An Extension Study of Ataluren (PTC124) in Participants With Nonsense Mutation Dystrophinopathy
- Conditions
- Muscular Disorders, AtrophicMuscular DiseasesMusculoskeletal DiseasesNervous System DiseasesGenetic Diseases, X-LinkedMuscular Dystrophy, DuchenneMuscular DystrophiesNeuromuscular DiseasesGenetic Diseases, Inborn
- Interventions
- Registration Number
- NCT02090959
- Lead Sponsor
- PTC Therapeutics
- Brief Summary
The primary objective of this study is to obtain long term safety data of ataluren in male participants with nonsense mutation dystrophinopathy (who participated and completed a previous Phase 3 study of ataluren \[PTC124-GD-020-DMD {NCT01826487}\]) to augment the overall safety database. Screening and baseline procedures are structured to avoid a gap in treatment between the double-blind study (PTC124-GD-020-DMD) and this extension study.
This study may be further extended by amendment until either ataluren becomes commercially available or the clinical development of ataluren in duchenne muscular dystrophy (DMD) is discontinued.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- Male
- Target Recruitment
- 219
- Completion of study treatment in the previous Phase 3, double-blind study (PTC124-GD-020-DMD).
- Evidence of signed and dated informed consent/assent document(s) indicating that the participant (and/or his parent/legal guardian) has been informed of all pertinent aspects of the trial. Note: If the study candidate is considered a child under local regulation, a parent or legal guardian must provide written consent prior to initiation of study screening procedures and the study candidate may be required to provide written assent. The rules of the responsible Institutional Review Board/Independent Ethic Committee (IRB/IEC) regarding whether 1 or both parents must provide consent and the appropriate ages for obtaining consent and assent from the participant should be followed.
- In participants who are sexually active, willingness to abstain from sexual intercourse or employ a barrier or medical method of contraception during the period of study drug administration and 6-week follow-up period.
- Willingness and ability to comply with scheduled visits, ataluren administration plan, study procedures, laboratory tests, and study restrictions.
- 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], and 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, electrocardiogram (ECG) 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Ataluren Ataluren Participants will receive ataluren suspension orally 3 times a day (TID), 10 milligrams/kilogram (mg/kg) at morning, 10 mg/kg at midday, and 20 mg/kg at evening (total daily dose 40 mg/kg) for up to 144 weeks.
- Primary Outcome Measures
Name Time Method Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Baseline (Day 1) up to 6 weeks post-treatment (Week 150) An adverse event (AE): any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Severity of AEs: graded per Common Terminology Criteria for AEs (CTCAE), Version 3.0 as Grade 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). Drug-related AEs: AEs with possible, probable, unlikely relationship, or unrelated to study drug. Serious AEs (SAEs): 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: an 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 SAEs, regardless of causality is located in Reported AE section.
Number of Participants With Abnormalities in Clinical Laboratory Parameters Baseline (Day 1) up to 6 weeks post-treatment (Week 150) Abnormalities in laboratory variables as pre-defined in protocol for safety-monitoring were: Hepatic (Serum alanine aminotransferase \[ALT\]: increase of greater than \[\>\] 150 units/liter \[U/L\] with stable or decrease of creatinine kinese \[CK\]; Serum glutamyl amino transferase \[GGT\] \[U/L\]: Grade 2 \[\>2.5 - 5.0 \* upper limit of normal {ULN}\]), renal (Serum cystatin C miiligrams/liter \[mg/L\] \>1.33 - 2.00 mg/L; Serum blood urea nitrogen \[UREAN\] \[millimoles/liter {mmol/L}\] greater than or equal to \[≥\]1.5 - 3.0 \* ULN; Urine occult blood: 2+ \[Small\], 3+ \[Moderate\], 4+ \[Large\]), and electrolytes (Serum sodium: low \[mmol/L\], Grade 3-4 \[less than {\<}130 mmol/L\]; serum potassium: high \[mmol/L\], Grade 3-4 \[\>6.0 mmol/L\]; and Serum bicarbonate \[mmol/L\]: Grade 2 \[\<16 - 11 mmol/L\]).
- Secondary Outcome Measures
Name Time Method Change From Baseline in PEF as Measured by Spirometry at Week 144 Baseline, Week 144 PEF was defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated.
Change From Baseline in PCF as Measured by Spirometry at Week 144 Baseline, Week 144 PCF measures an individual's maximum speed of expiration during cough.
Change From Baseline in 6MWD at Week 144 Baseline, Week 144 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.
Change From Baseline in Time to Descend 4 Stairs at Week 144 Baseline, Week 144 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 in Time to Stand From Supine Position at Week 144 Baseline, Week 144 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 in Time to Walk/Run 10 Meters at Week 144 Baseline, Week 144 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 in Time to Climb 4 Stairs at Week 144 Baseline, Week 144 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 in Physical Function Total Score as Measured by NSAA at Week 144 Baseline, Week 144 Physical function was assessed via the NSAA, a functional scale specifically designed for ambulant Duchenne muscular dystrophy (DMD) participants. The assessment comprised tests for 17 abilities of a participant, such as ability to stand, rise from the floor, get from lying to sitting, get from sitting to standing, raise one's head, stand on one's heels, hop, jump, and run. For each activity, a score of 0, 1, or 2 was recorded, with 0 = "unable to achieve independently," 1 = "modified method but achieves goal independent of physical assistance from another," or 2 = "normal- achieves goal without any assistance." The sum of these scores (except for 'raise one's head' activity score) was reported as the ordinal total score, which was transformed to a linear total score ranging from 0 (worst) to 100 (best). Participants with confirmed loss of ambulation at a particular visit were assigned a score of 0.
Change From Baseline in PUL Total Score at Week 144 Baseline, Week 144 The PUL was used to assess motor performance of the upper limb. The PUL scale includes 22 items; an entry item defining the starting functional level, and 21 items subdivided into shoulder level (4 items), elbow level (9 items), and distal level (8 items) dimensions. Scoring options per item may not be uniform and may vary from 0-1 and 0-6, according to the performance, with higher values corresponding to better performance. Each dimension was scored separately with a maximum score of 16 for shoulder level, 34 for elbow level, and 24 for distal level. Total score was calculated by adding the 3 level scores, with a maximum global score of 74 (total score range = 0-74). Higher score = better outcome.
Change From Baseline in Percent Predicted FVC as Measured by Spirometry at Week 144 Baseline, Week 144 FVC is a standard pulmonary function test. FVC was defined as the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. Percent predicted FVC (in %) = \[(observed FVC)/(predicted FVC)\]\*100.
Change From Baseline in Percent Predicted FEV1 as Measured by Spirometry at Week 144 Baseline, Week 144 FEV1 is a standard pulmonary function test. FEV1 was defined as the volume of air that can forcibly be blown out in 1 second, after full inspiration in the upright position, measured in liters. Percent predicted FEV1 (in %) = \[(observed FEV1)/(predicted FEV1)\]\*100.
Change From Baseline in PODCI Transfers/Basic Mobility Score at Week 144 Baseline, Week 144 Changes in health-related quality of life (HRQL) were measured via the PODCI questionnaire that has been shown to correlate with disease progression and clinical outcome measures in DMD. PODCI includes a Global Functioning Scale and 5 core scales: Upper Extremity and Physical Function,Transfer/Basic Mobility, Sports/Physical Functioning, Pain/Comfort,and Happiness. The following PODCI domain was prespecified in the protocol for analysis:Transfers/Basic Mobility domain assesses difficulty experienced in performing routine motor activities in daily life. Each domain was scored from 0 to 100, with 0 representing a poor outcome/worse health, while 100 representing the highest level of functioning and least pain.
Number of Participants With Change From Baseline in Activities of Daily Living and Disease Status at Week 144, as Assessed by a Standardized Survey Administered by Site Personnel Baseline, Week 144 Changes in activities of daily living and disease symptoms were captured via a DMD-specific survey administered by Site personnel. At screening or baseline, the participant and/or parent/caregiver were asked to identify any activities of daily living (for example, ambulation, balance, personal hygiene/grooming, dressing and undressing, self-feeding, using the bathroom, handwriting, school performance, behavior or energy level) or symptoms that were affected by the participant's DMD. At post-baseline visit (Week 144), the same participant and/or parent/caregiver was asked to describe any changes from baseline in those activities of daily living/symptoms, within the following categories: physical functioning; general energy level; cognition/school function; emotional/social functioning; and sleep. Changes from baseline were reported on a 5-point Likert scale: 1 (much better), 2 (slightly better), 3 (unchanged), 4 (slightly worse), or 5 (much worse).
Ataluren Plasma Concentration Pre-dose at Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, and 144 Pre-dose ataluren plasma concentrations prior to morning ataluren administration at each clinic visit was assessed using a validated high performance liquid chromatography with tandem mass spectrometry (HPLC/MS-MS) method.
Change From Baseline in Systolic and Diastolic Blood Pressure at Week 144 Baseline, Week 144 Blood pressure determination was performed with the participant in a sitting position after a 5-minute rest.
Change From Baseline in Pulse Rate at Week 144 Baseline, Week 144 Pulse rate determination was performed with the participant in a sitting position after a 5-minute rest.
Change From Baseline in Body Temperature at Week 144 Baseline, Week 144
Trial Locations
- Locations (58)
British Columbia Children's Hospital
🇨🇦Vancouver, British Columbia, Canada
University of Iowa
🇺🇸Iowa City, Iowa, United States
Oregon Health & Science University
🇺🇸Portland, Oregon, United States
Childrens Medical Center Dallas, Texas
🇺🇸Dallas, Texas, United States
Bambino Gesu Hospital
🇮🇹Rome, Italy
Stanford University Medical Center
🇺🇸Stanford, California, United States
U.O. Complessa di Neuropsichiatria Infantile
🇮🇹Rome, Italy
University of California, Los Angeles
🇺🇸Los Angeles, California, United States
UC Davis Medical Center
🇺🇸Sacramento, California, United States
Aleksandrovska Hospital
🇧🇬Sofia, Bulgaria
Astrid Lindgren Childrens Hospital
🇸🇪Stockholm, Sweden
Hacettepe Childrens Hospital
🇹🇷Ankara, Turkey
Sao Paulo University -HC/FMUSP
🇧🇷São Paulo, Brazil
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
CHUV Lausanne
🇨ðŸ‡Lausanne, Switzerland
Royal Manchester Children's Hospital
🇬🇧Manchester, United Kingdom
The Newcastle upon Tyne Hospitals, NHS Foundation Trust
🇬🇧Newcastle upon Tyne, United Kingdom
The Royal Children's Hospital
🇦🇺Parkville, Victoria, Australia
UZ Leuven
🇧🇪Leuven, Belgium
Children's Hospital Colorado - Center for Cancer and Blood Disorders
🇺🇸Aurora, Colorado, United States
Queen Silvia Children's Hospital
🇸🇪Goteburg, Sweden
Policlinico Universitario G. Martino
🇮🇹Sicily, Italy
University College London Institute of Child Health
🇬🇧London, United Kingdom
Hospital Luis Calvo Mackenna
🇨🇱Santiago, Región Metropolitana, Chile
Universitat Munchen - von Haunersche Kinder Clinic
🇩🇪Munchen, Germany
University Hospital Brno
🇨🇿Brno, Czechia
The Children's Hospital at Westmead
🇦🇺Westmead, New South Wales, Australia
Child Neurology Center of Northwest Florida
🇺🇸Gulf Breeze, Florida, United States
Rush University Medical Center
🇺🇸Chicago, Illinois, United States
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
Columbia University College of Physicians & Surgeons
🇺🇸New York, New York, United States
University of Minnesota
🇺🇸Minneapolis, Minnesota, United States
Children's Hospital Boston
🇺🇸Boston, Massachusetts, United States
Washington University School of Medicine, Division of Endocrinology, Metabolism and Lipid Research
🇺🇸Saint Louis, Missouri, United States
Children's Hospital Cincinnati
🇺🇸Cincinnati, Ohio, United States
Texas Children's Hospital
🇺🇸Houston, Texas, United States
Children's Hospital of Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States
The Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Seattle Children's Hospital - Childhood Cancer and Blood Disorders
🇺🇸Seattle, Washington, United States
Universidade Federal do Rio de Janeiro - Instituto de Puericultura e Pediatria Martagao Gesteira
🇧🇷Rio de Janeiro, Brazil
University of Utah
🇺🇸Salt Lake City, Utah, United States
Children's Hospital of Western Ontario
🇨🇦London, Ontario, Canada
Alberta Children's Hospital
🇨🇦Calgary, Alberta, Canada
Hospital Clinico Universidad Catolica
🇨🇱Santiago, Chile
Hospital de la Timone
🇫🇷Marseille, France
Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico di Milano
🇮🇹Milano, Italy
Motol University Hospital
🇨🇿Praha, Czechia
Hopital Necker - Enfants Malades
🇫🇷Paris, France
Universitaetsklinikum Essen
🇩🇪Essen, Germany
CHU de Nantes
🇫🇷Nantes Cedex 1, France
University Medical Center Freiburg
🇩🇪Freiburg, Germany
Groupe Hospitalier Pitie-Salpetriere
🇫🇷Paris Cedex 13, France
Hadassah University Hospital
🇮🇱Jerusalem, Israel
Medical University of Warsaw
🇵🇱Warsaw, Poland
Hospital Universitari i Politecnic la Fe
🇪🇸Valencia, Spain
Hospital Sant Joan de Deu
🇪🇸Barcelona, Spain
Erciyes University Faculty of Medicine
🇹🇷Talas/Kayseri, Turkey
University of Kansas Medical Center
🇺🇸Kansas City, Kansas, United States