Clinical trial NCT01557400: Study of Ataluren for Previously Treated Participants With Nonsense Mutation Duchenne/Becker Muscular Dystrophy (nmDBMD) in Europe, Israel, Australia, and Canada
Official title: An Open-Label Study for Previously Treated Ataluren (PTC124®) Patients With Nonsense Mutation Dystrophinopathy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Duchenne Muscular Dystrophy
Becker Muscular Dystrophy
Dystrophinopathy
Keywords: Duchenne muscular dystrophy
Becker muscular dystrophy
Nonsense mutation
Premature stop codon
DMD
BMD
nmDBMD
DBMD
Ataluren
PTC124
Lead sponsor: PTC Therapeutics
Sponsor class: INDUSTRY
First posted: 2012-03-19
Enrollment: 94
Sex: MALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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).

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).

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
timeFrame: Baseline up to Week 246
Secondary outcomes:
measure: Change From Baseline in 6MWD as Measured by the 6MWT
timeFrame: Baseline, Weeks 48, 96, 144, 192, and 240
measure: Change From Baseline in Physical Function as Measured by the NSAA
timeFrame: Baseline, Weeks 48, 96, 144, 192, and 240
measure: Change From Baseline in Time to Stand From Supine Position
timeFrame: Baseline, Weeks 48, 96, 144, 192, and 240
measure: Change From Baseline in Time to Walk/Run 10 Meters
timeFrame: Baseline, Weeks 48, 96, 144, 192, and 240
measure: Change From Baseline in Pulmonary Function as Measured by Spirometry
timeFrame: Baseline, Weeks 48, 96, 144, 192, and 240
measure: Change From Baseline in Participant and Parent/Caregiver-Reported ADL, as Measured by the EK Scale
timeFrame: Baseline, Weeks 48, 96, 144, 192, and 240
Other outcomes:
Locations:
city: Parkville
country: Australia
facility: Royal Children's Hospital
state: Melbourne
city: Westmead
country: Australia
facility: Institute For Neuromuscular Research, The Children's Hospital at Westmead
city: Leuven
country: Belgium
facility: University Hospital KU Leuven
city: Calgary
country: Canada
facility: Alberta Children's Hospital
state: Alberta
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital
state: British Columbia
city: London
country: Canada
facility: Children's Hospital of Western Ontario
state: Ontario
city: Marseille
country: France
facility: Hôpital d'Enfants CHU Timone
city: Nantes
country: France
facility: Laboratoire d'Exploration Fonctionnelles
city: Paris
country: France
facility: Groupe Hospitalier La Pitie-Salpetriere
city: Essen
country: Germany
facility: University of Essen - Clinic for Children
city: Freiburg
country: Germany
facility: University Hospital
city: Jerusalem
country: Israel
facility: Hadassah Medical Center, Hebrew University Hospital
city: Milan
country: Italy
facility: Ospedale Maggiore Policlinico in Milan
city: Rome
country: Italy
facility: Ospedale Pediatrico Bambino Gesu
city: Rome
country: Italy
facility: U.O. Complessa di Neuropsichiatria Infantile
city: Barcelona
country: Spain
facility: Hospital Sant Joan de déu
city: Valencia
country: Spain
facility: Hospital Universitari La Fe
city: Göteborg
country: Sweden
facility: Queen Silvia Children's Hospital
city: Stockholm
country: Sweden
facility: Astrid Lindgren Pediatric Hospital
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
city: Newcastle Upon Tyne
country: United Kingdom
facility: University of Newcastle Institute of Human Genetics
Study officials:
affiliation: PTC Therapeutics
name: Edward O'Mara, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.