Phase 2a Extension Study of Ataluren (PTC124) in Duchenne Muscular Dystrophy (DMD)

The 6MWD was assessed in participants who were ambulatory using standardized procedures. Participants were not permitted to use assistive devices during the 6MWD test. Only the results of the participant's best valid test at each visit were included in the analysis. The mean change from baseline in the distance the participant walked is reported.

Timed function tests included time to stand from supine position (rise to standing), time to run/walk 10 meters (m), and time to ascend/descend 4 stairs. Timed function tests were assessed in ambulatory participants. A decrease from baseline reflects faster completion of the functional task and, thus, better muscle function. If the time taken to perform a test exceeded 30 seconds or if a participant could not perform the test due to disease progression (PD), a value of 30 seconds was used. Test results were set to missing in the analysis for participants who could not perform the tests for reasons other than PD (for example, bone fracture).

Timed test evaluations included scoring of method that ambulatory participants used to complete test. Scale for method used for standing from supine position: 1) Unable to stand from supine, even with use of a chair. 2) Assisted Gowers, requires furniture to rise from supine to full upright posture. 3) Full Gowers, rolls over, stands with both hands "climbing up" legs to above knees to achieve full upright posture. 4) Half Gowers, rolls over, stands up with 1 hand support on lower legs. 5) Rolls to side and/or stands with 1 or both hands on floor to start to rise but does not touch legs. 6) Stands without rolling over or using hands. Increases from baseline are indicative of improving ability to perform functional task. If a participant could not perform a timed function test because of PD, a method value of "1" was assigned in analysis. Test results set to missing in analysis for participants who could not perform tests for reasons other than PD (for example, bone fracture).

Timed test evaluations included scoring of method that ambulatory participants used to complete test. Scale for method used to run/walk 10-meters: 1) Unable to walk independently. 2) Unable to walk independently but can walk with knee-ankle-foot orthoses (KAFOs) or with support from a person 3) Highly adapted, wide-based lordotic gait, cannot increase walking speed. 4) Moderately adapted gait, can pick up speed but cannot run. 5) Able to pick up speed but runs with a double stance phase (that is, cannot achieve both feet off the ground). 6) Runs and gets both feet off the ground (with no double-stance phase). At the visit, if a participant could not perform a timed function test because of PD, a method value of "1" was assigned in analysis. Test results set to missing in analysis for participants who could not perform tests for reasons other than PD (for example, bone fracture).

Timed test evaluations included scoring of method that ambulatory participants used to complete test. Scale for method used to ascend 4 stairs: 1) Unable to climb 4 standard stairs. 2) Climbs 4 standard stairs "marking time" (climbs 1 foot at a time, with both feet on a step before moving to next step), using both arms on 1 or both handrails. 3) Climbs 4 standard stairs "marking time" using 1 arm on 1 handrail. 4) Climbs 4 standard stairs "marking time" not needing handrail. 5) Climbs 4 standard stairs alternating feet, needs handrail for support. 6) Climbs 4 standard stairs alternating feet, not needing handrail support. At the visit, if a participant could not perform a timed function test because of PD, a method value of "1" was assigned in analysis. Test results set to missing in analysis for participants who could not perform tests for reasons other than PD (for example, bone fracture).

Timed test evaluations included scoring of method that ambulatory participants used to complete test. Scale for method used to descend 4 stairs: 1) Unable to descend 4 standard stairs. 2) Descends 4 standard stairs "marking time" (climbs 1 foot at a time, with both feet on a step before moving to next step), using both arms on 1 or both handrails. 3) Descends 4 standard stairs "marking time", using 1 arm on 1 handrail. 4) Descends 4 standard stairs "marking time", not needing handrail. 5) Descends 4 standard stairs alternating feet in both directions, needs handrail for support. 6) Descends 4 standard stairs alternating feet, not needing handrail support. At the visit, if a participant could not perform a timed function test because of PD, a method value of "1" was assigned in analysis. Test results set to missing in analysis for participants who could not perform tests for reasons other than PD (for example, bone fracture).

Upper extremity myometry was performed using a hand-held dynamometer following standardized procedures. With this system, evaluators judged the strength of each muscle using an 11-point descriptive scoring system. From the individual muscle-group scores, a total composite score was derived. Bilateral assessments were done, and 3 measurements were recorded from each muscle group on each side, when possible. The best of the 3 replicates was used in the analysis. An increase from Baseline is reflective of increased muscle strength, whereas a decrease from Baseline is reflective of decreased muscle strength. Participants who became unable to perform a myometry test because of disease progression were assigned a value of 0 for each visit at which the participant was no longer able to perform the test. Test results were set to missing in the analysis for participants who could not perform the tests for reasons other than disease progression (for example, bone fracture).

Heart rate was measured with a Polar RS400 heart rate monitor, which consists of a transmitter strap worn around the chest and a wristwatch receiver. The monitor produces a digital text file with 1 value per minute that represents the mean heart rate for that minute. Mean heart rate values were collected before, during, and after the 6MWT. The participant rested for 5 minutes in a sitting position before the 6MWT, and the mean heart rate for the last minute of this rest period was obtained and documented as the resting heart rate. During the 6MWT, the mean heart rate was collected and documented as the active heart rate. After completing the 6MWT and resting for 3 minutes, the mean heart rate for 1 minute was obtained and documented as the recovery heart rate.

The digit span task is a 2-part (forward and backward) test in which a series of digits (3 to 9) were presented to participant in an auditory format only. For forward condition, the participant was to repeat digits back in the order they were presented. For backward condition, the participant was to reverse the order of presentation. Maximum score for each part (digit forward and digit backward) of task is 14; participants received a score of 2 points if they passed both trials, score of 1 point if they passed only 1 trial, and score of 0 points if they failed both trials. A raw score of total number of correct forward and backward responses was age-normalized by subtracting corresponding mean and dividing by corresponding standard deviation of a reference population for that age. For each forward and backward result, the resulting Z score was transformed into percentile rank of normal distribution. Change from Baseline in number of digits recalled forward and backward is reported.

The PedsQL Generic Core Scales comprises 23 questions, which are grouped into 4 scales (physical functioning, emotional functioning, social functioning, and school functioning); the fatigue-specific module included an additional 18 questions. The appropriate age-specific version was completed. On PedsQL Generic Core Scales, items were reversed scored and linearly transformed to a 0 to 100 scale so that higher scores indicate a better HRQL (0=100, 1=75, 2=50, 3=25, and 4=0). Mean is the sum of the items over the number of items that were answered (which accounts for missing data) to create scale scores. If >50% of the items in a scale were missing, the scale score was not computed. Mean Total Scale Score is the sum of all of the items over the number of items that were answered on all scales.

The PedsQL Generic Core Scales comprises 23 questions, which are grouped into 4 scales (physical functioning, emotional functioning, social functioning, and school functioning); the fatigue-specific module included an additional 18 questions. The appropriate age-specific version was completed. On PedsQL Generic Core Scales, items were reversed scored and linearly transformed to a 0 to 100 scale so that higher scores indicate a better HRQL (0=100, 1=75, 2=50, 3=25, and 4=0). Mean is the sum of the items over the number of items that were answered (which accounts for missing data) to create scale scores. If >50% of the items in a scale were missing, the scale score was not computed. Mean Fatigue Scale Score is the sum of the items over the number of items that were answered in the Emotional, Social, and School Functioning Scales. Mean Total Scale Score is the sum of all of the items over the number of items that were answered on all scales.

Serum CK concentrations (as measured by the central laboratory) were quantified from the blood samples that were collected as part of the safety laboratory evaluations. The normal range for CK is 18 to 363 units/liter (U/L).

The biceps muscle was biopsied from 1 arm for confirmation of the absence or low levels of dystrophin prior to treatment initiation and from the other arm to assess for production of dystrophin post-treatment. Muscle tissue sections were processed and immunostained to detect muscle membrane-localized dystrophin. An increase in value indicates dystrophin production.

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 was prescribed. Physician-prescribed dose reductions and interruptions were factored into the calculations. "Not recorded" applies only to the days on which all dosing information was missing or for missing days. Invalid entries in the participant daily diary were assigned values of 0.0 for percentage of doses taken and 99.0 for percentage of doses not recorded.

Blood for ataluren concentrations over a 24-hour period was to be collected on Day 2 of Week 1 and Day 2 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 with a lower limit of quantitation (LLOQ) of 0.5 micrograms/milliliters (μg/mL). Plasma concentrations below qualification (BQ) is treated as 0 in the summary calculation.

Blood for ataluren concentrations were collected on Day 2 of Week 1 and Day 2 of Week 6. Analysis of the blood samples was to be conducted using a validated HPLC-MS/MS method with a LLOQ of 0.5 μg/mL. Plasma concentrations BQ is treated as 0 in the summary calculation.

Blood for prednisone and deflazacort concentrations were collected on Day 2 of Week 1 and Day 2 of Week 6. Plasma samples for the determination of prednisone concentrations were analyzed using a validated HPLC/MS/MS method, with LLOQs of 1.00 nanograms/milliliters (ng/mL). Prednisone concentrations <1.01 are treated as 1.01 in the summary calculation. Plasma samples for the determination of 21-desacetyl deflazacort concentrations were analyzed using a validated HPLC/MS/MS method with an LLOQ of 1.0 ng/mL. Deflazacort concentrations BQ are treated as 0 in the summary calculation.

This Outcome Measure is an exploratory study objective and data were not collected or analyzed for this extension study.