A Phase 2 interventional study of Ataluren and Placebo in Duchenne Muscular Dystrophy and Becker Muscular Dystrophy, sponsored by PTC Therapeutics. Completed at 37 sites in 11 countries. Open to male participants aged 5 Years and older. Per ClinicalTrials.gov, last updated 2020-04-07.
Sponsored by PTC Therapeutics · Phase 2, Interventional, and Treatment
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 13 percent (%) of boys with the disease. Ataluren is an orally delivered, investigational drug that has the potential to overcome the effects of the nonsense mutation. This study is a Phase 2b trial that will evaluate the clinical benefit of ataluren in boys with DMD/BMD due to a nonsense mutation. The main goals of the study are to understand whether ataluren can improve walking, activity, muscle function, and strength and whether the drug can safely be given for a long period of time.
This study is a Phase 2b, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, efficacy and safety study, designed to document the clinical benefit of ataluren when administered as therapy of patients with DMD/BMD due to a nonsense mutation (premature stop codon) in the dystrophin gene.
548 studies on the registry are indexed under Muscular Dystrophies; 89 are open to participants now.
This study's enrollment of 174 is above the median of 24 across 344 interventional studies indexed under Muscular Dystrophies.
Browse Muscular Dystrophies studies →PTC Therapeutics is the lead sponsor of 65 studies on the registry; 3 are open to participants now.
Of its 18 completed or terminated interventional studies of FDA-regulated products, 14 (78%) have results posted.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
Participants will receive ataluren suspension orally 3 times a day (TID), 20 milligrams/kilogram (mg/kg) at morning, 20 mg/kg at midday, and 40 mg/kg at evening (total daily dose 80 mg/kg) for 48 weeks.
Drug: Ataluren
Participants will receive ataluren suspension orally TID, 10 mg/kg at morning, 10 mg/kg at midday, and 20 mg/kg at evening (total daily dose 40 mg/kg) for 48 weeks.
Drug: Ataluren
Participants will receive placebo matched to ataluren orally TID at morning, midday, and evening for 48 weeks.
Drug: Placebo
Ataluren will be administered as per the dose and schedule specified in the respective arms.
Also known as: PTC124
Placebo matching to ataluren will be administered as the schedule specified in the respective arm.
Change From Baseline in 6MWD at Week 48
The 6MWD test was performed in a 30 meters long flat corridor, where the participant was instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. Ambulation was assessed via the 6MWD test following standardized procedures by measuring the 6MWD in meters. Participants were not permitted to use assistive devices (walker, long leg braces, or short leg braces) during the 6MWD test.
Time frame: Baseline, Week 48
Change From Baseline in Time to Stand From Supine Position at Week 48
If the time taken to perform this test exceeded 30 seconds or if a participant could not perform this test due to disease progression, a value of 30 seconds was used. Change from baseline data has been reported.
Time frame: Baseline, Week 48
Change From Baseline in Time to Walk/Run 10 Meters at Week 48
If the time taken to perform this test exceeded 30 seconds or if a participant could not perform this test due to disease progression, a value of 30 seconds was used. Change from baseline data has been reported.
Time frame: Baseline, Week 48
Change From Baseline in Time to Climb 4 Stairs at Week 48
If the time taken to perform this test exceeded 30 seconds or if a participant could not perform this test due to disease progression, a value of 30 seconds was used. Change from baseline data has been reported.
Time frame: Baseline, Week 48
Change From Baseline in Time to Descend 4 Stairs at Week 48
If the time taken to perform this test exceeded 30 seconds or if a participant could not perform this test due to disease progression, a value of 30 seconds was used. Change from baseline data has been reported.
Time frame: Baseline, Week 48
Change From Baseline in Force Exerted During Knee Flexion and Extension, Elbow Flexion and Extension, and Shoulder Abduction at Week 48, as Assessed by Myometry
Upper and lower extremity myometry was performed using a myometer following standardized procedures. Muscle groups evaluated included knee flexors, knee extensors, elbow flexors, elbow extensors, and shoulder abductors. Bilateral assessments were done and 3 measurements were recorded from each muscle group on each side if possible. Mean values for the left and right sides were calculated.
Time frame: Baseline, Week 48
Change From Baseline in Mean Activity Period/Day/Visit at Week 48, as Assessed by Step Activity Monitoring (SAM)
The SAM is a pedometer (worn on the ankle) that continuously records the number of steps per time interval. Participants were instructed to continue to wear the SAM for at least 9 consecutive days. SAM was used to record the number of strides/minute following each visit. A stride is the leg motion that begins when the foot with SAM leaves the floor and ends when the same foot touches the floor again (that is, a stride generally equals 2 steps). Mean activity period/day/visit was computed for each participant. Mean obtained during Screening (Week -6 to -1) and following Week 1 visit were used as baseline data for analysis. For each day, an active period was defined as the first time after 3:00 AM that greater than (\>) 2 strides/minute were recorded to the last time prior to midnight that \>2 strides/minute were recorded. Days were deleted on which such an active period was less than (\<) 50 percent (%) of the mean active period across all days for that participant's visit.
Time frame: Baseline, Week 48
Change From Baseline in Mean Total Step Count/Day/Visit During the Active Periods at Week 48, as Assessed by SAM
The SAM is a pedometer (worn on the ankle) that continuously records the number of steps per time interval. Participants were instructed to continue to wear the SAM for at least 9 consecutive days. SAM was used to record the number of strides/minute following each visit. A stride is the leg motion that begins when the foot with SAM leaves the floor and ends when the same foot touches the floor again (that is, a stride generally equals 2 steps). Mean total step count/day/visit during the active periods was computed for each participant. Mean obtained during Screening (Week -6 to -1) and following Week 1 visit were used as baseline data for analysis. For each day, an active period was defined as the first time after 3:00 AM that \>2 strides/minute were recorded to the last time prior to midnight that \>2 strides/minute were recorded. Days were deleted on which such an active period was \<50% of the mean active period across all days for that participant's visit.
Time frame: Baseline, Week 48
Change From Baseline in Mean Total Step Count/Hour During the Active Period at Week 48, as Assessed by SAM
The SAM is a pedometer (worn on the ankle) that continuously records the number of steps per time interval. Participants were instructed to continue to wear the SAM for at least 9 consecutive days. SAM was used to record the number of strides/minute following each visit. A stride is the leg motion that begins when the foot with SAM leaves the floor and ends when the same foot touches the floor again (that is, a stride generally equals 2 steps). Mean total step count/hour during the active periods for the days in a visit was computed for each participant. Mean obtained during Screening (Week -6 to -1) and following Week 1 visit were used as baseline data for analysis. For each day, an active period was defined as the first time after 3:00 AM that \>2 strides/minute were recorded to the last time prior to midnight that \>2 strides/minute were recorded. Days were deleted on which such an active period was \<50% of the mean active period across all days for that participant's visit.
Time frame: Baseline, Week 48
Change From Baseline in Maximum Continuous 10-minute, 20-minute, 30-minute, and 60-minute Total Step Count at Week 48, as Assessed by SAM
SAM is a pedometer (worn on the ankle) that continuously records the number of steps per time interval. Participants were instructed to continue to wear the SAM for at least 9 consecutive days. SAM was used to record the number of strides/minute following each visit. A stride is the leg motion that begins when the foot with SAM leaves the floor and ends when the same foot touches the floor again (that is, a stride generally equals 2 steps). The maximum continuous 10-minute, 20-minute, 30-minute, and 60-minute total step counts were computed for each participant. Mean obtained during Screening (Week -6 to -1) and following Week 1 visit were used as baseline data for analysis. For each day, an active period was defined as the first time after 3:00 AM that \>2 strides/minute were recorded to the last time prior to midnight that \>2 strides/minute were recorded. Days were deleted on which such an active period was \<50% of the mean active period across all days for that participant's visit.
Time frame: Baseline, Week 48
Change From Baseline in Percentage of Time During the Active Period Spent at Low Activity (Less Than or Equal to [≤] 15 Steps/Minute), Medium Activity (16-30 Steps/Minute), and High Activity (Greater Than [>]30 Steps/Minute) at Week 48
SAM is a pedometer(worn on the ankle) that continuously records the number of steps per time interval. Participants were instructed to continue to wear the SAM for at least 9 consecutive days. SAM was used to record the number of strides/minute following each visit. A stride is the leg motion that begins when the foot with SAM leaves the floor and ends when the same foot touches the floor again. Proportion of time during active periods spent at low activity(≤15 steps/minute), medium activity(16-30 steps/minute), and high activity(\>30 steps/minute) were computed for each participant. Mean obtained during Screening and following Week 1 visit were used as baseline data for analysis. For each day, an active period was defined as first time after 3:00 AM that \>2 strides/minute were recorded to the last time prior to midnight that \>2 strides/minute were recorded. Days were deleted on which such an active period was \<50% of the mean active period across all days for that participant's visit.
Time frame: Baseline, Week 48
Change From Baseline in Participant- Reported Health-Related Quality of Life (HRQL) as Measured by the Pediatric Quality of Life Inventory (PedsQL) Physical, Emotional, Social, and School Functioning Domain Scores at Week 48
HRQL was measured via the PedsQL. The generic core module (including physical, emotional, social and school functioning scales) comprises 23 questions and the fatigue-specific module (including general fatigue, sleep/rest fatigue, and cognitive fatigue scales) comprises an additional 18 questions. The PedsQL was completed by both the participant and/or a parent/caregiver. Examples of items in each of the generic core module scales include: "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 likert response scale from 0 (never a problem) to 4 (almost always a problem). Scores were transformed on a scale from 0 to 100 (0=100, 1=75, 2=50, 3=25, 4=0), with higher scores indicating better health-related quality of life. Change from Baseline was calculated by subtracting the Baseline value from the value at Week 48.
Time frame: Baseline, Week 48
Change From Baseline in Parent/Caregiver- Reported HRQL as Measured by the PedsQL Physical, Emotional, Social, and School Functioning Domain Scores at Week 48
HRQL was measured via the PedsQL. The generic core module (including physical, emotional, social and school functioning scales) comprises 23 questions and the fatigue-specific module (including general fatigue, sleep/rest fatigue, and cognitive fatigue scales) comprises an additional 18 questions. The PedsQL was completed by both the participant and/or a parent/caregiver. Examples of items in each of the generic core module scales include: "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 likert response scale from 0 (never a problem) to 4 (almost always a problem). Scores were transformed on a scale from 0 to 100 (0=100, 1=75, 2=50, 3=25, 4=0), with higher scores indicating better health-related quality of life. Change from Baseline was calculated by subtracting the Baseline value from the value at Week 48.
Time frame: Baseline, Week 48
Change From Baseline in Participant-Reported HRQL as Measured by the Total Fatigue Scale Score at Week 48
HRQL was measured via the PedsQL. The fatigue-specific module (including general fatigue, sleep/rest fatigue, and cognitive fatigue scales) comprises an additional 18 questions. PedsQL was completed by both the participant and/or a parent/caregiver. 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 likert response scale from 0 (never a problem) to 4 (almost always a problem). Scores were transformed on a scale from 0 to 100 (0=100, 1=75, 2=50, 3=25, 4=0), with higher scores indicating less fatigue. Total score was the sum of all items over the number of items answered on all scales. Change from Baseline was calculated by subtracting the Baseline value from the value at Week 48.
Time frame: Baseline, Week 48
Change From Baseline in Parent/Caregiver-Reported HRQL as Measured by the Total Fatigue Scale Score at Week 48
HRQL was measured via the PedsQL. The fatigue-specific module (including general fatigue, sleep/rest fatigue, and cognitive fatigue scales) comprises an additional 18 questions. The PedsQL was completed by both the participant and/or a parent/caregiver. 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 likert response scale from 0 (never a problem) to 4 (almost always a problem). Scores were transformed on a scale from 0 to 100 (0=100, 1=75, 2=50, 3=25, 4=0), with higher scores indicating less fatigue. Total score was the sum of all items over the number of items answered on all scales. Change from Baseline was calculated by subtracting the Baseline value from the value at Week 48.
Time frame: Baseline, Week 48
Parent/Caregiver-Reported Treatment Satisfaction Questionnaire for Medication (TSQM) Score
TSQM consisted of 14 questions about treatment satisfaction with drug in 4 domains: Effectiveness (Questions 1-3 scored as 1 \[extremely dissatisfied\] to 7 \[extremely satisfied\]), Side Effects (question 4 scored as 0 \[no\] or 1 \[yes\]; question 5 scored as 1 \[extremely bothersome\] to 5 \[not at all bothersome\]; questions 6 - 8 scored as 1 \[a great deal\] to 5 \[not at all\]), Convenience (questions 9 and 10 scored as 1 \[extremely difficult\] to 7 \[extremely easy\]; question 11 scored as 1 \[extremely inconvenient\] to 5 \[extremely convenient\]) and Global Satisfaction (question 12 scored as 1 \[not at all confident\] to 7 \[extremely confident\]; question 13 scored as 1 \[not at all certain\] to 5 \[extremely certain\]; question 14 scored as 1 \[extremely dissatisfied\] to 5 \[extremely satisfied\]). The scores of each of the domains were added together and an algorithm was used to create a score of 0 to 100, with higher scores indicating better treatment satisfaction.
Time frame: Week 48
Change From Baseline in Participant/Caregiver-Reported Number of Daily Accidental Falls at Week 48
Number of falls was determined by daily diary records maintained by participants and/or parent/caregivers.
Time frame: Baseline, Week 48
Change From Baseline in Number of Digits Recalled Forwards and Backwards on Digit Span Task at Week 48
Basic attention and working memory was measured using the digit span task. A series of digits (0-9) were presented to the child in an auditory format only. The task had 2 parts; in the forward condition, the child 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. A raw score of the total number of correct responses was converted to an age-scaled-score (z-score) by subtracting the corresponding mean and dividing by the corresponding standard deviation of a reference population for that age.
Time frame: Baseline, Week 48
Change From Baseline in Heart Rate Before, During, and After Each 6MWT at Week 48, as Assessed by Heart Rate Monitoring With the Polar® RS400
The 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 rates values were collected prior to, during, and after the 6MWT. The participant rested for 5 minutes in a sitting position prior to the 6MWT, and the mean heart rate for the last minute of this rest period was collected 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 collected and documented as the recovery heart rate.
Time frame: Baseline, Week 48
Change From Baseline in Serum Concentration of Creatine Kinase (CK) at Week 48
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.
Time frame: Baseline, Week 48
Percent Change From Pre-Treatment Visit (1 Week Prior to Baseline Visit) in Biceps Muscle Dystrophin Expression at Post-Treatment Visit (Week 36), as Determined by Immunofluorescence
Immunofluorescence evidence of a change in dystrophin expression on biceps muscle biopsy was defined as an increase in the staining of the sarcolemmal membrane with an antibody to the C-terminal portion of the dystrophin protein (excluding revertant fibers) between the pre-treatment (1 week prior to Baseline visit) and post-treatment (Week 36) biopsies. The biceps muscle was biopsied from one arm for confirmation of the absence or reduced levels of dystrophin prior to treatment initiation and from the other arm to assess for production of dystrophin post-treatment.
Time frame: Pre-Treatment (1 week prior to baseline), post-treatment (Week 36)
Percentage of Participants With Treatment-Emergent Adverse Events (AEs)
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an 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); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. Treatment-emergent adverse event (TEAE) was defined as an adverse event that occurred or worsened in the period extending from first dose of study drug to 6 weeks after the last dose of study drug. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'.
Time frame: Baseline up to Week 54
Study Drug Compliance
Study drug compliance was assessed by participant daily diary and quantification of used and unused study drug. Compliance was assessed in terms of the percentage of drug actually taken relative to the amount that should have been taken during the study.
Time frame: Baseline to Week 48
A total of 185 participants were screened for eligibility, of which 11 participants did not meet entry criteria.
| Milestone | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| Started | 60 | 57 | 57 |
| As-treated population | 60 | 57 | 57 |
| Itt population | 60 | 57 | 57 |
| Completed | 59 | 57 | 57 |
| Not completed | 1 | 0 | 0 |
| Withdrew: Protocol noncompliance | 1 | 0 | 0 |
The 6MWD test was performed in a 30 meters long flat corridor, where the participant was instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. Ambulation was assessed via the 6MWD test following standardized procedures by measuring the 6MWD in meters. Participants were not permitted to use assistive devices (walker, long leg braces, or short leg braces) during the 6MWD test.
| meters | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| Change From Baseline in 6MWD at Week 48 | -41.81 ± 89.234 | -12.86 ± 72.007 | -42.56 ± 90.046 |
If the time taken to perform this test exceeded 30 seconds or if a participant could not perform this test due to disease progression, a value of 30 seconds was used. Change from baseline data has been reported.
| seconds | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| Baseline | 12.25 ± 11.191 | 10.80 ± 9.924 | 11.50 ± 11.440 |
| Change at Week 48 | 3.00 ± 5.686 | 3.23 ± 5.761 | 3.24 ± 7.253 |
If the time taken to perform this test exceeded 30 seconds or if a participant could not perform this test due to disease progression, a value of 30 seconds was used. Change from baseline data has been reported.
| seconds | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| Baseline | 7.80 ± 5.243 | 7.45 ± 4.373 | 6.86 ± 2.813 |
| Change at Week 48 | 2.37 ± 6.149 | 1.68 ± 5.617 | 3.03 ± 6.691 |
If the time taken to perform this test exceeded 30 seconds or if a participant could not perform this test due to disease progression, a value of 30 seconds was used. Change from baseline data has been reported.
| seconds | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| Baseline | 7.63 ± 7.522 | 6.94 ± 6.474 | 6.04 ± 5.661 |
| Change at Week 48 | 3.51 ± 6.794 | 2.39 ± 4.618 | 4.79 ± 7.949 |
If the time taken to perform this test exceeded 30 seconds or if a participant could not perform this test due to disease progression, a value of 30 seconds was used. Change from baseline data has been reported.
| seconds | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| Baseline | 6.75 ± 7.219 | 6.08 ± 5.985 | 5.52 ± 5.753 |
| Change at Week 48 | 2.95 ± 7.323 | 2.41 ± 6.162 | 4.03 ± 7.828 |
Upper and lower extremity myometry was performed using a myometer following standardized procedures. Muscle groups evaluated included knee flexors, knee extensors, elbow flexors, elbow extensors, and shoulder abductors. Bilateral assessments were done and 3 measurements were recorded from each muscle group on each side if possible. Mean values for the left and right sides were calculated.
| pounds | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| Baseline: Force during knee flexion | 12.45 ± 4.684 | 12.08 ± 4.217 | 11.06 ± 3.494 |
| Change at Week 48: Force during knee flexion | 0.39 ± 3.148 | -0.07 ± 3.511 | 0.38 ± 2.991 |
| Baseline: Force during knee extension | 12.71 ± 7.910 | 12.81 ± 5.753 | 12.96 ± 6.162 |
| Change at Week 48: Force during knee extension | -0.59 ± 3.511 | -0.63 ± 3.616 | -1.85 ± 3.899 |
| Baseline: Force exerted during elbow flexion | 8.72 ± 4.709 | 7.66 ± 3.154 | 8.14 ± 2.972 |
| Change at Week 48: Force during elbow flexion | -0.50 ± 1.832 | -0.10 ± 1.680 | -0.35 ± 1.807 |
| Baseline: Force during elbow extension | 6.81 ± 3.815 | 6.19 ± 3.083 | 6.77 ± 2.785 |
| Change at Week 48: Force during elbow extension | -0.28 ± 1.473 | 0.10 ± 1.493 | -0.51 ± 2.333 |
The SAM is a pedometer (worn on the ankle) that continuously records the number of steps per time interval. Participants were instructed to continue to wear the SAM for at least 9 consecutive days. SAM was used to record the number of strides/minute following each visit. A stride is the leg motion that begins when the foot with SAM leaves the floor and ends when the same foot touches the floor again (that is, a stride generally equals 2 steps). Mean activity period/day/visit was computed for each participant. Mean obtained during Screening (Week -6 to -1) and following Week 1 visit were used as baseline data for analysis. For each day, an active period was defined as the first time after 3:00 AM that greater than (\>) 2 strides/minute were recorded to the last time prior to midnight that \>2 strides/minute were recorded. Days were deleted on which such an active period was less than (\<) 50 percent (%) of the mean active period across all days for that participant's visit.
| minutes | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| Baseline | 756.84 ± 84.612 | 761.86 ± 76.984 | 751.71 ± 60.513 |
| Change at Week 48 | 0.87 ± 57.833 | -22.23 ± 84.759 | -19.91 ± 91.960 |
The SAM is a pedometer (worn on the ankle) that continuously records the number of steps per time interval. Participants were instructed to continue to wear the SAM for at least 9 consecutive days. SAM was used to record the number of strides/minute following each visit. A stride is the leg motion that begins when the foot with SAM leaves the floor and ends when the same foot touches the floor again (that is, a stride generally equals 2 steps). Mean total step count/day/visit during the active periods was computed for each participant. Mean obtained during Screening (Week -6 to -1) and following Week 1 visit were used as baseline data for analysis. For each day, an active period was defined as the first time after 3:00 AM that \>2 strides/minute were recorded to the last time prior to midnight that \>2 strides/minute were recorded. Days were deleted on which such an active period was \<50% of the mean active period across all days for that participant's visit.
| steps/day | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| Baseline | 5302.31 ± 1907.058 | 4870.13 ± 2165.522 | 5602.31 ± 2023.543 |
| Change at Week 48 | -615.14 ± 1468.452 | -676.46 ± 1717.535 | -908.34 ± 1999.969 |
The SAM is a pedometer (worn on the ankle) that continuously records the number of steps per time interval. Participants were instructed to continue to wear the SAM for at least 9 consecutive days. SAM was used to record the number of strides/minute following each visit. A stride is the leg motion that begins when the foot with SAM leaves the floor and ends when the same foot touches the floor again (that is, a stride generally equals 2 steps). Mean total step count/hour during the active periods for the days in a visit was computed for each participant. Mean obtained during Screening (Week -6 to -1) and following Week 1 visit were used as baseline data for analysis. For each day, an active period was defined as the first time after 3:00 AM that \>2 strides/minute were recorded to the last time prior to midnight that \>2 strides/minute were recorded. Days were deleted on which such an active period was \<50% of the mean active period across all days for that participant's visit.
| steps/hour | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| Baseline | 423.67 ± 168.754 | 383.62 ± 161.911 | 446.37 ± 160.666 |
| Change at Week 48 | -44.51 ± 125.154 | -42.23 ± 126.429 | -59.62 ± 153.054 |
SAM is a pedometer (worn on the ankle) that continuously records the number of steps per time interval. Participants were instructed to continue to wear the SAM for at least 9 consecutive days. SAM was used to record the number of strides/minute following each visit. A stride is the leg motion that begins when the foot with SAM leaves the floor and ends when the same foot touches the floor again (that is, a stride generally equals 2 steps). The maximum continuous 10-minute, 20-minute, 30-minute, and 60-minute total step counts were computed for each participant. Mean obtained during Screening (Week -6 to -1) and following Week 1 visit were used as baseline data for analysis. For each day, an active period was defined as the first time after 3:00 AM that \>2 strides/minute were recorded to the last time prior to midnight that \>2 strides/minute were recorded. Days were deleted on which such an active period was \<50% of the mean active period across all days for that participant's visit.
| steps | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| Baseline: 10-minute total step count | 35.77 ± 10.222 | 32.24 ± 11.374 | 36.76 ± 8.935 |
| Change at Week 48: 10-minute total step count | -2.77 ± 8.569 | -2.79 ± 6.355 | -3.97 ± 9.720 |
| Baseline: 20-minute total step count | 29.13 ± 9.272 | 25.68 ± 10.038 | 29.74 ± 8.205 |
| Change at Week 48: 20-minute total step count | -2.49 ± 7.407 | -2.40 ± 5.806 | -3.55 ± 8.677 |
| Baseline: 30-minute total step count | 25.00 ± 8.053 | 22.08 ± 9.206 | 25.70 ± 7.350 |
| Change at Week 48: 30-minute total step count | -2.08 ± 6.519 | -2.31 ± 5.505 | -3.03 ± 7.604 |
| Baseline: 60-minute total step count | 18.58 ± 6.210 | 16.52 ± 7.199 | 19.50 ± 5.887 |
| Change at Week 48: 60-minute total step count | -1.50 ± 5.177 | -1.85 ± 4.616 | -2.33 ± 6.241 |
SAM is a pedometer(worn on the ankle) that continuously records the number of steps per time interval. Participants were instructed to continue to wear the SAM for at least 9 consecutive days. SAM was used to record the number of strides/minute following each visit. A stride is the leg motion that begins when the foot with SAM leaves the floor and ends when the same foot touches the floor again. Proportion of time during active periods spent at low activity(≤15 steps/minute), medium activity(16-30 steps/minute), and high activity(\>30 steps/minute) were computed for each participant. Mean obtained during Screening and following Week 1 visit were used as baseline data for analysis. For each day, an active period was defined as first time after 3:00 AM that \>2 strides/minute were recorded to the last time prior to midnight that \>2 strides/minute were recorded. Days were deleted on which such an active period was \<50% of the mean active period across all days for that participant's visit.
| percentage of time | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| Baseline: Time spent at low activity | 32.91 ± 7.842 | 32.38 ± 8.213 | 32.86 ± 6.239 |
| Change at Week 48: Time spent at low activity | -2.06 ± 7.903 | -1.12 ± 8.220 | -1.11 ± 5.586 |
| Baseline: Time spent at medium activity | 11.11 ± 4.013 | 10.00 ± 3.656 | 11.84 ± 4.304 |
| Change at Week 48: Time spent at medium activity | -1.35 ± 3.348 | -0.69 ± 3.828 | -1.92 ± 4.178 |
| Baseline: Time spent at high activity | 6.59 ± 4.077 | 5.78 ± 3.785 | 7.17 ± 3.700 |
| Change at Week 48: Time spent at high activity | -0.66 ± 2.790 | -0.96 ± 2.828 | -1.03 ± 3.783 |
HRQL was measured via the PedsQL. The generic core module (including physical, emotional, social and school functioning scales) comprises 23 questions and the fatigue-specific module (including general fatigue, sleep/rest fatigue, and cognitive fatigue scales) comprises an additional 18 questions. The PedsQL was completed by both the participant and/or a parent/caregiver. Examples of items in each of the generic core module scales include: "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 likert response scale from 0 (never a problem) to 4 (almost always a problem). Scores were transformed on a scale from 0 to 100 (0=100, 1=75, 2=50, 3=25, 4=0), with higher scores indicating better health-related quality of life. Change from Baseline was calculated by subtracting the Baseline value from the value at Week 48.
| units on a scale | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| Baseline: Physical functioning score | 63.63 ± 20.029 | 59.27 ± 22.782 | 61.87 ± 19.411 |
| Change at Week 48: Physical functioning score | -0.94 ± 19.125 | 2.37 ± 25.105 | -1.00 ± 24.022 |
| Baseline: Emotional functioning score | 73.92 ± 20.418 | 73.70 ± 20.223 | 70.13 ± 19.332 |
| Change at Week 48: Emotional functioning score | 2.36 ± 16.742 | -1.83 ± 23.725 | 4.30 ± 22.315 |
| Baseline: Social functioning score | 67.50 ± 21.749 | 65.09 ± 18.421 | 63.36 ± 20.476 |
| Change at Week 48: Social functioning score | 5.37 ± 20.463 | 3.89 ± 21.841 | 7.75 ± 18.870 |
| Baseline: School functioning score | 67.72 ± 19.276 | 64.55 ± 20.396 | 64.65 ± 17.841 |
| Change at Week 48: School functioning score | 3.61 ± 13.008 | 6.11 ± 23.765 | 4.06 ± 23.244 |
HRQL was measured via the PedsQL. The generic core module (including physical, emotional, social and school functioning scales) comprises 23 questions and the fatigue-specific module (including general fatigue, sleep/rest fatigue, and cognitive fatigue scales) comprises an additional 18 questions. The PedsQL was completed by both the participant and/or a parent/caregiver. Examples of items in each of the generic core module scales include: "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 likert response scale from 0 (never a problem) to 4 (almost always a problem). Scores were transformed on a scale from 0 to 100 (0=100, 1=75, 2=50, 3=25, 4=0), with higher scores indicating better health-related quality of life. Change from Baseline was calculated by subtracting the Baseline value from the value at Week 48.
| units on a scale | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| Baseline: Physical functioning score | 56.15 ± 19.955 | 54.96 ± 20.592 | 51.47 ± 19.274 |
| Change at Week 48: Physical functioning score | 0.03 ± 17.088 | -3.10 ± 16.550 | 0.23 ± 23.712 |
| Baseline: Emotional functioning score | 70.08 ± 16.836 | 69.11 ± 18.711 | 65.96 ± 17.964 |
| Change at Week 48: Emotional functioning score | 4.07 ± 15.382 | 3.39 ± 18.068 | 1.21 ± 17.794 |
| Baseline: Social functioning score | 61.58 ± 15.825 | 62.77 ± 16.540 | 55.79 ± 18.269 |
| Change at Week 48: Social functioning score | -0.40 ± 18.470 | -1.09 ± 14.268 | 3.71 ± 14.130 |
| Baseline: School functioning score | 66.17 ± 18.258 | 66.16 ± 16.320 | 61.93 ± 13.587 |
| Change at Week 48: School functioning score | 2.73 ± 18.490 | -2.32 ± 15.462 | 3.48 ± 13.913 |
HRQL was measured via the PedsQL. The fatigue-specific module (including general fatigue, sleep/rest fatigue, and cognitive fatigue scales) comprises an additional 18 questions. PedsQL was completed by both the participant and/or a parent/caregiver. 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 likert response scale from 0 (never a problem) to 4 (almost always a problem). Scores were transformed on a scale from 0 to 100 (0=100, 1=75, 2=50, 3=25, 4=0), with higher scores indicating less fatigue. Total score was the sum of all items over the number of items answered on all scales. Change from Baseline was calculated by subtracting the Baseline value from the value at Week 48.
| units on a scale | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| Baseline | 69.47 ± 16.525 | 71.62 ± 16.474 | 69.70 ± 15.263 |
| Change at Week 48 | 6.95 ± 13.460 | 0.45 ± 23.068 | 3.92 ± 16.512 |
HRQL was measured via the PedsQL. The fatigue-specific module (including general fatigue, sleep/rest fatigue, and cognitive fatigue scales) comprises an additional 18 questions. The PedsQL was completed by both the participant and/or a parent/caregiver. 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 likert response scale from 0 (never a problem) to 4 (almost always a problem). Scores were transformed on a scale from 0 to 100 (0=100, 1=75, 2=50, 3=25, 4=0), with higher scores indicating less fatigue. Total score was the sum of all items over the number of items answered on all scales. Change from Baseline was calculated by subtracting the Baseline value from the value at Week 48.
| units on a scale | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| Baseline | 73.39 ± 13.671 | 70.71 ± 12.720 | 68.27 ± 13.170 |
| Change at Week 48 | 1.97 ± 13.873 | 1.27 ± 12.095 | 2.51 ± 12.039 |
TSQM consisted of 14 questions about treatment satisfaction with drug in 4 domains: Effectiveness (Questions 1-3 scored as 1 \[extremely dissatisfied\] to 7 \[extremely satisfied\]), Side Effects (question 4 scored as 0 \[no\] or 1 \[yes\]; question 5 scored as 1 \[extremely bothersome\] to 5 \[not at all bothersome\]; questions 6 - 8 scored as 1 \[a great deal\] to 5 \[not at all\]), Convenience (questions 9 and 10 scored as 1 \[extremely difficult\] to 7 \[extremely easy\]; question 11 scored as 1 \[extremely inconvenient\] to 5 \[extremely convenient\]) and Global Satisfaction (question 12 scored as 1 \[not at all confident\] to 7 \[extremely confident\]; question 13 scored as 1 \[not at all certain\] to 5 \[extremely certain\]; question 14 scored as 1 \[extremely dissatisfied\] to 5 \[extremely satisfied\]). The scores of each of the domains were added together and an algorithm was used to create a score of 0 to 100, with higher scores indicating better treatment satisfaction.
| units on a scale | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| Effectiveness score | 55.97 ± 27.796 | 54.60 ± 22.307 | 51.26 ± 23.536 |
| Side-effects score | 96.36 ± 11.199 | 97.77 ± 7.578 | 96.89 ± 8.874 |
| Convenience score | 55.85 ± 17.008 | 58.23 ± 19.040 | 60.91 ± 16.665 |
| Global satisfaction score | 61.04 ± 25.967 | 61.19 ± 23.691 | 57.56 ± 21.851 |
Number of falls was determined by daily diary records maintained by participants and/or parent/caregivers.
| falls/day | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| Baseline | 0.40 ± 0.597 | 0.27 ± 0.480 | 0.54 ± 0.943 |
| Change at Week 48 | -0.10 ± 0.466 | -0.06 ± 0.501 | 0.20 ± 1.282 |
Basic attention and working memory was measured using the digit span task. A series of digits (0-9) were presented to the child in an auditory format only. The task had 2 parts; in the forward condition, the child 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. A raw score of the total number of correct responses was converted to an age-scaled-score (z-score) by subtracting the corresponding mean and dividing by the corresponding standard deviation of a reference population for that age.
| z-score | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| Baseline: Forward condition | 3.59 ± 2.554 | 2.89 ± 2.180 | 2.84 ± 1.675 |
| Change at Week 48: Forward condition | 0.39 ± 1.677 | 0.50 ± 1.767 | 0.40 ± 1.550 |
| Baseline: Backward condition | 1.73 ± 1.846 | 1.70 ± 1.868 | 1.59 ± 1.460 |
| Change at Week 48: Backward condition | 0.56 ± 1.500 | 0.33 ± 1.441 | 0.59 ± 1.203 |
The 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 rates values were collected prior to, during, and after the 6MWT. The participant rested for 5 minutes in a sitting position prior to the 6MWT, and the mean heart rate for the last minute of this rest period was collected 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 collected and documented as the recovery heart rate.
| beats/minute | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| Baseline: Resting heart rate | 105.47 ± 12.908 | 109.70 ± 9.908 | 104.07 ± 11.588 |
| Change at Week 48: Resting heart rate | -0.63 ± 13.008 | -0.36 ± 10.223 | -0.26 ± 15.614 |
| Baseline: Active heart rate | 142.67 ± 18.070 | 141.77 ± 15.574 | 136.67 ± 20.713 |
| Change at Week 48: Active heart rate | -5.00 ± 21.976 | 2.39 ± 19.095 | 1.65 ± 21.295 |
| Baseline: Recovery heart rate | 109.90 ± 12.633 | 113.48 ± 10.340 | 107.86 ± 12.066 |
| Change at Week 48: Recovery heart rate | -0.23 ± 13.475 | -1.33 ± 13.270 | 0.54 ± 15.181 |
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.
| units/liter (U/L) | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| Baseline | 10853.65 ± 6251.136 | 12084.70 ± 7772.631 | 10569.60 ± 6488.477 |
| Change at Week 48 | -1680.09 ± 4264.769 | -2146.32 ± 7151.944 | -1235.13 ± 4323.943 |
Immunofluorescence evidence of a change in dystrophin expression on biceps muscle biopsy was defined as an increase in the staining of the sarcolemmal membrane with an antibody to the C-terminal portion of the dystrophin protein (excluding revertant fibers) between the pre-treatment (1 week prior to Baseline visit) and post-treatment (Week 36) biopsies. The biceps muscle was biopsied from one arm for confirmation of the absence or reduced levels of dystrophin prior to treatment initiation and from the other arm to assess for production of dystrophin post-treatment.
| percent change | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| Pre-treatment | 336.096 ± 138.9753 | 359.797 ± 142.7361 | 357.271 ± 139.6650 |
| Percent change post-treatment | -1.278 ± 27.7432 | -2.128 ± 28.8287 | -0.898 ± 19.2112 |
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an 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); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. Treatment-emergent adverse event (TEAE) was defined as an adverse event that occurred or worsened in the period extending from first dose of study drug to 6 weeks after the last dose of study drug. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'.
| percentage of participants | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| Percentage of Participants With Treatment-Emergent Adverse Events (AEs) | 95.0 | 96.5 | 98.2 |
Study drug compliance was assessed by participant daily diary and quantification of used and unused study drug. Compliance was assessed in terms of the percentage of drug actually taken relative to the amount that should have been taken during the study.
| percentage of drug | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| Study Drug Compliance | 97.87 (34.9 to 99.6) | 97.03 (64.5 to 99.8) | 97.74 (76.6 to 99.9) |
Collected over Baseline up to 6 weeks after the last dose of study drug (Week 54). Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| High-Dose Ataluren | — | 2/60 (3.3%) | 58/60 (96.7%) |
| Low-Dose Ataluren | — | 2/57 (3.5%) | 56/57 (98.2%) |
| Placebo | — | 3/57 (5.3%) | 57/57 (100%) |
| Event | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| Abdominal painGastrointestinal disorders | 0/60 | 0/57 | 1/57 |
| AppendicitisInfections and infestations | 0/60 | 1/57 | 0/57 |
| InfluenzaInfections and infestations | 0/60 | 0/57 | 1/57 |
| VaricellaInfections and infestations | 0/60 | 0/57 | 1/57 |
| Femur fractureInjury, poisoning and procedural complications | 0/60 | 0/57 | 1/57 |
| DehydrationMetabolism and nutrition disorders | 0/60 | 1/57 | 0/57 |
| Grand mal convulsionNervous system disorders | 0/60 | 0/57 | 1/57 |
| Supraventricular tachycardiaCardiac disorders | 1/60 | 0/57 | 0/57 |
| Lower limb fractureInjury, poisoning and procedural complications | 1/60 | 0/57 | 0/57 |
| Event | High-Dose Ataluren | Low-Dose Ataluren | Placebo |
|---|---|---|---|
| VomitingGastrointestinal disorders | 28/60 | 33/57 | 22/57 |
| HeadacheNervous system disorders | 16/60 | 23/57 | 14/57 |
| DiarrhoeaGastrointestinal disorders | 18/60 | 11/57 | 15/57 |
| CoughRespiratory, thoracic and mediastinal disorders | 15/60 | 9/57 | 13/57 |
| PyrexiaGeneral disorders | 8/60 | 14/57 | 12/57 |
| NasopharyngitisInfections and infestations | 10/60 | 13/57 | 13/57 |
| Abdominal pain upperGastrointestinal disorders | 13/60 | 9/57 | 9/57 |
| Upper respiratory tract infectionInfections and infestations | 12/60 | 9/57 | 12/57 |
| Abdominal painGastrointestinal disorders | 12/60 | 8/57 | 4/57 |
| FallInjury, poisoning and procedural complications | 7/60 | 11/57 | 7/57 |
As-treated population included all randomized participants who actually received any study treatment.
| Age, Continuous(years) | High-Dose Ataluren | Low-Dose Ataluren | Placebo | Total |
|---|---|---|---|---|
| Mean | 8.4 ± 2.53 | 8.8 ± 2.91 | 8.3 ± 2.33 | 8.5 ± 2.59 |
| Sex: Female, Male(Participants) | High-Dose Ataluren | Low-Dose Ataluren | Placebo | Total |
|---|---|---|---|---|
| Female | 0 | 0 | 0 | 0 |
| Male | 60 | 57 | 57 | 174 |
| 6-Minute Walk Distance (6MWD)(meters) | High-Dose Ataluren | Low-Dose Ataluren | Placebo | Total |
|---|---|---|---|---|
| Mean | 358.2 ± 103.97 | 350.0 ± 97.55 | 359.6 ± 87.67 | 356.0 ± 96.30 |
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