Study of Ataluren (PTC124) in Nonambulatory Participants With Nonsense-Mutation-Mediated Duchenne/Becker Muscular Dystrophy (nmDMD/BMD)

Study Overview
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Brief Summary
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Duchenne/Becker muscular dystrophy (DMD/BMD) is a genetic disorder that develops in boys. It is caused by a mutation in the gene for dystrophin, a protein that is important for maintaining normal muscle structure and function. Loss of dystrophin causes muscle fragility that leads to weakness and loss of walking ability during childhood and teenage years. A specific type of mutation, called a nonsense (premature stop codon) mutation is the cause of DMD/BMD in approximately 10-15% of boys with the disease. Ataluren (PTC124) is an orally delivered, investigational drug that has the potential to overcome the effects of the nonsense mutation. This study is a Phase 2a trial that enrolled boys with nonsense mutation DMD/BMD who have lost independent mobility due to the disease. This study evaluated the safety and tolerability of ataluren (PTC124) and also evaluated efficacy outcomes in this participant population.

Detailed Description
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It was planned that this Phase 2a, open-label, safety and efficacy study to be performed at 5 sites in the US and 1 site in the United Kingdom. The study was to enroll  30 boys with nonsense mutation DMD/BMD (nmDBMD) who have been nonambulatory for at least 1 year. Enrollment was to be stratified to ensure evaluation of  15 participants who were receiving chronic corticosteroid therapy and of  15 participants who were not receiving chronic corticosteroid therapy. Participants were to take ataluren 3 times per day (at breakfast, lunch, and dinner) for 48 weeks ( 1 year). Study assessments were to be performed at clinic visits during screening, every 6 weeks for 2 visits and then every 12 weeks until the end of the study. Additional safety laboratory testing was to be required 4 times during the course of the study; this could have been performed at the investigational site, at an accredited local laboratory or clinic, or in the participant's home using a nursing service. When the blind for a similar study (PTC124-GD-007-DMD; NCT00592553) was revealed, the results indicated lack of efficacy for the high dose. Therefore, even though an independent data monitoring committee (DMC) agreed that both ataluren dose levels were well tolerated by the participants, the DMC recommended discontinuing ongoing studies with participants with nmDBMD receiving high-dose ataluren.

Official Title
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A Phase 2a Study of Ataluren (PTC124) in Nonambulatory Patients With Nonsense-Mutation-Mediated Duchenne/Becker Muscular Dystrophy

Conditions
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Duchenne Muscular Dystrophy, Becker Muscular Dystrophy

Intervention / Treatment
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* Drug: Ataluren
* Drug: Chronic Corticosteroid Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of DMD or BMD Presence of a nonsense mutation in the dystrophin gene Unable to ambulate independently for ≥1 year due to DMD/BMD Presence of sufficient shoulder and elbow function to perform study-related functional procedures (for example, 9-hole peg test) Adequate hepatic, renal, and adrenal function Ability to provide evaluable pretreatment echocardiogram and lung function assessments Willingness and ability to comply with scheduled visits, drug administration plan, study procedures, laboratory tests, and study restrictions Ability to provide written informed consent (parental/guardian consent if applicable)/assent (if <18 years of age) Exclusion Criteria: Initiation of systemic corticosteroid therapy within 6 months prior to start of study treatment or use of systemic aminoglycoside antibiotic within 3 months prior to start of study treatment Use of any intermittent systemic corticosteroid therapy regimen (for example, 10 days on followed by 10 days off, weekend dosing, every-other-day dosing); note that participants must have either been receiving a daily dosing regimen of prednisone, prednisolone, or deflazacort at the time of enrollment into the study or must have not been receiving any systemic corticosteroids Any change in treatment for congestive heart failure within 3 months prior to start of study treatment Ongoing warfarin or phenytoin therapy Prior therapy with ataluren Known hypersensitivity to any of the ingredients or excipients of ataluren (Litesse® UltraTM [refined polydextrose], polyethylene glycol 3350, Lutrol® micro F127 [poloxamer 407], mannitol 25C, crospovidone XL10, hydroxyethyl cellulose, vanilla, Cab O Sil® M5P [colloidal silica], magnesium stearate). Exposure to another investigational drug within 2 months prior to start of study treatment History of major surgical procedure within 1 month prior to start of study treatment or expectation of major surgical procedure (for example, scoliosis surgery) during the 48-week treatment period of the study Ongoing immunosuppressive therapy (other than corticosteroids) Ongoing participation in any other clinical trial Requirement for daytime ventilator assistance Uncontrolled clinical symptoms and signs of congestive heart failure Prior or ongoing medical condition (for example, concomitant illness, psychiatric condition, behavioral disorder, alcoholism, drug abuse), medical history, physical findings, electrocardiogram (ECG) findings, or laboratory abnormality that, in the investigator's opinion, could adversely affect the safety of the participant, makes it unlikely that the course of treatment or follow up would be completed, or could impair the assessment of study results

Ages Eligible for Study
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Minimum Age: 7 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ataluren<br>Ataluren was provided as a vanilla-flavored powder to be mixed with water, apple juice, or milk. Study drug dosing was based on milligrams of drug per kilogram of body weight. The dose level for ataluren was 20 milligrams/kilograms (mg/kg) in the morning, 20 mg/kg at midday, and 40 mg/kg in the evening. Administration within 30 minutes after a meal was recommended. Study drug was taken for up to 50 days. | Drug: Ataluren<br>* Oral powder<br>* Other names: PTC124;Drug: Chronic Corticosteroid Therapy<br>* Enrollment was stratified to ensure evaluation of approximately half of the participants were receiving chronic corticosteroid therapy and approximately half of participants were not receiving chronic corticosteroid therapy. Therefore, 3 out of 6 participants were receiving chronic corticosteriod therapy. For the participants receiving chronic corticosteriod therapy, a stable corticosteriod regimen was to be maintained during the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | A TEAE is any untoward medical occurrence or undesirable event(s) experienced in a participant that begins or worsens following administration of the study drug or study treatment, whether or not considered related to the treatment by the Investigator. A serious adverse event (SAE) was an adverse event (AE) resulting in any of the following outcomes or deemed significant for any other reason, death, initial or prolonged inpatient hospitalization, life-threatening experience (immediate risk of dying), or persistent or significant disability/incapacity not related to nmDBMD. AEs included both SAEs and non-serious AEs. AEs were classified according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (CTCAE) and coded using the Medical Dictionary for Regulatory Activities (MedDRA). A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module. | Baseline up to Day 50 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Complete Upper Limb Function Tasks as Measured by the Jebsen Test | Arm and hand function were assessed using the Jebsen test, a standardized clinical evaluation of tasks important to daily living. The test comprises of unilateral subtests performed with each hand (the dominant [DOM] hand and the non-DOM hand): moving and stacking light (250 grams) and heavy (500 grams) objects; picking up small, commonly encountered objects; stacking checkers; simulated feeding; simulated page turning; and writing. Participant performance of each task was timed. Longer time to complete the test indicates worse hand function. | Baseline and Week 6 | 
| Upper Limb Function as Measured by the Brooke Upper Extremity Functional Rating Scale | Upper extremity function was assessed using the Brooke Upper Extremity Functional Rating Scale, following standardized procedures. The Brooke Upper Extremity Functional Rating Scale graded arm and shoulder function from 1 to 6, with higher values indicating less function. A rating of 1 was used when the participant was able to abduct his arms in a full circle until they touch above his head, whereas a rating of 6 was used when the participant was unable to raise his hands to his mouth and had no useful function of hands. | Baseline and Week 6 | 
| Participant Activities of Daily Living as Assessed Using the Egen Klassifikation (EK) Scale | Activities of daily living after loss of ambulation were measured using the EK scale. The EK scale is an ordinal scale ranging from 0 to 30 points where 0 represents the highest level of independent function and 30 the lowest. The scale consists of 10 categories (each scored 0 to 3), involving different functional domains including 1) ability to use wheelchair, 2) ability to transfer from wheelchair, 3) ability to stand, 4) ability to balance in the wheelchair, 5) ability to move arms, 6) ability to use hands and arms when eating, 7) ability to turn in bed, 8) ability to cough, 9) ability to speak, and 10) physical well-being. The administration of the EK scale consisted of an interview of the participant to capture how he performs the tasks of daily life (as described by Categories 1 to 9) and how he perceives his wellbeing (as described by Category 10). The interviewer observed the participant and assigned the final score for the tasks that could be observed in the clinic. | Baseline and Week 6 | 
| Shoulder, Elbow, and Wrist Passive and Active Range of Motion as Measured by Goniometry | Goniometry was performed to test active and passive range-of motion (RoM) of the left (L) and right (R) shoulder, elbow, and wrist following standardized procedures. The observed angle for passive and active motion for each joint was measured in degrees. Greater degree of motion indicates better response. | Baseline and Week 6 | 
| Force Exerted During Elbow Flexion and Extension, Shoulder Abduction, Hand Grip, Key Grip, and Finger Pinch as Assessed by Upper Extremity Myometry | Upper extremity myometry was performed using a hand-held dynamometer following standardized procedures. The measured strength (peak force) was reported in Newtons. There are 0.22 pounds (lbs) in 1 Newton and approximately 10 Newton (9.80665 Newton) in 1 kilogram (kg). The threshold/range of the hand-held dynamometer is 0 to 500 Newtons. Bilateral assessments were done, and 3 measurements were recorded from each muscle group on each side, when possible. When the measurements were done in duplicate or triplicate, the best value was used. Greater value indicates better measurement. | Baseline and Week 6 | 
| Time to Complete Hand Fine Motor Coordination and Dexterity Tasks as Measured by 9-Hole Peg Test (9HPT) | Hand fine motor coordination and dexterity were assessed using the 9HPT using standardized procedures. The 9HPT is a unilateral test in which 9 pegs were placed in a board and then removed with the dominate and non-dominate hand within a 5-minute time limit. The amount of time required to put the pegs in the holes and remove them again with each hand was recorded. Each test was conducted twice per hand. Longer time to complete the test indicates worse hand fine motor coordination and dexterity. | Baseline and Week 6 | 
| Forced Vital Capacity (FVC) as Measured by Spirometry | Pulmonary function was assessed as FVC in participants by spirometry using a study-specific spirometer. Multiple tests were conducted, if needed. | Baseline and Week 6 | 
| Systolic and Diastolic Function as Measured by Echocardiography With Tissue Doppler | Cardiac function was assessed by echocardiography, which included standard parameters (for example, ejection fraction, left ventricle diastolic and systolic dimensions), as well as parameters integrating Doppler flow analysis with imaging to evaluate perturbations in wall motion. A standardized data collection process harmonized data from all participating institutions and allowed for centralized review. | Week 24 and Week 48 | 
| Heart Rate as Assessed by Radial Pulse | Heart rate was measured with the radial pulse. Following the Jebsen test, the participant rested for 5 minutes in a sitting position, and the heart rate for the last minute of this rest period was collected as the resting heart rate. | Baseline and Week 6 | 
| Verbal Memory and Attention as Assessed by the Digit Span Task | A series of digits (0-9) were presented to the participant in an auditory format only. The task had 2 parts: in the Forward Condition, the participant was requested to repeat back the digits in the order they were presented, and in the Backward Condition, he was requested to reverse the order of presentation. | Baseline and Week 6 | 
| HRQL as Measured by the PedsQL Inventory Generic Core Scale | Health-related quality of life (HRQL) was measured by the Pediatric Quality of Life Inventory (PedsQL) Inventory Generic Core Scale. The generic core module comprised of 23 questions evaluating physical, emotional, social, and school functioning. Examples of items in each of the generic core module scales included: It is hard for me to run; I feel sad or blue; I cannot do things that other kids my age can do; and It is hard to pay attention in class. Each of the generic core module items was scored on a 5-point response scale from 0 (never a problem) to 4 (almost always a problem). The appropriate age-specific version was completed. PedsQL Inventory Generic Core Scale data at Week 6 is presented. | Week 6 | 
| HRQL as Measured by the PedsQL Multidimensional Fatigue Scale | HRQL was measured by the PedsQL Multidimensional Fatigue Scale. The fatigue-specific module comprised of 18 questions evaluating general fatigue, sleep/rest fatigue, and cognitive fatigue. Fatigue-specific module obtains information relating to items such as: I feel too tired to do things that I like to do; I spend a lot of time in bed; and I have trouble remembering more than one thing at a time. Each of the fatigue-specific module items was scored on a 5-point response scale from 0 (never a problem) to 4 (almost always a problem). The appropriate age-specific version was completed. PedsQL Multidimensional Fatigue Scale data at Week 6 is presented. | Week 6 | 
| HRQL as Measured by the INQoL | HRQL was measured by the Individualized Neuromuscular Quality of Life Questionnaire (INQoL). The INQoL consisted of 45 questions within 10 sections. Four of the sections evaluate key muscle disease symptoms (that is, weakness, locking [myotonia], pain, and fatigue), 5 sections evaluate the degree and importance of the impact of muscle disease on particular areas of life, and 1 section asks about the positive and negative effects of treatment. A higher score indicates greater symptom impact or worse HRQL, with a range of 0-7. | Week 24 and Week 48 | 
| Muscle Fragility as Determined by Serum Creatine Kinase (CK) Levels | Blood samples collected for chemistry assays were used to quantify serum CK concentrations. Serum CK was assessed as a potential biomarker for muscle fragility, with a reduction in serum CK considered to be a positive outcome. The reference range was based on the age of the participant. | Baseline and Week 6 | 
| Gastrocnemius Muscle Dystrophin Expression as Determined by Immunofluoresence or by Western Blotting Techniques | The gastrocnemius muscle was to be biopsied from 1 leg to assess for the production of dystrophin at Week 36. The production of dystrophin was to be measured by immunofluorescene staining of the sarcolemmal membrane or by Western blotting techniques with an antibody to the C-terminal portion of the dystrophin protein (excluding revertant fibers). | Week 36 | 
| Study Drug Compliance | Study drug compliance was assessed by the participant daily diary and quantification of used and unused study drug. Compliance was assessed in terms of the amount of drug actually taken relative to the amount that should have been taken during the study. | Baseline to Day 50 | 
| Pharmacokinetics: Ataluren Plasma Exposure | Blood for ataluren concentrations over a 24-hour period was to be collected on Days 2 and 3 of Week 6. Analysis of the blood samples was to be conducted using a validated high performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) method. | 0, 2, 3, 6, 8, 9, 12, 14, 15, and 24 hours after the morning dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DMD, Duchenne muscular dystrophy, Becker muscular dystrophy, Nonsense mutation, Premature stop codon, BMD, Ataluren, PTC124