An Extension Study of Ataluren (PTC124) in Participants With Nonsense Mutation Dystrophinopathy

A Phase 3 Extension Study of Ataluren (PTC124) in Patients With Nonsense Mutation Dystrophinopathy

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.

Study Overview

• Status: Terminated
• Conditions: Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Dystrophy, Duchenne
• Intervention / Treatment: Drug: Ataluren

• Study Type: Interventional
• Enrollment (Actual): 219
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • The Children's Hospital at Westmead
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • The Royal Children's Hospital
• Belgium
  • Leuven, Belgium, 3000
    • UZ Leuven
• Brazil
  • Rio de Janeiro, Brazil, 21.941-912
    • Universidade Federal do Rio de Janeiro - Instituto de Puericultura e Pediatria Martagao Gesteira
  • São Paulo, Brazil, 05403-900
    • Sao Paulo University -HC/FMUSP
• Bulgaria
  • Sofia, Bulgaria, 1431
    • Aleksandrovska Hospital
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Alberta Children's Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • British Columbia Children's Hospital
  • Ontario
    • London, Ontario, Canada, N6C 2RC
      • Children's Hospital of Western Ontario
• Chile
  • Santiago, Chile, 8330073
    • Hospital Clínico Universidad Católica
  • Región Metropolitana
    • Santiago, Región Metropolitana, Chile
      • Hospital Luis Calvo Mackenna
• Czechia
  • Brno, Czechia, 635 00
    • University Hospital Brno
  • Praha, Czechia, 150 06
    • Motol University Hospital
• France
  • Marseille, France, 13385
    • Hôspital de la Timone
  • Nantes Cedex 1, France, 44093
    • CHU de Nantes
  • Paris, France, 75015
    • Hopital Necker - Enfants Malades
  • Paris Cedex 13, France, 75651
    • Groupe Hospitalier Pitie-Salpetriere
• Germany
  • Essen, Germany, 45122
    • Universitaetsklinikum Essen
  • Freiburg, Germany, 79106
    • University Medical Center Freiburg
  • Munchen, Germany, 80337
    • Universitat Munchen - von Haunersche Kinder Clinic
• Israel
  • Jerusalem, Israel, 91240
    • Hadassah University Hospital
• Italy
  • Milano, Italy, 20122
    • Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico di Milano
  • Rome, Italy, 00165
    • Bambino Gesu Hospital
  • Rome, Italy, 00168
    • U.O. Complessa di Neuropsichiatria Infantile
  • Sicily, Italy, 98125
    • Policlinico Universitario G. Martino
• Korea, Republic of
  • Seoul, Korea, Republic of, 110-744
    • Seoul National University Hospital
• Poland
  • Warsaw, Poland, 502-097
    • Medical University of Warsaw
• Spain
  • Barcelona, Spain, 08950
    • Hospital Sant Joan de Déu
  • Valencia, Spain, 46026
    • Hospital Universitari i Politecnic La Fe
• Sweden
  • Goteburg, Sweden, SE-416 85
    • Queen Silvia Children's Hospital
  • Stockholm, Sweden, 17176
    • Astrid Lindgren Childrens Hospital
• Switzerland
  • Lausanne, Switzerland, 1011
    • CHUV Lausanne
• Turkey
  • Ankara, Turkey, 06100
    • Hacettepe Childrens Hospital
  • Talas/Kayseri, Turkey, 38039
    • Erciyes University Faculty of Medicine
• United Kingdom
  • London, United Kingdom, WC1N 3JH
    • University College London Institute of Child Health
  • Manchester, United Kingdom, M13 9WL
    • Royal Manchester Children's Hospital
  • Newcastle upon Tyne, United Kingdom, NE1 3BZ
    • The Newcastle upon Tyne Hospitals, NHS Foundation Trust
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California, Los Angeles
    • Sacramento, California, United States, 95817
      • UC Davis Medical Center
    • Stanford, California, United States, 94305
      • Stanford University Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado - Center for Cancer and Blood Disorders
  • Florida
    • Gulf Breeze, Florida, United States, 32561
      • Child Neurology Center of Northwest Florida
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine, Division of Endocrinology, Metabolism and Lipid Research
  • New York
    • New York, New York, United States, 10032
      • Columbia University College of Physicians & Surgeons
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Children's Hospital Cincinnati
    • Columbus, Ohio, United States, 43209
      • Nationwide Children's Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh
  • Texas
    • Dallas, Texas, United States, 75207
      • Childrens Medical Center Dallas, Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital - Childhood Cancer and Blood Disorders

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 15 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• 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.

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], 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Ataluren; Ataluren will be administered per the dose and schedule specified in the arm.; Other Names: PTC124

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	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.	Baseline (Day 1) up to 6 weeks post-treatment (Week 150)
Number of Participants With Abnormalities in Clinical Laboratory Parameters	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]).	Baseline (Day 1) up to 6 weeks post-treatment (Week 150)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in 6MWD at 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.	Baseline, Week 144
Change From Baseline in Time to Stand From Supine Position at 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.	Baseline, Week 144
Change From Baseline in Time to Walk/Run 10 Meters at 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.	Baseline, Week 144
Change From Baseline in Time to Climb 4 Stairs at 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.	Baseline, Week 144
Change From Baseline in Time to Descend 4 Stairs at 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.	Baseline, Week 144
Change From Baseline in Physical Function Total Score as Measured by NSAA at 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.	Baseline, Week 144
Change From Baseline in PUL Total Score at 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.	Baseline, Week 144
Change From Baseline in Percent Predicted FVC as Measured by Spirometry at 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.	Baseline, Week 144
Change From Baseline in Percent Predicted FEV1 as Measured by Spirometry at 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.	Baseline, Week 144
Change From Baseline in PEF as Measured by Spirometry at Week 144	PEF was defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated.	Baseline, Week 144
Change From Baseline in PCF as Measured by Spirometry at Week 144	PCF measures an individual's maximum speed of expiration during cough.	Baseline, Week 144
Change From Baseline in PODCI Transfers/Basic Mobility Score at 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.	Baseline, Week 144
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	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).	Baseline, Week 144
Ataluren Plasma Concentration	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.	Pre-dose at Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, and 144
Change From Baseline in Systolic and Diastolic Blood Pressure at Week 144	Blood pressure determination was performed with the participant in a sitting position after a 5-minute rest.	Baseline, Week 144
Change From Baseline in Pulse Rate at Week 144	Pulse rate determination was performed with the participant in a sitting position after a 5-minute rest.	Baseline, Week 144
Change From Baseline in Body Temperature at Week 144		Baseline, Week 144

Collaborators and Investigators

• Sponsor: PTC Therapeutics
• Investigators: Study Director: Francesco Bibbiani, M.D., PTC Therapeutics

Publications and helpful links

General Publications

• Thangarajh M, Elfring GL, Trifillis P, McIntosh J, Peltz SW; Ataluren Phase 2b Study Group. The relationship between deficit in digit span and genotype in nonsense mutation Duchenne muscular dystrophy. Neurology. 2018 Sep 25;91(13):e1215-e1219. doi: 10.1212/WNL.0000000000006245. Epub 2018 Aug 22.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2014
• Primary Completion (Actual): June 12, 2018
• Study Completion (Actual): June 12, 2018

Study Registration Dates

• First Submitted: March 17, 2014
• First Submitted That Met QC Criteria: March 17, 2014
• First Posted (Estimate): March 19, 2014

Study Record Updates

• Last Update Posted (Actual): August 11, 2020
• Last Update Submitted That Met QC Criteria: August 10, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: Duchenne muscular dystrophy; Becker muscular dystrophy; Nonsense mutation; Premature stop codon; Ataluren; PTC124; Dystrophinopathy; DMD/BMD
• Additional Relevant MeSH Terms: Muscular Dystrophies; Nervous System Diseases; Musculoskeletal Diseases; Muscular Diseases; Muscular Dystrophy, Duchenne; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Neuromuscular Diseases; Muscular Disorders, Atrophic
• Other Study ID Numbers: PTC124-GD-020e-DMD

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No