A Clinical Study to Assess Two Doses of GSK2402968 in Subjects With Duchenne Muscular Dystrophy (DMD)

Study Overview
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Brief Summary
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The purpose of this study is to determine if 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. Two doses of GSK2402968 and placebo will be used in this study.

Detailed Description
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Boys with Duchenne Muscular Dystrophy (DMD) suffer from a relentless, progressive and fatal disease due to lack of dystrophin, a critical muscle protein. There is currently no known cure for the disease. GSK2402968 is thought to correct several genetic mutations through skipping of exon 51 and therefore targets only those boys with these mutations. A reasonable hypothesis is that increasing dystrophin will result in clinical improvement, and that the amount of dystrophin expressed will correlate with clinical improvement above a threshold level (e.g. around 30% of control). The initial limited efficacy data from completed and ongoing unblinded studies with GSK2402968 are encouraging as they have demonstrated de novo production of dystrophin and improved walking ability (primary efficacy endpoint) after 48 weeks of treatment which has been generally well tolerated. This study is designed to explore the efficacy, safety and pharmacokinetics of two doses of GSK2402968 given over 24 weeks. The two doses to be assessed are 6mg/kg/week and 3mg/kg/week. Based on pharmacokinetic and pharmacodynamic modeling, it is predicted at steady-state that the 6 mg/kg/week dose will induce dystrophin expression greater than 30% of control. The 3 mg/kg/week dose was chosen as modeling predicts 3 mg/kg/week of GSK2402968 will produce dystrophin expression in the range of 18-22%. Potential variability between subjects could theoretically produce higher expression and lead to a dystrophin level correlated with clinical improvement. Following the treatment period, the study has a 24 week post-treatment phase. The purpose of the post-treatment phase is to model the half-life of dystrophin, assess maintenance of response, and provide information about resolution of adverse event and laboratory abnormalities following cessation of treatment.

Official Title
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An Exploratory Study to Assess Two Doses of GSK2402968 in the Treatment of Ambulant Boys With Duchenne Muscular Dystrophy

Conditions
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Muscular Dystrophies

Intervention / Treatment
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* Drug: GSK2402968 3mg/kg/week
* Drug: GSK2402968 6 mg/kg/week
* Drug: Placebo to match GSK2402968 3 mg/kg/week
* Drug: Placebo to match GSK2402968 6 mg/kg/week


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ambulant subjects with Duchenne muscular dystrophy (DMD) 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, Life expectancy of at least 1 year, Able to rise from floor in < or =15 seconds (without aids/orthoses) at Screening Visit 1 and Screening Visit 2, Able to complete 6 Minute Walk Distance (6MWD) test with minimal distance of at least 75 meters, with reproducible results (within 20% of each other) at Screening Visit 1, Screening Visit 2 and at the baseline visit prior to randomization, Receiving oral 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 48 week duration of the study (Dose adjustments that are based on weight changes are permitted), 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 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). Exclusion Criteria: Any additional missing exon for DMD that cannot be treated with GSK2402968, Current or history of liver disease or impairment including : an INR vaue above 1.5 is in and of itself exclusionary a total bilirubin greater than 2 times the Upper Limit of Normal is in and of itself exclusionary a GGT greater than 2 times the Upper Limit of Normal is in and of itself exclusionary Current or history of renal disease or impairment, Baseline platelet count below the Lower Limit of Normal, aPPT above the Upper Limit of Normal, History of significant medical disorder which may confound the interpretation of either efficacy or safety data e.g. inflammatory disease 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, 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

Ages Eligible for Study
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Minimum Age: 5 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK2402968 3 mg/kg/week<br>3 mg/kg/week of investigational product | Drug: GSK2402968 3mg/kg/week<br>* Comparison of 2 doses of GSK2402968<br>|
| Experimental: GSK2402968 6 mg/kg/week<br>6 mg/kg/week of investigational Product | Drug: GSK2402968 6 mg/kg/week<br>* Comparison of 2 doses of GSK2402968<br>|
| Experimental: Placebo to match GSK2402968 3 mg/kg/week<br>Placebo | Drug: Placebo to match GSK2402968 3 mg/kg/week<br>* Matched placebo<br>|
| Experimental: Placebo to match GSK2402968 6 mg/kg/week<br>Placebo | Drug: Placebo to match GSK2402968 6 mg/kg/week<br>* Matched Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Muscle Function Using the 6 Minute Walking Distance | The participants during this assessment were asked to walk, at their own preferred speed, up and down a fixed distance until they were told to stop after 6 minutes. The participants were warned of the time and were told to stop earlier if they feel unable to continue. The total distance walked within the duration of 6 minutes (or until the participant stopped in case of early termination of the test), was recorded in meters. Change from Baseline, was defined as the post-randomization value minus the Baseline value. Baseline was defined as Week 0. | Baseline (Week 0) and Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Rise From Floor Time at Week 24 | The rise from floor was assessed, when the participants stood from a standardized supine position as quickly as possible when told to go. Time was recorded with a stopwatch from the initiation of movement until the assumption of upright standing. No aids or orthoses were allowed. Change from Baseline, was defined as the post-randomization value minus the Baseline value. Baseline was defined as Week 0. | Baseline (Week 0) and Week 24 | 
| Change From Baseline in 4 Stair Climb Ascent/Descent Time at Week 24 | During this assessment, the participants were asked to ascend and descend four steps. The time for this was recorded with a stopwatch from the initiation of movement until the participant stands on the fourth step, (going up and going down separately). A flight of steps with handrail were used for this test. Change from Baseline, was defined as the post-randomization value minus the Baseline value. Baseline was defined as Week 0. | Baseline (Week 0) and Week 24 | 
| Change From Baseline in 10 Meter Walk/Run at Week 24 | The participants during this assessment were asked to traverse marked 10-meter measured walkway as quickly as he safely can. Time was recorded to one tenth of a second with a stop watch from when his first foot crossed the start line until when the second foot crossed the finish line. How often the participant , touched the wall was to be noted. Care was taken to ensure that the participants were safe when completing this test. The assessor was allowed to walk nearby to provide 'emergency' help if needed, but must not support or provide manual assistance for the participant in any way. If the participant was unable to complete the 10-meter walk, the total distance was recorded. The participants were to perform the test in bare feet. No aids or orthoses were allowed. Change from Baseline, was defined as the post-randomization value minus the Baseline value. Baseline was defined as Week 0. | Baseline (Week 0) and Week 24 | 
| Change From Baseline in Muscle Strength Total Score at Week 24 | The muscle strength was recorded by handheld myometry using a microFET2 myometer. Upper and lower limb proximal muscles were evaluated including knee flexors, knee extensors, elbow flexors, elbow extensors, shoulder abductors and hip flexors. Total score was calculated by summing up all individual scores. If data for any of the individual muscle strength tests was missing, the total score were set to missing for that visit. Change from Baseline, was defined as the post-randomization value minus the Baseline value. Baseline was defined as Week 0. | Baseline (Week 0) and Week 24 | 
| Change From Baseline in Muscle Strength Tests For-Knee Extensor, Knee Flexor, Hip Flexor, Elbow Flexor, Elbow Extensor, Shoulder Abductor at Week 24 | The muscle strength was recorded by handheld myometry using a microFET2 myometer. Upper and lower limb proximal muscles were evaluated including knee flexors, knee extensors, elbow flexors, elbow extensors, shoulder abductors and hip flexors. Change from Baseline, was defined as the post-randomization value minus the Baseline value. Baseline was defined as Week 0. | Baseline (Week 0) and Week 24 | 
| Change From Baseline in the North Star Ambulatory Assessment (NSAA) Total Score | The NSAA was a functional scale devised from Hammersmith Scale of Motor Ability specifically for use in ambulant children with DMD. It consists of 17 activities graded 0 (unable to perform), 1 (performs with modifications), 2 (normal movement). The scale assessed activities that required for ambulatory activity and included items that were rarely achieved in untreated DMD (jump, hop, raise head) as well as items that are known to progressively deteriorate over time (stand from a chair, walk). A standardized manual is available within the SPM with specific instructions for grading. Video snaps used in training program to ensure evaluator reliability. The total score ranged from 0-34 where the highest score of 34 implies absence of symptoms and lower score implies more severe symptoms. Change from Baseline, was defined as the post-randomization value minus the baseline value. Baseline was defined as Week 0. | Baselie (Week 0) and Week 24 | 
| Number of Participants With Accidental Falls During 6 Minute Walk Distance Test | The participants during the 6 minute walk distance were asked to walk, at their own preferred speed, up and down a fixed distance until they were told to stop after 6 minutes. The participants were warned of the time and were told to stop earlier if they feel unable to continue. The total distance walked within the duration of 6 minutes (or until the participant stopped in case of early termination of the test), was recorded in metersThe number of accident falls during the 6 minute walk distance were reported. Data is reported for the number of participants with accidental falls of 0, 1 and 2. | Baseline (Week 0), Week 24, Week 36 and Week 48 | 
| Change From Baseline in Creatinine Kinase Serum Concentrations | Creatine kinase (CK) is a muscle-specific enzyme; its level in plasma is considered to reflect the extent of muscle damage. In the blood samples drawn to this purpose, the plasma level of CK was measured. Change from Baseline, was defined as the post-randomization value minus the baseline value. Baseline was defined as Week 0. | Baseline (Week 0) and Week 48 | 
| Change From Baseline in Forced Expiratory Volume in the First Second of Exhalation (FEV1) at Week 24 | FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Change from Baseline, was defined as the post-randomization value minus the Baseline value. Baseline was defined as Week 0. | Baseline (Week 0) and Week 24 | 
| Change From Baseline in Forced Vital Capacity (FVC) at Week 24 | FVC is defined as the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Change from Baseline, was defined as the post-randomization value minus the baseline value. Baseline was defined as Week 0. | Baseline (Week 0) and Week 24 | 
| Change From Baseline in Peak Cough Flow at Week 24 | The peak cough flow was conducted using a spirometer. Change from Baseline, was defined as the post-randomization value minus the Baseline value. Baseline was defined as Week 0. | Baseline (Week 0) and Week 24 | 
| Change From Baseline in Peak Expiratory Flow at Week 24 | The peak expiratory flow is a measure of the amount of air that can be pushed through the airways in a single rapid exhalation. The peak expiratory flow was measured using spirometry. Change from Baseline, was defined as the post-randomization value minus the baseline value. Baseline was defined as Week 0. | Baseline (Week 0) and Week 24 | 
| Change From Baseline in Sniff Pressure Test at Week 24 | This was one of the pulmonary function test which was a non-invasive procedure. It measured the inspiratory muscle strength by transdiaphragmatic (Pdi) and esophageal pressures (Pes) generated during volitional and nonvolitional maneuvers. Change from Baseline, was defined as the post-randomization value minus the baseline value. Baseline was defined as Week 0. | Baseline (Week 0) and Week 24 | 
| Number of Participants With Change From Baseline in Dystrophin Expression at Week 24 by Immunofluorescence Assay (IFA) | A muscle biopsy from the tibialis anterior muscle was taken to assess the expression of dystrophin. The muscle biopsy samples were collected by open biopsy or with the conchotome method according to standard hospital procedures for obtaining muscle biopsies from children. The minimum amount of muscle tissue required is a small piece of muscle of at least 0.5 x 0.5 x 0.5 centimeters. The muscle tissue was immediately frozen in liquid nitrogen-cooled 2-methylbutane and stored at -80°Celsius (C) or -70°C till shipment. In case of DMD participants , there is defect in the dystrophin producing gene or absence. Data for number of participants with change from baseline in dystrophin expression, was diagnosed using IFA and was categorized as strong increase, increase, and no change, decrease. | Baseline (Week 0) and Week 24 | 
| Number of Clinician Global Impression of Improvement (CGI-I) Responders | Single item question designed to provide a brief, stand-alone assessment of the clinician's view of the participant's global functioning after initiating a study medication, compared to their global functioning just prior to initiating treatment. Evaluated by an expert physician or evaluator familiar with DMD and who could make an expert clinical global judgement about severity of illness across various time points within context of clinical experience. The CGI-I reflects the clinician's judgment about the total picture of the participant : the illness severity, the level of distress and other aspects of impairment, and impact of illness on functioning. The CGI-I is rated without regard to clinician's belief that any clinical changes are or are not due to medication and without consideration of etiology of symptoms. It is measured on 7-point Likert scale (1 = 'very much improved', 2 = 'much improved', 4 = 'no change', 5 = 'minimally worse', 6 = 'much worse', 7 = 'very much worse'). | Week 24 and Week 48 | 
| Assessment of Functional Outcome by : Functional Outcomes Survey During Treatment Period | This was conducted by the family or caregiver. This helped to document the observed changes in the participant's functional outcome like the day to day activities; general health, mobility, and other general daily activities. The data for Week 24 has been reported as improved, not improved and not applicable. | Up to Week 24 | 
| Assessment of Functional Outcome by : Physician Assessment of Daily Living | This was conducted by the physician, which helped to assess and document observed changes in the participant by the physician reported by the participant or his family or caregiver. This was reported as any worsening and any improvement up to week 24. | Week 24 and Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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968, Duchenne Muscular Dystrophy, GSK2402968, DMD, Duchenne, GSK