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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00847379
Recruitment Status : Terminated
First Posted : February 19, 2009
Results First Posted : July 15, 2020
Last Update Posted : July 15, 2020
Sponsor:
Collaborator:
Genzyme, a Sanofi Company
Information provided by (Responsible Party):
PTC Therapeutics

Brief Summary:
Duchenne/Becker muscular dystrophy (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 10-15% of boys with the disease. Ataluren (PTC124) is an orally delivered, investigational drug that has the potential to overcome the effects of the nonsense mutation. This study is a Phase 2b extension trial that will evaluate the long-term safety of ataluren (PTC124) in boys with nonsense mutation DMD/BMD, as determined by adverse events and laboratory abnormalities. The study will also assess changes in walking, muscle function, and other important clinical and laboratory measures.

Condition or disease Intervention/treatment Phase
Duchenne Muscular Dystrophy Becker Muscular Dystrophy Drug: Ataluren Phase 2

Detailed Description:
This is a Phase 2b, international, multicenter, open-label extension study for participants who successfully completed blinded study drug in Study 007. This extension study will evaluate the long-term administration of ataluren administered 3 times per day (TID) at morning, midday, and evening doses of 20, 20, and 40 milligrams/kilogram (mg/kg), respectively, in participants with nonsense mutation Duchenne/Becker muscular dystrophy (nmDBMD).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 173 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2B Extension Study of PTC124 in Subjects With Nonsense-Mutation-Mediated Duchenne and Becker Muscular Dystrophy
Actual Study Start Date : January 31, 2009
Actual Primary Completion Date : May 24, 2010
Actual Study Completion Date : May 24, 2010


Arm Intervention/treatment
Experimental: Overall Participants: High-Dose Ataluren
All participants will receive ataluren suspension orally three times a day (TID), 20 mg/kg at morning, 20 mg/kg at midday, and 40 mg/kg at evening (total daily dose 80 mg/kg) for up to 96 weeks in this study. Any participant who was receiving a reduced dose of ataluren at the end of treatment visit in study PTC124-GD-007-DMD, will be initiated ataluren therapy in this extension study at the 5-, 5-, and 10-mg/kg dose level; dose will be increased to 10, 10, and 20 mg/kg at Week 6 and to 20, 20, and 40 mg/kg at Week 12, if the preceding dose level is well tolerated.
Drug: Ataluren
Ataluren oral powder for suspension will be administered as per dose and schedule specified in the arm.
Other Name: PTC124




Primary Outcome Measures :
  1. Number of Participants With Treatment-Emergent Adverse Events (AEs) [ Time Frame: Baseline (Week 48 of Study 007) up to Week 102 ]
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Severity of an AE was classified as: mild (does not interfere with usual function), moderate (interferes to some extent with usual function) and severe (interferes significantly with usual function). Drug-related AEs: AEs with a possible or probable relationship to study drug. Serious AEs: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention. TEAE: AE that occurred or worsened in the period extending from first dose of study drug in this study to 6 weeks after last dose of study drug in this study. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

  2. Number of Participants With Clinically Significant Abnormal Laboratory Parameters [ Time Frame: Baseline (Week 48 of Study 007) up to Week 102 ]
    Laboratory parameters tests included hematology, biochemistry assay (hepatic, renal, and serum electrolyte values), adrenal assays, and urinalysis. Clinical significance was defined as per investigator's judgement.


Secondary Outcome Measures :
  1. Change From Baseline in 6-Minute Walk Distance (6MWD) at Week 60 [ Time Frame: Baseline (Week 48 of Study 007), Week 60 ]
    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.

  2. Change From Baseline in Mean Activity Period/Day/Visit at Week 60, as Assessed by Step Activity Monitoring (SAM) [ Time Frame: Baseline (Week 48 of Study 007), Week 60 ]
    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. 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.

  3. Change From Baseline in Mean Total Step Count/Day/Visit During the Active Periods at Week 60, as Assessed by SAM [ Time Frame: Baseline (Week 48 of Study 007), Week 60 ]
    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. 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.

  4. Change From Baseline in Mean Total Step Count/Hour During the Active Period at Week 60, as Assessed by SAM [ Time Frame: Baseline (Week 48 of Study 007), Week 60 ]
    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. 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.

  5. Change From Baseline in Maximum Continuous 10-minute, 20-minute, 30-minute, and 60-minute Total Step Count at Week 60, as Assessed by SAM [ Time Frame: Baseline (Week 48 of Study 007), Week 60 ]
    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. 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.

  6. Change From Baseline in Percentage of Time During Active Period Spent at No Activity (0 Steps/Minute[Min]), Low Activity (Less Than or Equal to [≤]15 Steps/Min), Medium Activity (16-30 Steps/Min), and High Activity (Greater Than[>]30 Steps/Min) at Week 60 [ Time Frame: Baseline (Week 48 of Study 007), Week 60 ]
    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 SAM for at least 9 consecutive days. SAM was used to record number of strides/minute following each visit. A stride is leg motion that begins when the foot with SAM leaves the floor and ends when the same foot touches the floor again. Percentage of time during active periods spent at no activity (0 steps/min), low activity (≤15 steps/min), medium activity (16-30 steps/min), and high activity (>30 steps/min) were computed for each participant. 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.

  7. Change From Baseline in Time to Stand From Supine Position at Week 60 [ Time Frame: Baseline (Week 48 of Study 007), Week 60 ]
    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.

  8. Change From Baseline in Time to Walk/Run 10 Meters at Week 60 [ Time Frame: Baseline (Week 48 of Study 007), Week 60 ]
    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.

  9. Change From Baseline in Time to Climb 4 Stairs at Week 60 [ Time Frame: Baseline (Week 48 of Study 007), Week 60 ]
    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.

  10. Change From Baseline in Time to Descend 4 Stairs at Week 60 [ Time Frame: Baseline (Week 48 of Study 007), Week 60 ]
    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.

  11. Change From Baseline in Heart Rate Before, During, and After Each 6MWD Test at Week 60, as Assessed by Heart Rate Monitoring With the Polar® RS400 [ Time Frame: Baseline (Week 48 of Study 007), Week 60 ]
    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.

  12. Change From Baseline in Number of Digits Recalled Forwards and Backwards on Digit Span Task at Week 60 [ Time Frame: Baseline (Week 48 of Study 007), Week 60 ]
    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.

  13. 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 60 [ Time Frame: Baseline (Week 48 of Study 007), Week 60 ]
    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 60.

  14. Change From Baseline in Parent/Caregiver- Reported HRQL as Measured by the PedsQL Physical, Emotional, Social, and School Functioning Domain Scores at Week 60 [ Time Frame: Baseline (Week 48 of Study 007), Week 60 ]
    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.

  15. Change From Baseline in Participant-Reported HRQL as Measured by the Total Fatigue Scale Score at Week 60 [ Time Frame: Baseline (Week 48 of Study 007), Week 60 ]
    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 60.

  16. Change From Baseline in Parent/Caregiver-Reported HRQL as Measured by the Total Fatigue Scale Score at Week 60 [ Time Frame: Baseline (Week 48 of Study 007), Week 60 ]
    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 60.

  17. Change From Baseline in Participant and Parent/Caregiver Reported Activities of Daily Living of Participants Who Were Unable to Complete the 6MWT (Nonambulatory Participants), as Measured by the Egen Klassifikation (EK) Scale at Week 60 [ Time Frame: Baseline (Week 48 of Study 007), Week 60 ]
    Activities of daily living were measured using the EK scale in all participants who were unable to complete the 6MWT at Screening/Baseline on Day 1. The EK scale is an ordinal scale ranging from 0 to 30 points where 0 represents the highest level of independent function and 30 the lowest. The scale consists of 10 categories (each scored 0 to 3), involving different functional domains including 1) ability to use wheelchair, 2) ability to transfer from wheelchair, 3) ability to stand, 4) ability to balance in the wheelchair, 5) ability to move the arms, 6) ability to use the hands and arms when eating, 7) ability to turn in bed, 8) ability to cough, 9) ability to speak, and 10) physical well-being. The administration of the EK scale consisted of an interview of the participant to capture how he performed the tasks of daily life (as described by Categories 1 to 9) and how he perceived his well-being (as described by Category 10).

  18. Change From Baseline in Parent/Caregiver-Reported Treatment Satisfaction Questionnaire for Medication (TSQM) Score at Week 60 [ Time Frame: Baseline (Week 48 of Study 007), Week 60 ]
    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.

  19. Change From Baseline in Serum Concentration of Creatine Kinase (CK) at Week 60 [ Time Frame: Baseline (Week 48 of Study 007), Week 60 ]
    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.

  20. Study Drug Compliance [ Time Frame: Baseline (Week 48 of Study 007) to Week 96 ]
    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.

  21. Trough Ataluren Plasma Concentration [ Time Frame: Pre-morning dose (0 hour) at Baseline (Week 48 of 007 study), Weeks 54, 60, 72, 84, and 96 ]
    Plasma samples for the determination of ataluren concentrations were analyzed at the bioanalytical laboratory for ataluren parent drug using a validated high performance liquid chromatography with tandem mass spectrometry (HPLC/MS-MS) method with a lower limit of quantitation (LLOQ) of 0.5 micrograms/millilitre (mcg/mL). Values below the LLOQ were set to 0.



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Ages Eligible for Study:   5 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Completion of blinded study drug treatment in the previous Phase 2b study (PTC124-GD-007-DMD).
  • Ability to provide written informed consent (parental/guardian consent if applicable)/assent (if less than [<]18 years of age).
  • In participants who are sexually active, willingness to abstain from sexual intercourse or employ a barrier or medical method of contraception during PTC124 administration and the 6-week follow up period.
  • Willingness and ability to comply with scheduled visits, drug administration plan, study procedures, laboratory tests, and study restrictions.

Exclusion Criteria:

  • 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).
  • Ongoing participation in any other therapeutic clinical trial.
  • Prior or ongoing medical condition (for example, concomitant illness, psychiatric condition, behavioral disorder, alcoholism, drug abuse), medical history, physical findings, ECG findings, or laboratory abnormality that, in the investigator's opinion, could adversely affect the safety of the subject, makes it unlikely that the course of treatment or follow up would be completed, or could impair the assessment of study results.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00847379


Locations
Show Show 37 study locations
Sponsors and Collaborators
PTC Therapeutics
Genzyme, a Sanofi Company
Investigators
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Study Director: Leone Atkinson, M.D., Ph.D. PTC Therapeutics
Additional Information:
Publications:
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Responsible Party: PTC Therapeutics
ClinicalTrials.gov Identifier: NCT00847379    
Other Study ID Numbers: PTC124-GD-007e-DMD
First Posted: February 19, 2009    Key Record Dates
Results First Posted: July 15, 2020
Last Update Posted: July 15, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by PTC Therapeutics:
Duchenne muscular dystrophy
Becker muscular dystrophy
Nonsense mutation
Premature stop codon
DMD
BMD
Ataluren
PTC124
Additional relevant MeSH terms:
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Muscular Dystrophies
Muscular Dystrophy, Duchenne
Muscular Disorders, Atrophic
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Genetic Diseases, Inborn
Genetic Diseases, X-Linked