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Trial record 2 of 7 for:    GSK and Duchenne

A Clinical Study to Assess the Efficacy and Safety of GSK2402968 in Subjects With Duchenne Muscular Dystrophy (DMD114044)

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01254019
First Posted: December 6, 2010
Last Update Posted: October 12, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
GlaxoSmithKline
  Purpose
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.

Condition Intervention Phase
Muscular Dystrophies Drug: GSK2402968 6mg/kg/week Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Change from Baseline in muscle function using the 6 Minute Walking Distance (6MWD) test assessed at Week 48 [ Time Frame: Baseline (Day 0) and Week 48 ]
    During the 6MWD, participants were asked to walk, at their own preferred speed, up and down a fixed distance until they were told to stop after 6 minutes (M). The participants were warned of the time and were told that they may stop earlier if they feel unable to continue. The total distance walked within 6M (or until the participant stopped in case of early termination of the test), the 6MWD, was recorded in meters as well as any falls. Baseline was defined as participants randomization assessment at Visit 3 (Day 0). Change from Baseline was calculated by subtracting the Baseline value from the value at Week 48.


Secondary Outcome Measures:
  • Change from Baseline in the linearized North Star Ambulatory Assessment (NSAA) total score at Week 48 [ Time Frame: Baseline (Day 0) and Week 48 ]
    The NSAA is a functional scale devised from the Hammersmith Scale of Motor Ability specifically 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). The scale assesses activities required to remain functionally ambulant (e.g. rise from the floor), activities that can be difficult even early in the disease (e.g. standing on heels) and activities that are known to progressively deteriorate over time (stand from a chair, walk). NSAA Total Score ranges from 0 to 34, with a score of 34 implying normal function. Baseline was defined as participants randomization assessment at Visit 3 (Day 0). Change from Baseline was calculated by subtracting the Baseline value from the value at Week 48.

  • Change from Baseline in the 4 stair climb (ascent) velocity at Week 48 [ Time Frame: Baseline (Day 0) and Week 48 ]
    The participant was asked to ascend four steps. Time was recorded with a stopwatch from the initiation of movement until the participant stood on the fourth step. A flight of steps with handrail was used for this test. Number of stairs ascended per second was calculated as 4 divided by the time to ascend 4 complete. Baseline was defined as participants randomization assessment at Visit 3 (Day 0). Change from Baseline was calculated by subtracting the Baseline value from the value at Week 48.

  • Change from Baseline in the 10-meter walk/run velocity at Week 48 [ Time Frame: Baseline (Day 0) and Week 48 ]
    The participant was instructed to perform the test bare foot. No aids or orthoses were allowed. The participant was asked to traverse a marked 10-meter measured walkway as quickly as he safely could. 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. If the wall was touched, it was noted how often. Care was taken to ensure that the participant was safe when completing this test. The assessor walked nearby to provide emergency help if needed, but did not support or provide manual assistance to the participant in any way. If the participant could not complete the 10-meter walk, the total distance was recorded. 10 minute walk/run speed was equal to 10 divided by time taken to complete 10 minute walk/run. Baseline was defined as participants randomization assessment at Visit 3 (Day 0). Change from Baseline was calculated by subtracting the Baseline value from the value at Week 48.

  • Change from Baseline in the timed function test Rise from floor at Week 48 [ Time Frame: Baseline (Day 0) and Week 48 ]
    The participant 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 are allowed. Baseline was defined as participants randomization assessment at Visit 3 (Day 0). Change from Baseline was calculated by subtracting the Baseline value from the value at Week 48.

  • Change from Baseline in the 4 stair climb (descent) velocity at Week 48 [ Time Frame: Baseline (Day 0) and Week 48 ]
    The participant was asked to descend four steps. Time was recorded with a stopwatch from the initiation of movement until the participant stood on the fourth step. A flight of steps with handrail was used for this test. Number of stairs descended per second was calculated as 4 divided by the time to descend 4 complete stairs. Baseline was defined as participants randomization assessment at Visit 3 (Day 0). Change from Baseline was calculated by subtracting the Baseline value from the value at Week 48.

  • Change from Baseline in muscle strength (total score) at Week 48 [ Time Frame: Baseline (Day 0) and Week 48 ]
    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. The muscle strength total score (pounds) was the sum of the 12 individual muscle strength tests. Baseline was defined as participants randomization assessment at Visit 3 (Day 0). Change from Baseline was calculated by subtracting the Baseline value from the value at Week 48.

  • Kaplan-Meier Estimates for Time to loss of ambulation [ Time Frame: Week 48 ]
    All participants were ambulant when entered into the study; however they could have become non-ambulant at some time during the study. The date was recorded and the variable time to loss of ambulation was calculated as: time to loss of ambulation = date of loss of ambulation - date of first dose.

  • Number of participants who experienced accidental falls during 6MWD assessments at Week 48 [ Time Frame: Week 48 ]
    The number of accidental falls occurring during the 6MWD were counted. Data has been presented for the number of participants who experienced accidental falls (from 0 to 1) during the 6MWD assessment.

  • Change from Baseline in creatine kinase serum concentrations at Week 48 [ Time Frame: Baseline (Day 0) and Week 48 ]
    Creatine kinase is a muscle-specific enzyme; its level in serum is considered to reflect the extent of muscle damage. In the blood samples drawn to this purpose, the serum level of creatine kinase were measured. Baseline was defined as participants randomization assessment at Visit 3 (Day 0). Change from Baseline was calculated by subtracting the Baseline value from the value at Week 48.

  • Change from Baseline in Pulmonary Function test Forced vital capacity (FVC) and Forced expiratory volume in 1 second (FEV1) at Week 48 [ Time Frame: Baseline (Day 0) and Week 48 ]
    The FEV1 is the volume of air forcefully exhaled in 1 second, whereas the FVC is the volume of air that can be maximally forcefully exhaled using non-invasive spirometry was conducted to determine actual and percentage values for FVC and FEV1. Baseline was defined as participants randomization assessment at Visit 3 (Day 0). Change from Baseline was calculated by subtracting the Baseline value from the value at Week 48.

  • Number of participants with Identified Mutation: DMD Exon 51 skip (upon muscle biopsies) at Week 48 [ Time Frame: Week 48 ]
    Most participants had biopsies taken from their tibialis anterior muscle (only 3 participants used their quadriceps).1 at Week 8, 12, 24, or 36 (participants were arbitrarily assigned to these visits) and 1 at Week 48 (all participants). Small samples of the muscle biopsy were stored for retrospective analysis. These were only analyzed in the event that any participant did not respond. Total muscle ribonucleic acid (RNA) was isolated from muscle tissue sections and was analyzed by reverse transcriptase polymer chain reaction (RT-PCR). RT-PCR analysis focused on the area flanking the targeted exon 51 was performed to detect specific exon 51 skipping in muscle. Depending on the participants mutation different sets of DMD-gene specific RT and PCR primers were used. Sequence analysis was performed on isolated PCR products to confirm specific exon 51 skip band detection.

  • Change from Baseline in Pediatric Quality of Life (PedsQL) Total Score at Week 48 [ Time Frame: Baseline (Day 0) and Week 48 ]
    The PedsQL 3.0 scale is used to measure pediatric quality of life (QOL) in children with neuromuscular disorders. The 25-item PedsQL Module encompasses 3 scales About My/My Childs Neuromuscular Disease (AMND,17 items related to the disease process and associated symptomatology), Communication (3 items related to the participant ability to communicate with health care providers about his/her illness), About Our Family Resources (AOFR, 5 items related to family financial and social support systems). A 5-point response scale is utilized (where 0=never a problem and 4=almost always a problem). The AMND Scale uses a 3-point response scale using smiley faces to assess problems for the child (0 =not at all and 4=a lot). The PedsQL total score ranges from 0-100, where higher scores indicate better health-related QOL. Baseline was defined as participants randomization assessment at Visit 3 (Day 0). Change from Baseline was calculated by subtracting the Baseline value from the value at Week 48.

  • Change from Baseline in Pulmonary Function test peak cough flow (PCF) and peak flow (PF) at Week 48 [ Time Frame: Baseline (Day 0) and Week 48 ]
    The PF also called peak expiratory flow rate (PEFR) is a participants maximum speed of expiration, as measured with a peak flow meter, a small, hand-held device used to monitor a participants ability to breathe out air. PCF was measured for participants wearing a nose clip and performing a maximum cough into a pocket peak flow meter. Baseline was defined as participants randomization assessment at Visit 3 (Day 0). Change from Baseline was calculated by subtracting the Baseline value from the value at Week 48.

  • Number of participants who showed improvement on Clinician Global Impression of Improvement (CGI-I) scale at Week 48 [ Time Frame: Week 48 ]
    The CGI-I is scored based on the clinician's reflection of the participant's current overall clinical condition compared to the overall clinical condition just prior to the initiation of medication use (i.e., the period prior to Randomization). The CGI-I is rated without regard to the clinician's belief that any clinical changes are or are not due to medication and without consideration of the etiology of the symptoms. The CGI-I is measured on a 7-point Likert scale (where 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, 7 = very much worse).

  • Change from Baseline in Health Utilities Index (HUI) Scores at Week 48 [ Time Frame: Baseline (Day 0) and Week 48 ]
    A 15-item HUI questionnaire for proxy-administered completion was used to assess Health-related quality of life (HRQoL).Responses from the 15-item HUI were used to quantify HRQoL according to two complementary health status classification systems, the HUI Mark 2 (HUI2) and HUI Mark 3 (HUI3). The HUI2 assessed seven HRQoL dimensions: sensation, mobility, emotion, cognition, self care, pain and fertility. The HUI3 assessed eight HRQoL dimensions: vision, hearing, speech, ambulation, dexterity, emotion, cognition and pain. A utility value of 1.0 represented perfect health and a utility value of 0.0 represented death. The lowest possible HUI2 score was -0.03 and the lowest possible HUI3 score was -0.36, where scores less than zero represented health states considered worse than death. Baseline was defined as participants randomization assessment at Visit 3 (Day 0). Change from Baseline was calculated by subtracting the Baseline value from the value at Week 48.

  • Number of participants with adverse events (AE) and severe adverse events (SAE) [ Time Frame: Upto Week 48 ]
    An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect. Participants with AE and SAE on-treatment have been presented.

  • 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 [ Time Frame: Upto Week 48 ]
    Blood pressure SBP,DBP and HR was recorded after five minutes rest in a semi-supine position. SBP and DBP measurements were carried out at Screening, Randomization and at Weeks 4, 8, 16, 24, 32, 40 and 48. The PCC range for vital sign DBP was defined as high (increase >= 20 and >= 40 millimeters of mercury [mmHg] and low (decrease >= 20 and >= 40 mmHg), SBP high (increase >= 10 and >= 20 mmHg and low (decrease >= 10 and >= 20 mmHg) and for HR high (increase >= 20 and >= 40 mmHg and low (decrease >= 20 and >= 40 mmHg). Data has been presented for number of participants with vital signs of PCC values any visit post Baseline in a consolidated format.

  • Number of participants with abnormal Electrocardiogram (ECG) findings at any visit post Baseline [ Time Frame: Upto Week 48 ]
    ECG measurements were carried out at Screening, Randomization and at Weeks 4, 8, 16, 24, 32, 40 and 48. The clinical interpretation of the ECG by the investigator was recorded as Normal, Abnormal but not clinically significant (A-NCS) and Abnormal clinically significant (A-CS). Data has been presented for number of participants with A-CS findings any visit post Baseline in a consolidated format.

  • Number of participants with hematology parameters of PCC at any visit post Baseline [ Time Frame: Upto Week 48 ]
    Laboratory samples for hematology were collected at Screening, Randomization, and Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40,44 and 48. The PCC values for hematology parameters hematocrit was 1.02 x Upper limit of normal (ULN), for hemoglobin was 1.03 x ULN, for lymphocytes was 0.81 x lower limit of normal (LLN), for platelet count was 0.67xx LLN and 1.57 x ULN, for total neutrophils was 0.83 x LLN, and that for white blood cell count was 0.67 x LLN and value of 1.82 x ULN. Data has been presented for number of participants with values high and low from reference range at any visit post Baseline in a consolidated format.

  • Number of participants with coagulation parameters of PCC at any visit post Baseline [ Time Frame: Upto Week 48 ]
    Laboratory samples for coagulation were collected at Screening, Randomization, and Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48. The PCC values for coagulation parameters activated partial thromboplastin time (aPTT) was 1.5 x ULN. aPTT ratio also known as international normalized ration (INR) and was 1.2 x ULN. Data has been presented for number of participants with values high and low from reference range at any visit post Baseline in a consolidated format.

  • Number of participants with clinical chemistry parameters of PCC at any visit post Baseline [ Time Frame: Upto Week 48 ]
    Laboratory samples for chemistry were collected at Screening, Randomization, and Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40,44 and 48. The PCC values for chemistry parameters for alanine amino transferase (ALT) plus total bilirubin (TB) was >= 1.5 x ULN for T.B and >= 2 x ULN for ALT, for albumin was 0.86 x LLN, for asparatate amino transferase (AST) was >= 2 x ULN, for calcium was 0.91 x LLN and 1.06 x ULN, for glucose was 0.71 x LLN and 1.41 x ULN, for phosphorus was 0.80 x LLN and 1.14 x ULN, for sodium was 0.96 x LLN and 1.03 x ULN. for potassium was 0.86 x LLN and 1.10 x ULN. and that for alkaline phosphatase was >= 2x ULN. Data has been presented for number of participants with values high and low from reference range at any visit post Baseline in a consolidated format.

  • Number of participants with urinalysis data outside the reference range at any visit post Baseline [ Time Frame: Upto Week 48 ]
    Urinalysis samples were collected at Screening, Randomization and Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46 and 48. Quantitative examination included the assessment for Urine Albumin excretion rate and Urine Protein excretion - 24 hour. Data has been presented for number of participants with values > reference range high at any visit post Baseline in a consolidated format.

  • Pharmacokinetic Assessment of Median Trough Plasma Concentrations of GSK2402968 Following Subcutaneous Administration [ Time Frame: Weeks 8,12,24,36 and 47 pre-dose and between 1 and 4 hours post-dose ]
    Blood samples for pharmacokinetic assay were taken at Week 0 at 0.5, 1,3 hours post-dose at Week 8,12,24 or 36 pre-dose and between 1 and 4 hours post-dose and at Week 47 pre-dose, and between 1 and 4 hours post-dose. Data has been presented for median trough plasma concentrations of GSK2402968 following subcutaneous administration.


Enrollment: 186
Actual Study Start Date: December 2, 2010
Study Completion Date: June 28, 2013
Primary Completion Date: June 28, 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: GSK2402968
6mg/kg
Drug: GSK2402968 6mg/kg/week
subcutaneous
Experimental: Placebo
dose-matched
Drug: GSK2402968 6mg/kg/week
subcutaneous

  Eligibility

Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   5 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01254019


  Show 47 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01254019     History of Changes
Other Study ID Numbers: 114044
First Submitted: October 21, 2010
First Posted: December 6, 2010
Last Update Posted: October 12, 2017
Last Verified: September 2017

Keywords provided by GlaxoSmithKline:
Duchenne Muscular Dystrophy
DMD
968
GSK
Duchenne

Additional relevant MeSH terms:
Muscular Dystrophies
Muscular Dystrophy, Duchenne
Muscular Disorders, Atrophic
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Genetic Diseases, Inborn
Genetic Diseases, X-Linked