrame: Baseline (Day 0) and Week 48
measure: Change From Baseline in the 4 Stair Climb (Descent) Velocity at Week 48
timeFrame: Baseline (Day 0) and Week 48
measure: Change From Baseline in Muscle Strength (Total Score) at Week 48
timeFrame: Baseline (Day 0) and Week 48
measure: Kaplan-Meier Estimates for Time to Loss of Ambulation
timeFrame: Week 48
measure: Number of Participants Who Experienced Accidental Falls During 6MWD Assessments at Week 48
timeFrame: Week 48
measure: Change From Baseline in Creatine Kinase Serum Concentrations at Week 48
timeFrame: Baseline (Day 0) and Week 48
measure: Change From Baseline in Pulmonary Function Test Forced Vital Capacity (FVC) and Forced Expiratory Volume in 1 Second (FEV1) at Week 48
timeFrame: Baseline (Day 0) and Week 48
measure: Number of Participants With Identified Mutation: DMD Exon 51 Skip (Upon Muscle Biopsies) at Week 48
timeFrame: Week 48
measure: Change From Baseline in Pediatric Quality of Life (PedsQL) Total Score at Week 48
timeFrame: Baseline (Day 0) and Week 48
measure: Change From Baseline in Pulmonary Function Test Peak Cough Flow (PCF) and Peak Flow (PF) at Week 48
timeFrame: Baseline (Day 0) and Week 48
measure: Number of Participants Who Showed Improvement on Clinician Global Impression of Improvement (CGI-I) Scale at Week 48
timeFrame: Week 48
measure: Change From Baseline in Health Utilities Index (HUI) Scores at Week 48
timeFrame: Baseline (Randomization Visit, Day 0) and Week 48
measure: Number of Participants With Adverse Events (AE) and Severe Adverse Events (SAE)
timeFrame: Up to Follow-up (Week 68)
measure: Number of Participants With Vital Sign Data for Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) and Heart Rate (HR) of Potential Clinical Concern (PCC) at Any Visit Post-Baseline
timeFrame: Up to Week 48
measure: Number of Participants With Abnormal-clinically Significant Electrocardiogram (ECG) Findings at Any Visit Post-Baseline
timeFrame: Up to Week 48
measure: Number of Participants With Hematology Parameters of PCC at Any Visit Post-Baseline
timeFrame: Up to Week 48
measure: Number of Participants With Coagulation Parameters of PCC at Any Visit Post-Baseline
timeFrame: Up to Week 48
measure: Number of Participants With Clinical Chemistry Parameters of PCC at Any Visit Post-Baseline
timeFrame: Up to Week 48
measure: Number of Participants With Urinalysis Data Outside the Reference Range (>Reference Range High) at Any Visit Post- Baseline
timeFrame: Up to Week 48
measure: Plasma Concentrations of GSK2402968 Following Subcutaneous Administration
timeFrame: Randomization (Week 0 at 0.5, 1 and 3 hours), Week 8 (pre-dose, 1-4 hours), Week 12 (pre-dose, 1-4 hours), Week 24 (pre-dose, 1-4 hours), Week 36 (pre-dose, 1-4 hours), Week 47 (pre-dose, 1-4 hours)
Other outcomes:
Locations:
city: Buenos Aries
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Leuven
country: Belgium
facility: GSK Investigational Site
city: Curitiba
country: Brazil
facility: GSK Investigational Site
state: Paraná
city: Porto Alegre
country: Brazil
facility: GSK Investigational Site
state: Rio Grande Do Sul
city: Ribeirao Preto
country: Brazil
facility: GSK Investigational Site
state: São Paulo
city: Santo Andre
country: Brazil
facility: GSK Investigational Site
state: São Paulo
city: Rio de Janeiro
country: Brazil
facility: GSK Investigational Site
city: São Paulo
country: Brazil
facility: GSK Investigational Site
city: Vancouver
country: Canada
facility: GSK Investigational Site
state: British Columbia
city: London
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Santiago
country: Chile
facility: GSK Investigational Site
state: Región Metro De Santiago
city: Santiago
country: Chile
facility: GSK Investigational Site
state: Región Metro De Santiago
city: Santiago
country: Chile
facility: GSK Investigational Site
city: Brno
country: Czechia
facility: GSK Investigational Site
city: Praha 5
country: Czechia
facility: GSK Investigational Site
city: Koebenhavn Oe
country: Denmark
facility: GSK Investigational Site
city: Lille cedex
country: France
facility: GSK Investigational Site
city: Marseille cedex 5
country: France
facility: GSK Investigational Site
city: Nantes cedex 01
country: France
facility: GSK Investigational Site
city: Paris cedex 15
country: France
facility: GSK Investigational Site
city: Toulouse cedex 9
country: France
facility: GSK Investigational Site
city: Freiburg
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Muenchen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Goettingen
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Essen
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Kiel
country: Germany
facility: GSK Investigational Site
state: Schleswig-Holstein
city: Budapest
country: Hungary
facility: GSK Investigational Site
city: Ferrara
country: Italy
facility: GSK Investigational Site
state: Emilia-Romagna
city: Roma
country: Italy
facility: GSK Investigational Site
state: Lazio
city: Roma
country: Italy
facility: GSK Investigational Site
state: Lazio
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Messina
country: Italy
facility: GSK Investigational Site
state: Sicilia
city: Hyogo
country: Japan
facility: GSK Investigational Site
city: Kumamoto
country: Japan
facility: GSK Investigational Site
city: Saitama
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Leiden
country: Netherlands
facility: GSK Investigational Site
city: Oslo
country: Norway
facility: GSK Investigational Site
city: Warszawa
country: Poland
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Esplugues De Llobregat. Barcelona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Valencia
country: Spain
facility: GSK Investigational Site
city: Kaohsiung
country: Taiwan
facility: GSK Investigational Site
city: Ankara
country: Turkey
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Goemans N, Mercuri E, Belousova E, Komaki H, Dubrovsky A, McDonald CM, Kraus JE, Lourbakos A, Lin Z, Campion G, Wang SX, Campbell C; DEMAND III study group. A randomized placebo-controlled phase 3 trial of an antisense oligonucleotide, drisapersen, in Duchenne muscular dystrophy. Neuromuscul Disord. 2018 Jan;28(1):4-15. doi: 10.1016/j.nmd.2017.10.004. Epub 2017 Dec 6.