Duchenne Muscular Dystrophy
Conditions
Brief summary
This is a Phase 2, multiple-dose, open-label study evaluating the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ataluren in participants aged ≥2 to \<5 years old with Duchenne muscular dystrophy (DMD) caused by a nonsense mutation in the dystrophin gene.
Detailed description
In nonsense mutation DMD (nmDMD), early start of treatment is important and necessary and, therefore, it is relevant to understand the correct and tolerable dose in this age group, particularly since ataluren is dosed by weight. This study included a 4-week screening period, a 52-week treatment period (the first 4 weeks of which included PK parameters), and a 4-week follow-up period for participants who completed the treatment period (60 weeks total duration). The objective of the extension period (treatment period after PK parameters have been completed) was to assess the long-term safety of chronic administration of ataluren in this participant population.
Interventions
DRUGAtaluren
White to off-white powder for oral suspension.
Sponsors
PTC Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
2 Years to 5 Years
Healthy volunteers
No
Inclusion criteria
* Males ≥2 to \<5 years of age * Body weight ≥12 kg * Diagnosis of DMD * Nonsense mutation in at least 1 allele of the dystrophin gene
Exclusion criteria
* Participation in any other drug or device clinical investigation * Ongoing use of prohibited concomitant medications
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), TEAEs Leading to Discontinuation, and Serious Adverse Events (SAEs) | Baseline up to Week 56 | A TEAE was any untoward medical occurrence or undesirable event that begins or worsens following administration of study drug, whether or not considered related to study drug by Investigator. An 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 dystrophinopathy. An event was not reported as an SAE, if event was exclusively a relapse or expected change or progression of baseline dystrophinopathy. AEs included both SAEs and nonserious AEs. AEs classified according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 and coded using Medical Dictionary for Regulatory Activities. A summary of SAEs and all non-serious AEs, regardless of causality, is located in the Reported Adverse Events section. |
| Number of Participants With a Clinically Meaningful Abnormal Clinical Laboratory (Biochemistry, Hematology, and Urinalysis) Parameter | Baseline up to Week 56 | Clinical laboratory results that were considered clinically meaningful were to be determined by the Investigator and Sponsor. Biochemistry parameters included sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, magnesium, calcium, phosphorus, uric acid, glucose, total protein, albumin, bilirubin (total, direct, and indirect), aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, creatine kinase, lactate dehydrogenase, alkaline phosphatase, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, and cystatin C. Hematology parameters included white blood cell count with differential, hemoglobin, hematocrit, other red cell parameters, and platelet count. Urinalysis parameters included pH, specific gravity, glucose, ketones, blood, protein, urobilinogen, bilirubin, nitrite, and leukocyte esterase. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. |
| Number of Participants With a Clinically Meaningful Abnormal Electrocardiogram (ECG) Test Results | Baseline up to Week 56 | ECG results that were considered clinically meaningful were to be determined by the Investigator. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. |
| Number of Participants With a Dose-Limiting Toxicity as Measured by Hepatic and Renal Toxicity | Baseline up to Week 56 | Dose-limiting toxicity was measured through clinical evaluations for potential hepatic and renal toxicities. The clinical evaluations included the following: * Hepatic: The participant's medical history, hepatitis screening results, all clinical blood values (particularly serum bilirubin, gamma-glutamyl transferase \[GGT\], aspartate aminotransferase \[AST\], and alanine aminotransferase \[ALT\] values), and all concomitant medications were reviewed. * Renal: The participant's medical history, all clinical blood and urine renal values, serum electrolytes, medications, and potential pre- or post-renal conditions were reviewed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Proximal Muscle Function as Assessed by Speed During TFTs | Baseline, Week 28 and Week 52 | TFTs included time to stand from supine position (rise to standing), time to run/walk 10 meters (m), and time to ascend/descend 4 stairs. 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. |
| Change From Baseline in Physical Function as Measured by the NSAA | Baseline, Week 28 and Week 52 | NSAA consists of 17 activities, including items assessing abilities necessary to remain functionally ambulant (that is, ability to rise from floor, to get from lying to sitting/sitting to standing, and that are known to progressively deteriorate); items that can be partly present in DMD early stages (that is, assessing head raise and standing on heels); and a number of activities such as hopping, jumping, and running. Since the boys were \<5 years old, revised 16 point, 8-point, and 3-point scales were used over the 17 point scale. Scores for evaluations=0 (Unable to achieve independently), 1 (Modified method but achieved goal independent of physical assistance), or 2 (Normal, no obvious modification of activity). Maximum total score for the 16-point scale=32, 8-point scale=16, and 3-point scale=6. If an activity couldn't be performed due to PD/loss of ambulation, a score of 0 was assigned. Change from Baseline calculated by subtracting Baseline value from value at Week 28 and Week 52. |
| Change From Baseline in Height of Participants at Weeks 4, 16, 28, 40, 52, and 56 | Baseline, Weeks 4, 16, 28, 40, 52, and 56 | — |
| Pharmacokinetics: Maximum Observed Plasma Concentration From Time Zero up to 6 Hours After the Morning Dose (Cmax0-6hr) | 0 (predose), 1, 2, 4, and 6 (postdose) hours on Days 1 and 28 | Ataluren concentrations in plasma were analyzed using a validated high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. |
| Change From Baseline in Body Mass Index of Participants at Weeks 4, 16, 28, 40, 52, and 56 | Baseline, Weeks 4, 16, 28, 40, 52, and 56 | Body mass index is an estimate of body fat based on body weight divided by height squared. |
| Ataluren Palatability Characteristics as Determined by a Parent/Caregiver Questionnaire | Baseline up to Week 28 | To assess palatability characteristics, participants/parents or guardians were asked to provide a response of Strongly disagree, Disagree, Neither agree or disagree, Agree, or Strongly Agree to the following 3 questions: Question 1. Is the medicine palatable? Question 2. On the basis of reaction / facial expression of your child, do you think that the medication is pleasant? Question 3.You sometimes have problems in giving the medication to your child because he/she refuses to take it or throws it up? |
| Change From Baseline in Weight of Participants at Weeks 4, 16, 28, 40, 52, and 56 | Baseline, Weeks 4, 16, 28, 40, 52, and 56 | — |
| Pharmacokinetics: Time to Reach Maximum Observed Plasma Concentration From Time Zero up to 6 Hours After the Morning Dose (Tmax0-6hr) | 0 (predose), 1, 2, 4, and 6 (postdose) hours on Days 1 and 28 | Ataluren concentrations in plasma were analyzed using a validated HPLC-MS/MS method. |
| Area Under the Plasma Concentration Time Curve From Time Zero up to 10 Hours After the Morning Dose (AUC0-10hr) | 0 (predose), 1, 2, 4, 6, 8, and 10 (postdose) hours on Days 1 and 28 | Ataluren concentrations in plasma were analyzed using a validated HPLC-MS/MS method. AUC0-10hr was measured using the linear trapezoidal rule during the ascending portion of the curve and the log-trapezoidal rule during the descending portion of the curve. |
| Pharmacokinetics: Concentration at the End of the First (Morning) Dose Interval (Ctrough6hr) | 0 (predose), 1, 2, 4, and 6 (postdose) hours on Days 1 and 28 | Ataluren concentrations in plasma were analyzed using a validated HPLC-MS/MS method. |
Countries
United States
Participant flow
Recruitment details
Participants aged ≥2 to \<5 years old with Duchenne muscular dystrophy (DMD) caused by a nonsense mutation in the dystrophin gene were recruited for this study.
Pre-assignment details
Participants in the Evaluable Population included all participants who received at least 1 dose of ataluren and had a baseline and at least 1 postbaseline measurement for Timed Function Test (TFT), North Star Ambulatory Assessment (NSAA), or response to the palatability of ataluren questions.
Participants by arm
| Arm | Count |
|---|---|
| Ataluren Participants were administered ataluren orally at a dose of 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening (for a total of 40 mg/kg/day) for up to 52 weeks. Dose was provided based upon the weight of each participant, which was assessed every 12 weeks. | 14 |
| Total | 14 |
Baseline characteristics
| Characteristic | Ataluren |
|---|---|
| Age, Continuous | 3.4 years STANDARD_DEVIATION 0.76 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 11 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 14 |
| other Total, other adverse events | 14 / 14 |
| serious Total, serious adverse events | 0 / 14 |
Outcome results
Primary
Number of Participants With a Clinically Meaningful Abnormal Clinical Laboratory (Biochemistry, Hematology, and Urinalysis) Parameter
Clinical laboratory results that were considered clinically meaningful were to be determined by the Investigator and Sponsor. Biochemistry parameters included sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, magnesium, calcium, phosphorus, uric acid, glucose, total protein, albumin, bilirubin (total, direct, and indirect), aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, creatine kinase, lactate dehydrogenase, alkaline phosphatase, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, and cystatin C. Hematology parameters included white blood cell count with differential, hemoglobin, hematocrit, other red cell parameters, and platelet count. Urinalysis parameters included pH, specific gravity, glucose, ketones, blood, protein, urobilinogen, bilirubin, nitrite, and leukocyte esterase. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Time frame: Baseline up to Week 56
Population: All participants who received at least 1 dose of ataluren (Safety Population).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ataluren | Number of Participants With a Clinically Meaningful Abnormal Clinical Laboratory (Biochemistry, Hematology, and Urinalysis) Parameter | 0 Participants |
Primary
Number of Participants With a Clinically Meaningful Abnormal Electrocardiogram (ECG) Test Results
ECG results that were considered clinically meaningful were to be determined by the Investigator. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Time frame: Baseline up to Week 56
Population: All participants who received at least 1 dose of ataluren (Safety Population).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ataluren | Number of Participants With a Clinically Meaningful Abnormal Electrocardiogram (ECG) Test Results | 0 Participants |
Primary
Number of Participants With a Dose-Limiting Toxicity as Measured by Hepatic and Renal Toxicity
Dose-limiting toxicity was measured through clinical evaluations for potential hepatic and renal toxicities. The clinical evaluations included the following: * Hepatic: The participant's medical history, hepatitis screening results, all clinical blood values (particularly serum bilirubin, gamma-glutamyl transferase \[GGT\], aspartate aminotransferase \[AST\], and alanine aminotransferase \[ALT\] values), and all concomitant medications were reviewed. * Renal: The participant's medical history, all clinical blood and urine renal values, serum electrolytes, medications, and potential pre- or post-renal conditions were reviewed.
Time frame: Baseline up to Week 56
Population: All participants who received at least 1 dose of ataluren (Safety Population).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ataluren | Number of Participants With a Dose-Limiting Toxicity as Measured by Hepatic and Renal Toxicity | 0 participants |
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs), TEAEs Leading to Discontinuation, and Serious Adverse Events (SAEs)
A TEAE was any untoward medical occurrence or undesirable event that begins or worsens following administration of study drug, whether or not considered related to study drug by Investigator. An 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 dystrophinopathy. An event was not reported as an SAE, if event was exclusively a relapse or expected change or progression of baseline dystrophinopathy. AEs included both SAEs and nonserious AEs. AEs classified according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 and coded using Medical Dictionary for Regulatory Activities. A summary of SAEs and all non-serious AEs, regardless of causality, is located in the Reported Adverse Events section.
Time frame: Baseline up to Week 56
Population: All participants who received at least 1 dose of ataluren (Safety Population).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ataluren | Number of Participants With Treatment Emergent Adverse Events (TEAEs), TEAEs Leading to Discontinuation, and Serious Adverse Events (SAEs) | At least 1 TEAE | 14 Participants |
| Ataluren | Number of Participants With Treatment Emergent Adverse Events (TEAEs), TEAEs Leading to Discontinuation, and Serious Adverse Events (SAEs) | Mild TEAE | 5 Participants |
| Ataluren | Number of Participants With Treatment Emergent Adverse Events (TEAEs), TEAEs Leading to Discontinuation, and Serious Adverse Events (SAEs) | Severe TEAE | 1 Participants |
| Ataluren | Number of Participants With Treatment Emergent Adverse Events (TEAEs), TEAEs Leading to Discontinuation, and Serious Adverse Events (SAEs) | TEAE Related to Study Drug | 5 Participants |
| Ataluren | Number of Participants With Treatment Emergent Adverse Events (TEAEs), TEAEs Leading to Discontinuation, and Serious Adverse Events (SAEs) | TEAE Leading to Participant Study Discontinuation | 0 Participants |
| Ataluren | Number of Participants With Treatment Emergent Adverse Events (TEAEs), TEAEs Leading to Discontinuation, and Serious Adverse Events (SAEs) | Serious TEAE | 0 Participants |
| Ataluren | Number of Participants With Treatment Emergent Adverse Events (TEAEs), TEAEs Leading to Discontinuation, and Serious Adverse Events (SAEs) | Moderate TEAE | 8 Participants |
Secondary
Area Under the Plasma Concentration Time Curve From Time Zero up to 10 Hours After the Morning Dose (AUC0-10hr)
Ataluren concentrations in plasma were analyzed using a validated HPLC-MS/MS method. AUC0-10hr was measured using the linear trapezoidal rule during the ascending portion of the curve and the log-trapezoidal rule during the descending portion of the curve.
Time frame: 0 (predose), 1, 2, 4, 6, 8, and 10 (postdose) hours on Days 1 and 28
Population: All participants who received at least 1 dose of ataluren and had at least 1 PK concentration datum (PK Population).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Area Under the Plasma Concentration Time Curve From Time Zero up to 10 Hours After the Morning Dose (AUC0-10hr) | Day 1 | 101.64 hour*μg/mL | Standard Deviation 58.52 |
| Ataluren | Area Under the Plasma Concentration Time Curve From Time Zero up to 10 Hours After the Morning Dose (AUC0-10hr) | Day 28 | 82.13 hour*μg/mL | Standard Deviation 27.43 |
Secondary
Ataluren Palatability Characteristics as Determined by a Parent/Caregiver Questionnaire
To assess palatability characteristics, participants/parents or guardians were asked to provide a response of Strongly disagree, Disagree, Neither agree or disagree, Agree, or Strongly Agree to the following 3 questions: Question 1. Is the medicine palatable? Question 2. On the basis of reaction / facial expression of your child, do you think that the medication is pleasant? Question 3.You sometimes have problems in giving the medication to your child because he/she refuses to take it or throws it up?
Time frame: Baseline up to Week 28
Population: All participants who received at least 1 dose of ataluren and had a baseline and at least 1 postbaseline measurement for TFT, NSAA, or response to the palatability of ataluren questions (Evaluable Population).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ataluren | Ataluren Palatability Characteristics as Determined by a Parent/Caregiver Questionnaire | Question 1, Strongly disagree | 0 Participants |
| Ataluren | Ataluren Palatability Characteristics as Determined by a Parent/Caregiver Questionnaire | Question 1, Disagree | 0 Participants |
| Ataluren | Ataluren Palatability Characteristics as Determined by a Parent/Caregiver Questionnaire | Question 1, Neither Agree nor Disagree | 2 Participants |
| Ataluren | Ataluren Palatability Characteristics as Determined by a Parent/Caregiver Questionnaire | Question 1, Agree | 0 Participants |
| Ataluren | Ataluren Palatability Characteristics as Determined by a Parent/Caregiver Questionnaire | Question 1, Strongly agree | 0 Participants |
| Ataluren | Ataluren Palatability Characteristics as Determined by a Parent/Caregiver Questionnaire | Question 1, No Response | 12 Participants |
| Ataluren | Ataluren Palatability Characteristics as Determined by a Parent/Caregiver Questionnaire | Question 2, Strongly disagree | 0 Participants |
| Ataluren | Ataluren Palatability Characteristics as Determined by a Parent/Caregiver Questionnaire | Question 2, Disagree | 2 Participants |
| Ataluren | Ataluren Palatability Characteristics as Determined by a Parent/Caregiver Questionnaire | Question 2, Neither Agree nor Disagree | 2 Participants |
| Ataluren | Ataluren Palatability Characteristics as Determined by a Parent/Caregiver Questionnaire | Question 2, Agree | 6 Participants |
| Ataluren | Ataluren Palatability Characteristics as Determined by a Parent/Caregiver Questionnaire | Question 2, Strongly Agree | 4 Participants |
| Ataluren | Ataluren Palatability Characteristics as Determined by a Parent/Caregiver Questionnaire | Question 2, No response | 0 Participants |
| Ataluren | Ataluren Palatability Characteristics as Determined by a Parent/Caregiver Questionnaire | Question 3, Strongly Disagree | 5 Participants |
| Ataluren | Ataluren Palatability Characteristics as Determined by a Parent/Caregiver Questionnaire | Question 3, Disagree | 7 Participants |
| Ataluren | Ataluren Palatability Characteristics as Determined by a Parent/Caregiver Questionnaire | Question 3, Neither agree or disagree | 0 Participants |
| Ataluren | Ataluren Palatability Characteristics as Determined by a Parent/Caregiver Questionnaire | Question 3, Agree | 2 Participants |
| Ataluren | Ataluren Palatability Characteristics as Determined by a Parent/Caregiver Questionnaire | Question 3, Strongly Agree | 0 Participants |
| Ataluren | Ataluren Palatability Characteristics as Determined by a Parent/Caregiver Questionnaire | Question 3, No response | 0 Participants |
Secondary
Change From Baseline in Body Mass Index of Participants at Weeks 4, 16, 28, 40, 52, and 56
Body mass index is an estimate of body fat based on body weight divided by height squared.
Time frame: Baseline, Weeks 4, 16, 28, 40, 52, and 56
Population: All participants who received at least 1 dose of ataluren (Safety Population).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Change From Baseline in Body Mass Index of Participants at Weeks 4, 16, 28, 40, 52, and 56 | Baseline | 17.094 kilograms per square meter (kg/m^2) | Standard Deviation 2.2196 |
| Ataluren | Change From Baseline in Body Mass Index of Participants at Weeks 4, 16, 28, 40, 52, and 56 | Change at Week 4 | -0.346 kilograms per square meter (kg/m^2) | Standard Deviation 0.6804 |
| Ataluren | Change From Baseline in Body Mass Index of Participants at Weeks 4, 16, 28, 40, 52, and 56 | Change at Week 16 | 0.026 kilograms per square meter (kg/m^2) | Standard Deviation 0.3822 |
| Ataluren | Change From Baseline in Body Mass Index of Participants at Weeks 4, 16, 28, 40, 52, and 56 | Change at Week 28 | 0.030 kilograms per square meter (kg/m^2) | Standard Deviation 0.5567 |
| Ataluren | Change From Baseline in Body Mass Index of Participants at Weeks 4, 16, 28, 40, 52, and 56 | Change at Week 40 | 0.008 kilograms per square meter (kg/m^2) | Standard Deviation 0.6399 |
| Ataluren | Change From Baseline in Body Mass Index of Participants at Weeks 4, 16, 28, 40, 52, and 56 | Change at Week 52 | -0.186 kilograms per square meter (kg/m^2) | Standard Deviation 0.9237 |
| Ataluren | Change From Baseline in Body Mass Index of Participants at Weeks 4, 16, 28, 40, 52, and 56 | Change at Week 56 | 0.015 kilograms per square meter (kg/m^2) | Standard Deviation 1.2161 |
Secondary
Change From Baseline in Height of Participants at Weeks 4, 16, 28, 40, 52, and 56
Time frame: Baseline, Weeks 4, 16, 28, 40, 52, and 56
Population: All participants who received at least 1 dose of ataluren (Safety Population) and had evaluable height data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Change From Baseline in Height of Participants at Weeks 4, 16, 28, 40, 52, and 56 | Baseline | 99.43 centimeters | Standard Deviation 5.278 |
| Ataluren | Change From Baseline in Height of Participants at Weeks 4, 16, 28, 40, 52, and 56 | Change at Week 4 | 0.83 centimeters | Standard Deviation 1.595 |
| Ataluren | Change From Baseline in Height of Participants at Weeks 4, 16, 28, 40, 52, and 56 | Change at Week 16 | 1.84 centimeters | Standard Deviation 1.466 |
| Ataluren | Change From Baseline in Height of Participants at Weeks 4, 16, 28, 40, 52, and 56 | Change at Week 28 | 3.11 centimeters | Standard Deviation 1.386 |
| Ataluren | Change From Baseline in Height of Participants at Weeks 4, 16, 28, 40, 52, and 56 | Change at Week 40 | 3.82 centimeters | Standard Deviation 1.506 |
| Ataluren | Change From Baseline in Height of Participants at Weeks 4, 16, 28, 40, 52, and 56 | Change at Week 52 | 5.95 centimeters | Standard Deviation 2.096 |
| Ataluren | Change From Baseline in Height of Participants at Weeks 4, 16, 28, 40, 52, and 56 | Change at Week 56 | 6.04 centimeters | Standard Deviation 2.075 |
Secondary
Change From Baseline in Physical Function as Measured by the NSAA
NSAA consists of 17 activities, including items assessing abilities necessary to remain functionally ambulant (that is, ability to rise from floor, to get from lying to sitting/sitting to standing, and that are known to progressively deteriorate); items that can be partly present in DMD early stages (that is, assessing head raise and standing on heels); and a number of activities such as hopping, jumping, and running. Since the boys were \<5 years old, revised 16 point, 8-point, and 3-point scales were used over the 17 point scale. Scores for evaluations=0 (Unable to achieve independently), 1 (Modified method but achieved goal independent of physical assistance), or 2 (Normal, no obvious modification of activity). Maximum total score for the 16-point scale=32, 8-point scale=16, and 3-point scale=6. If an activity couldn't be performed due to PD/loss of ambulation, a score of 0 was assigned. Change from Baseline calculated by subtracting Baseline value from value at Week 28 and Week 52.
Time frame: Baseline, Week 28 and Week 52
Population: All participants who received at least 1 dose of ataluren and had a baseline and at least 1 postbaseline measurement for TFT, NSAA, or response to the palatability of ataluren questions (Evaluable Population) and had evaluable NSAA data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Change From Baseline in Physical Function as Measured by the NSAA | 16-Point Scale, Change from Baseline at Week 28 | 3.5 units on a scale | Standard Deviation 3.43 |
| Ataluren | Change From Baseline in Physical Function as Measured by the NSAA | 16-Point Scale, Change from Baseline at Week 52 | 5.5 units on a scale | Standard Deviation 4.43 |
| Ataluren | Change From Baseline in Physical Function as Measured by the NSAA | 8-Point Scale, Baseline | 10.5 units on a scale | Standard Deviation 2.56 |
| Ataluren | Change From Baseline in Physical Function as Measured by the NSAA | 8-Point Scale, Change from Baseline at Week 52 | 2.3 units on a scale | Standard Deviation 2.13 |
| Ataluren | Change From Baseline in Physical Function as Measured by the NSAA | 3-Point Scale, Baseline | 5.4 units on a scale | Standard Deviation 0.63 |
| Ataluren | Change From Baseline in Physical Function as Measured by the NSAA | 3-Point Scale, Change from Baseline at Week 28 | 0.5 units on a scale | Standard Deviation 0.78 |
| Ataluren | Change From Baseline in Physical Function as Measured by the NSAA | 3-Point Scale, Change from Baseline at Week 52 | 0.3 units on a scale | Standard Deviation 0.73 |
| Ataluren | Change From Baseline in Physical Function as Measured by the NSAA | 16-Point Scale, Baseline | 16.0 units on a scale | Standard Deviation 4.66 |
| Ataluren | Change From Baseline in Physical Function as Measured by the NSAA | 8-Point Scale, Change from Baseline at Week 28 | 1.5 units on a scale | Standard Deviation 1.39 |
Secondary
Change From Baseline in Proximal Muscle Function as Assessed by Speed During TFTs
TFTs included time to stand from supine position (rise to standing), time to run/walk 10 meters (m), and time to ascend/descend 4 stairs. 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.
Time frame: Baseline, Week 28 and Week 52
Population: All participants who received at least 1 dose of ataluren and had a baseline and at least 1 postbaseline measurement for TFT, NSAA, or response to the palatability of ataluren questions (Evaluable Population) and had evaluable data for the applicable timed function test.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Change From Baseline in Proximal Muscle Function as Assessed by Speed During TFTs | Rise to Standing, Baseline | 7.2 seconds | Standard Deviation 7.21 |
| Ataluren | Change From Baseline in Proximal Muscle Function as Assessed by Speed During TFTs | Rise to Standing, Change from Baseline at Week 28 | -3.1 seconds | Standard Deviation 6.47 |
| Ataluren | Change From Baseline in Proximal Muscle Function as Assessed by Speed During TFTs | Rise to Standing, Change from Baseline at Week 52 | -3.1 seconds | Standard Deviation 6.5 |
| Ataluren | Change From Baseline in Proximal Muscle Function as Assessed by Speed During TFTs | Walk/Run 10 m, Baseline | 6.6 seconds | Standard Deviation 2.37 |
| Ataluren | Change From Baseline in Proximal Muscle Function as Assessed by Speed During TFTs | Walk/Run 10 m, Change from Baseline at Week 28 | -0.8 seconds | Standard Deviation 1.54 |
| Ataluren | Change From Baseline in Proximal Muscle Function as Assessed by Speed During TFTs | Walk/Run 10 m, Change from Baseline at Week 52 | -1.1 seconds | Standard Deviation 1.35 |
| Ataluren | Change From Baseline in Proximal Muscle Function as Assessed by Speed During TFTs | Ascend 4 Stairs, Baseline | 7.1 seconds | Standard Deviation 6.95 |
| Ataluren | Change From Baseline in Proximal Muscle Function as Assessed by Speed During TFTs | Ascend 4 Stairs, Change from Baseline at Week 28 | -1.8 seconds | Standard Deviation 4.85 |
| Ataluren | Change From Baseline in Proximal Muscle Function as Assessed by Speed During TFTs | Ascend 4 Stairs, Change from Baseline at Week 52 | -2.6 seconds | Standard Deviation 5 |
| Ataluren | Change From Baseline in Proximal Muscle Function as Assessed by Speed During TFTs | Descend 4 Stairs, Baseline | 7.5 seconds | Standard Deviation 3.95 |
| Ataluren | Change From Baseline in Proximal Muscle Function as Assessed by Speed During TFTs | Descend 4 Stairs, Change from Baseline at Week 28 | -0.6 seconds | Standard Deviation 1.93 |
| Ataluren | Change From Baseline in Proximal Muscle Function as Assessed by Speed During TFTs | Descend 4 Stairs, Change from Baseline at Week 52 | -2.2 seconds | Standard Deviation 2.58 |
Secondary
Change From Baseline in Weight of Participants at Weeks 4, 16, 28, 40, 52, and 56
Time frame: Baseline, Weeks 4, 16, 28, 40, 52, and 56
Population: All participants who received at least 1 dose of ataluren (Safety Population) and had evaluable weight data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Change From Baseline in Weight of Participants at Weeks 4, 16, 28, 40, 52, and 56 | Baseline | 16.99 kg | Standard Deviation 3.257 |
| Ataluren | Change From Baseline in Weight of Participants at Weeks 4, 16, 28, 40, 52, and 56 | Change at Week 4 | -0.04 kg | Standard Deviation 0.502 |
| Ataluren | Change From Baseline in Weight of Participants at Weeks 4, 16, 28, 40, 52, and 56 | Change at Week 16 | 0.73 kg | Standard Deviation 0.974 |
| Ataluren | Change From Baseline in Weight of Participants at Weeks 4, 16, 28, 40, 52, and 56 | Change at Week 28 | 1.16 kg | Standard Deviation 0.94 |
| Ataluren | Change From Baseline in Weight of Participants at Weeks 4, 16, 28, 40, 52, and 56 | Change at Week 40 | 1.39 kg | Standard Deviation 0.882 |
| Ataluren | Change From Baseline in Weight of Participants at Weeks 4, 16, 28, 40, 52, and 56 | Change at Week 52 | 1.90 kg | Standard Deviation 1.259 |
| Ataluren | Change From Baseline in Weight of Participants at Weeks 4, 16, 28, 40, 52, and 56 | Change at Week 56 | 2.13 kg | Standard Deviation 1.34 |
Secondary
Pharmacokinetics: Concentration at the End of the First (Morning) Dose Interval (Ctrough6hr)
Ataluren concentrations in plasma were analyzed using a validated HPLC-MS/MS method.
Time frame: 0 (predose), 1, 2, 4, and 6 (postdose) hours on Days 1 and 28
Population: All participants who received at least 1 dose of ataluren and had at least 1 PK concentration datum (PK Population).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Pharmacokinetics: Concentration at the End of the First (Morning) Dose Interval (Ctrough6hr) | Day 1 | 9.12 microgram per milliliter (µg/ml) | Standard Deviation 8.88 |
| Ataluren | Pharmacokinetics: Concentration at the End of the First (Morning) Dose Interval (Ctrough6hr) | Day 28 | 5.43 microgram per milliliter (µg/ml) | Standard Deviation 3.15 |
Secondary
Pharmacokinetics: Maximum Observed Plasma Concentration From Time Zero up to 6 Hours After the Morning Dose (Cmax0-6hr)
Ataluren concentrations in plasma were analyzed using a validated high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method.
Time frame: 0 (predose), 1, 2, 4, and 6 (postdose) hours on Days 1 and 28
Population: All participants who received at least 1 dose of ataluren and had at least 1 PK concentration datum (PK Population).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Pharmacokinetics: Maximum Observed Plasma Concentration From Time Zero up to 6 Hours After the Morning Dose (Cmax0-6hr) | Day 1 | 15.95 microgram/milliliter (µg/mL) | Standard Deviation 9.51 |
| Ataluren | Pharmacokinetics: Maximum Observed Plasma Concentration From Time Zero up to 6 Hours After the Morning Dose (Cmax0-6hr) | Day 28 | 12.54 microgram/milliliter (µg/mL) | Standard Deviation 4.43 |
Secondary
Pharmacokinetics: Time to Reach Maximum Observed Plasma Concentration From Time Zero up to 6 Hours After the Morning Dose (Tmax0-6hr)
Ataluren concentrations in plasma were analyzed using a validated HPLC-MS/MS method.
Time frame: 0 (predose), 1, 2, 4, and 6 (postdose) hours on Days 1 and 28
Population: All participants who received at least 1 dose of ataluren and had at least 1 PK concentration datum (PK Population).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Pharmacokinetics: Time to Reach Maximum Observed Plasma Concentration From Time Zero up to 6 Hours After the Morning Dose (Tmax0-6hr) | Day 1 | 3.84 hours | Standard Deviation 1.82 |
| Ataluren | Pharmacokinetics: Time to Reach Maximum Observed Plasma Concentration From Time Zero up to 6 Hours After the Morning Dose (Tmax0-6hr) | Day 28 | 2.72 hours | Standard Deviation 1.98 |