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Phase 2B Study of PTC124 (Ataluren) in Duchenne/Becker Muscular Dystrophy (DMD/BMD)

Primary Purpose

Duchenne Muscular Dystrophy, Becker Muscular Dystrophy

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Ataluren

Placebo

About this trial

This is an interventional treatment trial for Duchenne Muscular Dystrophy focused on measuring Duchenne muscular dystrophy, Becker muscular dystrophy, Nonsense mutation, Premature stop codon, DMD/BMD, PTC124

Eligibility Criteria

5 Years - undefined (Child, Adult, Older Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

Ability to provide written informed consent (parental/guardian consent if applicable)/assent (if <18 years of age).
Male sex.
Age ≥5 years.
Phenotypic evidence of DMD/BMD based on the onset of characteristic clinical symptoms or signs (that is, proximal muscle weakness, waddling gait, and Gowers' maneuver) by 9 years of age, an elevated serum CK level, and ongoing difficulty with ambulation.
Documentation of the presence of a nonsense point mutation in the dystrophin gene as determined by gene sequencing from a laboratory certified by the College of American Pathologists (CAP), the Clinical Laboratory Improvement Act/Amendment (CLIA), or an equivalent organization.
Documentation that a blood sample has been drawn for confirmation of the presence of a nonsense mutation in the dystrophin gene.
Ability to walk ≥75 meters unassisted during the screening 6-minute walk test. Note: Other personal assistance or use of assistive devices for ambulation (for example, short leg braces, long leg braces or walkers) were not permitted.
Confirmed screening laboratory values within the central laboratory ranges (hepatic, adrenal, renal, and serum electrolytes parameters).
In participants who were sexually active, willingness to abstain from sexual intercourse or employ a barrier or medical method of contraception during the study drug administration and 6-week follow-up periods.
Willingness and ability to comply with scheduled visits, drug administration plan, study procedures, laboratory tests, and study restrictions. Note: Psychological, social, familial, or geographical factors that might preclude adequate study participation (in particular, the ability to satisfactorily perform the 6MWT) should have been considered.

Exclusion Criteria:

Treatment with systemic aminoglycoside antibiotics within 3 months prior to start of study treatment.
Initiation of systemic corticosteroid therapy within 6 months prior to start of study treatment or change in systemic corticosteroid therapy (for example, initiation, change in type of drug, dose modification not related to body weight change, schedule modification, interruption, discontinuation, or reinitiation) within 3 months prior to start of study treatment.
Any change (initiation, change in type of drug, dose modification, schedule modification, interruption, discontinuation, or reinitiation) in prophylaxis/treatment for congestive heart failure within 3 months prior to start of study treatment.
Treatment with warfarin within 1 month prior to start of study treatment.
Prior therapy with ataluren.
Known hypersensitivity to any of the ingredients or excipients of the study drug (Litesse® UltraTM [refined polydextrose], polyethylene glycol 3350, Lutrol® micro F127 [poloxamer 407], mannitol 25C, crospovidone XL10, hydroxyethyl cellulose, vanilla, Cab-O-Sil® M5P [colloidal silica], magnesium stearate).
Exposure to another investigational drug within 2 months prior to start of study treatment.
History of major surgical procedure within 30 days prior to start of study treatment.
Ongoing immunosuppressive therapy (other than corticosteroids).
Ongoing participation in any other therapeutic clinical trial.
Expectation of major surgical procedure (for example, scoliosis surgery) during the 12-month treatment period of the study.
Requirement for daytime ventilator assistance.
Clinical symptoms and signs of congestive heart failure (American College of Cardiology/American Heart Association Stage C or Stage D) or evidence on echocardiogram of clinically significant myopathy.
Prior or ongoing medical condition (for example, concomitant illness, psychiatric condition, behavioral disorder, alcoholism, drug abuse), medical history, physical findings, electrocardiogram findings, or laboratory abnormality that, in the investigator's opinion, could adversely affect the safety of the participant, makes it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results.

Sites / Locations

University of California-Davis
The Children's Hospital
Child Neurology Center of Pensacola
University of Iowa Healthcare
University of Kansas Medical Centre
Children's Hospital of Boston/Harvard Medical School
University of Minnesota
Washington University School of Medicine
Columbia University Medical School
Duke University Medical Center
Cincinnati Children's Hospital Medical Center
Shriners Hospital for Children
Children's Hospital of Philadelphia
Southwestern University
University of Utah
Royal Children's Hospital
Institute For Neuromuscular Research, The Children's Hospital at Westmead
University Hospital KU Leuven
Alberta Children's Hospital
British Columbia Children's Hospital
London Health Sciences Center
Service de Neuropediatrie, hôpital La Timone
Neuromuscular center of Nantes
Groupe Hospitalier La Pitie-Salpetriere
University Clinic for Children, University of Essen
University Hospital
Hadassah Medical Center, Hebrew University Hospital
Ospedale Maggiore Policlinico in Milan
Ospedale Pediatrico Bambino Gesu
U.O. Complessa di Neuropsichiatria Infantile
Hospital Sant Joan de déu
Hospital Universitari La Fe
Queen Silvia Children's Hospital
Astrid Lindgren Pediatric Hospital
Imperial College London, Hammersmith Hospital
Univ of Newcastle, Institute of Human Genetics
Robert Jones and Agnes Hunt Orthopaedic NHS Trust

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Placebo Comparator

Arm Label

High-Dose Ataluren

Low-Dose Ataluren

Placebo

Arm Description

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.

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.

Participants will receive placebo matched to ataluren orally TID at morning, midday, and evening for 48 weeks.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

Change From Baseline in Time to Walk/Run 10 Meters at Week 48

Change From Baseline in Time to Climb 4 Stairs at Week 48

Change From Baseline in Time to Descend 4 Stairs at 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.

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.

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.

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.

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.

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.

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.

Change From Baseline in Parent/Caregiver- Reported HRQL as Measured by the PedsQL Physical, Emotional, Social, and School Functioning Domain Scores at 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.

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.

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.

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT00592553

First Posted

January 1, 2008

Last Updated

March 26, 2020

Sponsor

PTC Therapeutics

1. Study Identification

Unique Protocol Identification Number

NCT00592553

Brief Title

Phase 2B Study of PTC124 (Ataluren) in Duchenne/Becker Muscular Dystrophy (DMD/BMD)

Official Title

A Phase 2B Efficacy and Safety Study of PTC124 in Subjects With Nonsense-Mutation-Mediated Duchenne and Becker Muscular Dystrophy

Study Type

Interventional

2. Study Status

Record Verification Date

March 2020

Overall Recruitment Status

Completed

Study Start Date

February 29, 2008 (Actual)

Primary Completion Date

December 31, 2009 (Actual)

Study Completion Date

December 31, 2009 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

PTC Therapeutics

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

Detailed Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Duchenne Muscular Dystrophy, Becker Muscular Dystrophy

Keywords

Duchenne muscular dystrophy, Becker muscular dystrophy, Nonsense mutation, Premature stop codon, DMD/BMD, PTC124

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

174 (Actual)

8. Arms, Groups, and Interventions

Arm Title

High-Dose Ataluren

Arm Type

Experimental

Arm Description

Arm Title

Low-Dose Ataluren

Arm Type

Experimental

Arm Description

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.

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Participants will receive placebo matched to ataluren orally TID at morning, midday, and evening for 48 weeks.

Intervention Type

Drug

Intervention Name(s)

Ataluren

Other Intervention Name(s)

PTC124

Intervention Description

Ataluren will be administered as per the dose and schedule specified in the respective arms.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Placebo matching to ataluren will be administered as the schedule specified in the respective arm.

Primary Outcome Measure Information:

Title

Change From Baseline in 6MWD at Week 48

Description

Time Frame

Baseline, Week 48

Secondary Outcome Measure Information:

Title

Change From Baseline in Time to Stand From Supine Position at Week 48

Description

Time Frame

Baseline, Week 48

Title

Change From Baseline in Time to Walk/Run 10 Meters at Week 48

Description

Time Frame

Baseline, Week 48

Title

Change From Baseline in Time to Climb 4 Stairs at Week 48

Description

Time Frame

Baseline, Week 48

Title

Change From Baseline in Time to Descend 4 Stairs at Week 48

Description

Time Frame

Baseline, Week 48

Title

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

Description

Time Frame

Baseline, Week 48

Title

Change From Baseline in Mean Activity Period/Day/Visit at Week 48, as Assessed by Step Activity Monitoring (SAM)

Description

Time Frame

Baseline, Week 48

Title

Change From Baseline in Mean Total Step Count/Day/Visit During the Active Periods at Week 48, as Assessed by SAM

Description

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

Title

Change From Baseline in Mean Total Step Count/Hour During the Active Period at Week 48, as Assessed by SAM

Description

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

Title

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

Description

Time Frame

Baseline, Week 48

Title

Description

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

Title

Description

Time Frame

Baseline, Week 48

Title

Change From Baseline in Parent/Caregiver- Reported HRQL as Measured by the PedsQL Physical, Emotional, Social, and School Functioning Domain Scores at Week 48

Description

Time Frame

Baseline, Week 48

Title

Change From Baseline in Participant-Reported HRQL as Measured by the Total Fatigue Scale Score at Week 48

Description

Time Frame

Baseline, Week 48

Title

Change From Baseline in Parent/Caregiver-Reported HRQL as Measured by the Total Fatigue Scale Score at Week 48

Description

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

Title

Parent/Caregiver-Reported Treatment Satisfaction Questionnaire for Medication (TSQM) Score

Description

Time Frame

Week 48

Title

Change From Baseline in Participant/Caregiver-Reported Number of Daily Accidental Falls at Week 48

Description

Number of falls was determined by daily diary records maintained by participants and/or parent/caregivers.

Time Frame

Baseline, Week 48

Title

Change From Baseline in Number of Digits Recalled Forwards and Backwards on Digit Span Task at Week 48

Description

Time Frame

Baseline, Week 48

Title

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

Description

Time Frame

Baseline, Week 48

Title

Change From Baseline in Serum Concentration of Creatine Kinase (CK) at Week 48

Description

Time Frame

Baseline, Week 48

Title

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

Description

Time Frame

Pre-Treatment (1 week prior to baseline), post-treatment (Week 36)

Other Pre-specified Outcome Measures:

Title

Percentage of Participants With Treatment-Emergent Adverse Events (AEs)

Description

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

Title

Study Drug Compliance

Description

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

10. Eligibility

Sex

Male

Gender Based

Yes

Gender Eligibility Description

Consistent with the X-linked genetic basis and natural history of DBMD, all of the participants were males.

Minimum Age & Unit of Time

5 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Ability to provide written informed consent (parental/guardian consent if applicable)/assent (if <18 years of age). Male sex. Age ≥5 years. Phenotypic evidence of DMD/BMD based on the onset of characteristic clinical symptoms or signs (that is, proximal muscle weakness, waddling gait, and Gowers' maneuver) by 9 years of age, an elevated serum CK level, and ongoing difficulty with ambulation. Documentation of the presence of a nonsense point mutation in the dystrophin gene as determined by gene sequencing from a laboratory certified by the College of American Pathologists (CAP), the Clinical Laboratory Improvement Act/Amendment (CLIA), or an equivalent organization. Documentation that a blood sample has been drawn for confirmation of the presence of a nonsense mutation in the dystrophin gene. Ability to walk ≥75 meters unassisted during the screening 6-minute walk test. Note: Other personal assistance or use of assistive devices for ambulation (for example, short leg braces, long leg braces or walkers) were not permitted. Confirmed screening laboratory values within the central laboratory ranges (hepatic, adrenal, renal, and serum electrolytes parameters). In participants who were sexually active, willingness to abstain from sexual intercourse or employ a barrier or medical method of contraception during the study drug administration and 6-week follow-up periods. Willingness and ability to comply with scheduled visits, drug administration plan, study procedures, laboratory tests, and study restrictions. Note: Psychological, social, familial, or geographical factors that might preclude adequate study participation (in particular, the ability to satisfactorily perform the 6MWT) should have been considered. Exclusion Criteria: Treatment with systemic aminoglycoside antibiotics within 3 months prior to start of study treatment. Initiation of systemic corticosteroid therapy within 6 months prior to start of study treatment or change in systemic corticosteroid therapy (for example, initiation, change in type of drug, dose modification not related to body weight change, schedule modification, interruption, discontinuation, or reinitiation) within 3 months prior to start of study treatment. Any change (initiation, change in type of drug, dose modification, schedule modification, interruption, discontinuation, or reinitiation) in prophylaxis/treatment for congestive heart failure within 3 months prior to start of study treatment. Treatment with warfarin within 1 month prior to start of study treatment. Prior therapy with ataluren. Known hypersensitivity to any of the ingredients or excipients of the study drug (Litesse® UltraTM [refined polydextrose], polyethylene glycol 3350, Lutrol® micro F127 [poloxamer 407], mannitol 25C, crospovidone XL10, hydroxyethyl cellulose, vanilla, Cab-O-Sil® M5P [colloidal silica], magnesium stearate). Exposure to another investigational drug within 2 months prior to start of study treatment. History of major surgical procedure within 30 days prior to start of study treatment. Ongoing immunosuppressive therapy (other than corticosteroids). Ongoing participation in any other therapeutic clinical trial. Expectation of major surgical procedure (for example, scoliosis surgery) during the 12-month treatment period of the study. Requirement for daytime ventilator assistance. Clinical symptoms and signs of congestive heart failure (American College of Cardiology/American Heart Association Stage C or Stage D) or evidence on echocardiogram of clinically significant myopathy. Prior or ongoing medical condition (for example, concomitant illness, psychiatric condition, behavioral disorder, alcoholism, drug abuse), medical history, physical findings, electrocardiogram findings, or laboratory abnormality that, in the investigator's opinion, could adversely affect the safety of the participant, makes it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Leone Atkinson, MD, PhD

Organizational Affiliation

PTC Therapeutics

Official's Role

Study Director

Facility Information:

Facility Name

University of California-Davis

City

Sacramento

State/Province

California

Country

United States

Facility Name

The Children's Hospital

City

Aurora

State/Province

Colorado

Country

United States

Facility Name

Child Neurology Center of Pensacola

City

Pensacola

State/Province

Florida

Country

United States

Facility Name

University of Iowa Healthcare

City

Iowa City

State/Province

Iowa

Country

United States

Facility Name

University of Kansas Medical Centre

City

Kansas City

State/Province

Kansas

Country

United States

Facility Name

Children's Hospital of Boston/Harvard Medical School

City

Boston

State/Province

Massachusetts

Country

United States

Facility Name

University of Minnesota

City

Minneapolis

State/Province

Minnesota

Country

United States

Facility Name

Washington University School of Medicine

City

Saint Louis

State/Province

Missouri

Country

United States

Facility Name

Columbia University Medical School

City

New York

State/Province

New York

Country

United States

Facility Name

Duke University Medical Center

City

Durham

State/Province

North Carolina

Country

United States

Facility Name

Cincinnati Children's Hospital Medical Center

City

Cincinnati

State/Province

Ohio

ZIP/Postal Code

45229-3039

Country

United States

Facility Name

Shriners Hospital for Children

City

Portland

State/Province

Oregon

Country

United States

Facility Name

Children's Hospital of Philadelphia

City

Philadelphia

State/Province

Pennsylvania

Country

United States

Facility Name

Southwestern University

City

Dallas

State/Province

Texas

Country

United States

Facility Name

University of Utah

City

Salt Lake City

State/Province

Utah

Country

United States

Facility Name

Royal Children's Hospital

City

Parkville

State/Province

Victoria

Country

Australia

Facility Name

Institute For Neuromuscular Research, The Children's Hospital at Westmead

City

Westmead

Country

Australia

Facility Name

University Hospital KU Leuven

City

Leuven

Country

Belgium

Facility Name

Alberta Children's Hospital

City

Calgary

State/Province

Alberta

Country

Canada

Facility Name

British Columbia Children's Hospital

City

Vancouver

State/Province

British Columbia

Country

Canada

Facility Name

London Health Sciences Center

City

London

State/Province

Ontario

Country

Canada

Facility Name

Service de Neuropediatrie, hôpital La Timone

City

Marseille

Country

France

Facility Name

Neuromuscular center of Nantes

City

Nantes

Country

France

Facility Name

Groupe Hospitalier La Pitie-Salpetriere

City

Paris

Country

France

Facility Name

University Clinic for Children, University of Essen

City

Essen

Country

Germany

Facility Name

University Hospital

City

Freiburg

Country

Germany

Facility Name

Hadassah Medical Center, Hebrew University Hospital

City

Jerusalem

Country

Israel

Facility Name

Ospedale Maggiore Policlinico in Milan

City

Milan

Country

Italy

Facility Name

Ospedale Pediatrico Bambino Gesu

City

Rome

Country

Italy

Facility Name

U.O. Complessa di Neuropsichiatria Infantile

City

Rome

Country

Italy

Facility Name

Hospital Sant Joan de déu

City

Barcelona

Country

Spain

Facility Name

Hospital Universitari La Fe

City

Valencia

Country

Spain

Facility Name

Queen Silvia Children's Hospital

City

Göteborg

Country

Sweden

Facility Name

Astrid Lindgren Pediatric Hospital

City

Stockholm

Country

Sweden

Facility Name

Imperial College London, Hammersmith Hospital

City

London

Country

United Kingdom

Facility Name

Univ of Newcastle, Institute of Human Genetics

City

Newcastle

Country

United Kingdom

Facility Name

Robert Jones and Agnes Hunt Orthopaedic NHS Trust

City

Oswestry

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

34693725

Citation

Shieh PB, Elfring G, Trifillis P, Santos C, Peltz SW, Parsons JA, Apkon S, Darras BT, Campbell C, McDonald CM; Members of the Ataluren Phase IIb Study Group; Members of the Ataluren Phase IIb Study Clinical Evaluator Training Group; Members of the ACT DMD Study Group; Members of the ACT DMD Clinical Evaluator Training Group. Meta-analyses of deflazacort versus prednisone/prednisolone in patients with nonsense mutation Duchenne muscular dystrophy. J Comp Eff Res. 2021 Dec;10(18):1337-1347. doi: 10.2217/cer-2021-0018. Epub 2021 Oct 25.

Results Reference

derived

PubMed Identifier

32851872

Citation

Campbell C, Barohn RJ, Bertini E, Chabrol B, Comi GP, Darras BT, Finkel RS, Flanigan KM, Goemans N, Iannaccone ST, Jones KJ, Kirschner J, Mah JK, Mathews KD, McDonald CM, Mercuri E, Nevo Y, Pereon Y, Renfroe JB, Ryan MM, Sampson JB, Schara U, Sejersen T, Selby K, Tulinius M, Vilchez JJ, Voit T, Wei LJ, Wong BL, Elfring G, Souza M, McIntosh J, Trifillis P, Peltz SW, Muntoni F; PTC124-GD-007-DMD Study Group; ACT DMD Study Group; Clinical Evaluator Training Groups. Meta-analyses of ataluren randomized controlled trials in nonsense mutation Duchenne muscular dystrophy. J Comp Eff Res. 2020 Oct;9(14):973-984. doi: 10.2217/cer-2020-0095. Epub 2020 Aug 27.

Results Reference

derived

Learn more about this trial

Phase 2B Study of PTC124 (Ataluren) in Duchenne/Becker Muscular Dystrophy (DMD/BMD)

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