Study of Ataluren (PTC124) in Nonambulatory Participants With Nonsense-Mutation-Mediated Duchenne/Becker Muscular Dystrophy (nmDMD/BMD)
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|ClinicalTrials.gov Identifier: NCT01009294|
Recruitment Status : Terminated (Terminated early because a similar study with Ataluren exhibited lack of efficacy at the high dose (not due to safety concerns).)
First Posted : November 6, 2009
Results First Posted : July 29, 2020
Last Update Posted : July 29, 2020
|Condition or disease||Intervention/treatment||Phase|
|Duchenne Muscular Dystrophy Becker Muscular Dystrophy||Drug: Ataluren Drug: Chronic Corticosteroid Therapy||Phase 2|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||6 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 2a Study of Ataluren (PTC124) in Nonambulatory Patients With Nonsense-Mutation-Mediated Duchenne/Becker Muscular Dystrophy|
|Actual Study Start Date :||January 13, 2010|
|Actual Primary Completion Date :||March 23, 2010|
|Actual Study Completion Date :||March 23, 2010|
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.
Other Name: PTC124
Drug: Chronic Corticosteroid Therapy
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.
- Number of Participants With Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Baseline up to Day 50 ]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.
- Time to Complete Upper Limb Function Tasks as Measured by the Jebsen Test [ Time Frame: Baseline and Week 6 ]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.
- Upper Limb Function as Measured by the Brooke Upper Extremity Functional Rating Scale [ Time Frame: Baseline and Week 6 ]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.
- Participant Activities of Daily Living as Assessed Using the Egen Klassifikation (EK) Scale [ Time Frame: Baseline and Week 6 ]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.
- Shoulder, Elbow, and Wrist Passive and Active Range of Motion as Measured by Goniometry [ Time Frame: Baseline and Week 6 ]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.
- Force Exerted During Elbow Flexion and Extension, Shoulder Abduction, Hand Grip, Key Grip, and Finger Pinch as Assessed by Upper Extremity Myometry [ Time Frame: Baseline and Week 6 ]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.
- Time to Complete Hand Fine Motor Coordination and Dexterity Tasks as Measured by 9-Hole Peg Test (9HPT) [ Time Frame: Baseline and Week 6 ]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.
- Forced Vital Capacity (FVC) as Measured by Spirometry [ Time Frame: Baseline and Week 6 ]Pulmonary function was assessed as FVC in participants by spirometry using a study-specific spirometer. Multiple tests were conducted, if needed.
- Systolic and Diastolic Function as Measured by Echocardiography With Tissue Doppler [ Time Frame: Week 24 and Week 48 ]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.
- Heart Rate as Assessed by Radial Pulse [ Time Frame: Baseline and Week 6 ]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.
- Verbal Memory and Attention as Assessed by the Digit Span Task [ Time Frame: Baseline and Week 6 ]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.
- HRQL as Measured by the PedsQL Inventory Generic Core Scale [ Time Frame: Week 6 ]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.
- HRQL as Measured by the PedsQL Multidimensional Fatigue Scale [ Time Frame: Week 6 ]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.
- HRQL as Measured by the INQoL [ Time Frame: Week 24 and Week 48 ]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.
- Muscle Fragility as Determined by Serum Creatine Kinase (CK) Levels [ Time Frame: Baseline and Week 6 ]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.
- Gastrocnemius Muscle Dystrophin Expression as Determined by Immunofluoresence or by Western Blotting Techniques [ Time Frame: Week 36 ]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).
- Study Drug Compliance [ Time Frame: Baseline to Day 50 ]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.
- Pharmacokinetics: Ataluren Plasma Exposure [ Time Frame: 0, 2, 3, 6, 8, 9, 12, 14, 15, and 24 hours after the morning dose ]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.
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): NCT01009294
|United States, California|
|University of California-Davis|
|Davis, California, United States, 95616|
|United States, Massachusetts|
|Children's Hospital of Boston|
|Boston, Massachusetts, United States, 02115|
|United States, Minnesota|
|University of Minnesota|
|Minneapolis, Minnesota, United States, 55455|
|United States, Missouri|
|Washington University Medical School|
|Saint Louis, Missouri, United States, 63110|
|United States, Ohio|
|Nationwide Children's Hospital|
|Columbus, Ohio, United States, 43205|
|University of Newcastle|
|Newcastle upon Tyne, United Kingdom, NE1 3BZ|
|Study Director:||Leone Atkinson, MD, PhD||PTC Therapeutics|