Study of Ataluren for Previously Treated Participants With Nonsense Mutation Duchenne/Becker Muscular Dystrophy (nmDBMD) in Europe, Israel, Australia, and Canada

An Open-Label Study for Previously Treated Ataluren (PTC124®) Patients With Nonsense Mutation Dystrophinopathy

Duchenne/Becker muscular dystrophy (DBMD) 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 DBMD in approximately 10-15% 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 comprises a Phase 3, open-label study of ataluren in participants with nmDBMD who previously received ataluren at an Investigator site in a prior PTC-sponsored clinical study. A separate open-label study (PTC124-GD-016-DMD; NCT01247207) is being conducted for nmDBMD participants who previously received ataluren at an Investigator site in the United States (US).

Study Overview

• Status: Completed
• Conditions: Duchenne Muscular Dystrophy; Becker Muscular Dystrophy; Dystrophinopathy
• Intervention / Treatment: Drug: Ataluren

Detailed Description

All participating sites must have had at least 1 participant that received ataluren treatment in prior PTC-sponsored clinical studies in DBMD (Phase 2b double-blind, placebo-controlled study [PTC124-GD-007-DMD; NCT00592553] and the subsequent open-label extension study [Study PTC124-GD-007e-DMD; NCT00847379]). It is planned that up to ~96 participants will be enrolled.

It is also planned that participants will receive ataluren 3 times per day (TID) at respective morning, midday, and evening doses of 10 milligrams/kilograms (mg/kg), 10 mg/kg, and 20 mg/kg for approximately 336 weeks. Study assessments will be performed at clinic visits during screening, on the first day of ataluren dosing, and then every 48 weeks during the ataluren treatment period, except for weight, which will be measured every 24 weeks at a primary care physician (PCP).

• Study Type: Interventional
• Enrollment (Actual): 94
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Westmead, Australia
    • Institute For Neuromuscular Research, The Children's Hospital at Westmead
  • Melbourne
    • Parkville, Melbourne, Australia
      • Royal Children's Hospital
• Belgium
  • Leuven, Belgium
    • University Hospital KU Leuven
• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • Alberta Children's Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada
      • British Columbia Children's Hospital
  • Ontario
    • London, Ontario, Canada
      • Children's Hospital of Western Ontario
• France
  • Marseille, France
    • Hopital d'Enfants CHU Timone
  • Nantes, France
    • Laboratoire d'Exploration Fonctionnelles
  • Paris, France
    • Groupe Hospitalier La Pitie-Salpetriere
• Germany
  • Essen, Germany
    • University of Essen - Clinic for Children
  • Freiburg, Germany
    • University Hospital
• Israel
  • Jerusalem, Israel
    • Hadassah Medical Center, Hebrew University Hospital
• Italy
  • Milan, Italy
    • Ospedale Maggiore Policlinico in Milan
  • Rome, Italy
    • Ospedale Pediatrico Bambino Gesù
  • Rome, Italy
    • U.O. Complessa di Neuropsichiatria Infantile
• Spain
  • Barcelona, Spain
    • Hospital Sant Joan de Déu
  • Valencia, Spain
    • Hospital Universitari La Fe
• Sweden
  • Göteborg, Sweden
    • Queen Silvia Children's Hospital
  • Stockholm, Sweden
    • Astrid Lindgren Pediatric Hospital
• United Kingdom
  • London, United Kingdom
    • Great Ormond Street Hospital
  • Newcastle Upon Tyne, United Kingdom
    • University of Newcastle Institute of Human Genetics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. 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 Ethics 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.
2. History of exposure to ataluren in a prior PTC study in nmDBMD. Note: Participants are considered eligible only if they received ataluren during their participation in 1 or more prior PTC-sponsored studies of ataluren in nmDBMD. Note: Participants who have participated in a prior or ongoing PTC study with ataluren in nmDBMD at a trial site in the US or Canada, but reside outside of the US and Canada, may be eligible for this study (with the approval of the PTC Therapeutics Medical Monitor).
3. Male sex.
4. In participants who are sexually active, willingness to abstain from sexual intercourse or employ a barrier or medical method of contraception during ataluren administration and the 6-week follow-up period.
5. 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 should be considered.

Exclusion Criteria:

1. Exposure to another investigational drug within 1 month prior to start of study treatment.
2. Eligibility for another ataluren clinical trial that is actively enrolling study participants.
3. Known hypersensitivity to any of the ingredients or excipients of ataluren (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).

4. Ongoing use of the following medications:

   1. Coumarin-based anticoagulants (for example, warfarin), phenytoin, tolbutamide, or paclitaxel.
   2. Systemic aminoglycoside therapy
5. Ongoing uncontrolled medical/surgical condition, electrocardiogram (ECG) findings, or laboratory abnormality that, in the Investigator's opinion, could adversely affect the safety of the participant or make it unlikely that follow-up would be completed.

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; Ataluren will be provided as a vanilla-flavored powder to be mixed with water, milk, fruit juice (except apple juice) fruit punch, or in semi-solid food (for example, yogurt, pudding, or applesauce). The dose level for ataluren will be 10 milligrams/kilograms (mg/kg) in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening. Administration within 30 minutes after a meal will be recommended. Study drug dosing will be based on milligrams of drug per kilogram of body weight. Because of potential changes in participant body weight over time, weight-based dose adjustment can occur every 24 weeks as required. Study drug will be taken for up to 240 weeks.

Drug: Ataluren; Oral powder for suspension; 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)	A TEAE is any untoward medical occurrence or undesirable event(s) experienced in a participant that begins or worsens following administration of the study drug or study treatment, whether or not considered related to the treatment by the Investigator. A serious adverse event (SAE) was an adverse event (AE) resulting in any of the following outcomes or deemed significant for any other reason, death, initial or prolonged inpatient hospitalization, life-threatening experience (immediate risk of dying), or persistent or significant disability/incapacity not related to nmDBMD. AEs included both SAEs and non-serious AEs. AEs were classified according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (CTCAE) and coded using the Medical Dictionary for Regulatory Activities (MedDRA). A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module.	Baseline up to Week 246

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in 6MWD as Measured by the 6MWT	The 6MWD was assessed in participants who were ambulatory using standardized procedures. Participants were not permitted to use assistive devices (walker, long leg braces, or short leg braces) during the 6MWD test.	Baseline, Weeks 48, 96, 144, 192, and 240
Change From Baseline in Physical Function as Measured by the NSAA	The NSAA was used to evaluate physical function in participants who were ambulatory at study entry, using standardized procedures. The NSAA consisted of 17 activities, each scored as 0 (activity could not be performed), 1 (modified method but achieved goal without physical assistance from another), or 2 (normal, achieved goal without assistance). The sum of these 17 scores was used to form a total score. If fewer than 13 of the 17 activities were performed, the total score was considered missing. If 13 to 16 activities were performed, the total score was calculated by multiplying the sum of the scores in the x activities that were performed by 17/x. If an activity could not be performed due to disease progression/loss of ambulation, a score of 0 was assigned. The linear score was the linear transformation of the NSAA score to a scale of 0 (worst) to 100 (best).	Baseline, Weeks 48, 96, 144, 192, and 240
Change From Baseline in Time to Stand From Supine Position	Time to stand from the supine position to a standing position was assessed in ambulatory participants. If the time taken to perform a test exceeded 30 seconds or if a participant could not perform the test due to disease progression, a value of 30 seconds was used.	Baseline, Weeks 48, 96, 144, 192, and 240
Change From Baseline in Time to Walk/Run 10 Meters	Time to walk/run 10 meters was measured in ambulatory participants. If the time taken to perform a test exceeded 30 seconds or if a participant could not perform the test due to disease progression, a value of 30 seconds was used.	Baseline, Weeks 48, 96, 144, 192, and 240
Change From Baseline in Pulmonary Function as Measured by Spirometry	Pulmonary function parameters of %-predicated FVC, percent-predicted FEV1 (adjusted using ulna length and age), PEF, and PCF was assessed in non-ambulatory participants by using a spirometer. Due to the difficulty in obtaining an accurate standing height measurement in non-ambulatory participants, ulna length and arm span were used as a surrogate measure for height when calculating percent-predicted FVC.	Baseline, Weeks 48, 96, 144, 192, and 240
Change From Baseline in Participant and Parent/Caregiver-Reported ADL, as Measured by the EK Scale	Activities of daily living after loss of ambulation were measured using the EK scale. 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 arms, 6) ability to use 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 performs the tasks of daily life (as described by Categories 1 to 9) and how he perceives his wellbeing (as described by Category 10). The interviewer observed the participant and assigned the final score for the tasks that could be observed in the clinic.	Baseline, Weeks 48, 96, 144, 192, and 240

Collaborators and Investigators

• Sponsor: PTC Therapeutics
• Investigators: Study Director: Edward O'Mara, MD, PTC Therapeutics

Publications and helpful links

General Publications

• Hirawat S, Welch EM, Elfring GL, Northcutt VJ, Paushkin S, Hwang S, Leonard EM, Almstead NG, Ju W, Peltz SW, Miller LL. Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers. J Clin Pharmacol. 2007 Apr;47(4):430-44. doi: 10.1177/0091270006297140.
• Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ, Trifillis P, Paushkin S, Patel M, Trotta CR, Hwang S, Wilde RG, Karp G, Takasugi J, Chen G, Jones S, Ren H, Moon YC, Corson D, Turpoff AA, Campbell JA, Conn MM, Khan A, Almstead NG, Hedrick J, Mollin A, Risher N, Weetall M, Yeh S, Branstrom AA, Colacino JM, Babiak J, Ju WD, Hirawat S, Northcutt VJ, Miller LL, Spatrick P, He F, Kawana M, Feng H, Jacobson A, Peltz SW, Sweeney HL. PTC124 targets genetic disorders caused by nonsense mutations. Nature. 2007 May 3;447(7140):87-91. doi: 10.1038/nature05756. Epub 2007 Apr 22.
• McDonald CM, Muntoni F, Penematsa V, Jiang J, Kristensen A, Bibbiani F, Goodwin E, Gordish-Dressman H, Morgenroth L, Werner C, Li J, Able R, Trifillis P, Tulinius M; Study 019 investigators. Ataluren delays loss of ambulation and respiratory decline in nonsense mutation Duchenne muscular dystrophy patients. J Comp Eff Res. 2022 Feb;11(3):139-155. doi: 10.2217/cer-2021-0196. Epub 2021 Nov 18.

Helpful Links

• 16-2-9 CINRG Listing

Study record dates

Study Major Dates

• Study Start (Actual): May 20, 2012
• Primary Completion (Actual): January 19, 2018
• Study Completion (Actual): January 19, 2018

Study Registration Dates

• First Submitted: March 15, 2012
• First Submitted That Met QC Criteria: March 15, 2012
• First Posted (Estimate): March 19, 2012

Study Record Updates

• Last Update Posted (Actual): November 25, 2020
• Last Update Submitted That Met QC Criteria: November 3, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: DMD; Duchenne muscular dystrophy; Becker muscular dystrophy; Nonsense mutation; Premature stop codon; BMD; Ataluren; PTC124; nmDBMD; DBMD
• Additional Relevant MeSH Terms: Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Muscular Disorders, Atrophic; Muscular Dystrophies; Muscular Dystrophy, Duchenne
• Other Study ID Numbers: PTC124-GD-019-DMD

Plan for Individual participant data (IPD)

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