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

Nervous System Diseases Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02090959
• Other study ID #: PTC124-GD-020e-DMD
• Status: Terminated
• Phase: Phase 3
• Start date: March 20, 2014
• Est. completion date: June 12, 2018

Study information

• Verified date: August 2020
• Source: PTC Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 219
• Est. completion date: June 12, 2018
• Est. primary completion date: June 12, 2018
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 7 Years to 15 Years

Eligibility

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.

Related Conditions & MeSH terms

• Genetic Diseases, Inborn
• Genetic Diseases, X-Linked
• Muscular Diseases
• Muscular Disorders, Atrophic
• Muscular Dystrophies
• Muscular Dystrophy, Duchenne
• Musculoskeletal Diseases
• Nervous System Diseases
• Neuromuscular Diseases

Intervention

Drug:
• Ataluren
Ataluren will be administered per the dose and schedule specified in the arm.

Locations

Country	Name	City	State
Australia	The Royal Children's Hospital	Parkville	Victoria
Australia	The Children's Hospital at Westmead	Westmead	New South Wales
Belgium	UZ Leuven	Leuven
Brazil	Universidade Federal do Rio de Janeiro - Instituto de Puericultura e Pediatria Martagao Gesteira	Rio de Janeiro
Brazil	Sao Paulo University -HC/FMUSP	São Paulo
Bulgaria	Aleksandrovska Hospital	Sofia
Canada	Alberta Children's Hospital	Calgary	Alberta
Canada	Children's Hospital of Western Ontario	London	Ontario
Canada	British Columbia Children's Hospital	Vancouver	British Columbia
Chile	Hospital Clinico Universidad Catolica	Santiago
Chile	Hospital Luis Calvo Mackenna	Santiago	Región Metropolitana
Czechia	University Hospital Brno	Brno
Czechia	Motol University Hospital	Praha
France	Hospital de la Timone	Marseille
France	CHU de Nantes	Nantes Cedex 1
France	Hopital Necker - Enfants Malades	Paris
France	Groupe Hospitalier Pitie-Salpetriere	Paris Cedex 13
Germany	Universitaetsklinikum Essen	Essen
Germany	University Medical Center Freiburg	Freiburg
Germany	Universitat Munchen - von Haunersche Kinder Clinic	Munchen
Israel	Hadassah University Hospital	Jerusalem
Italy	Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico di Milano	Milano
Italy	Bambino Gesu Hospital	Rome
Italy	U.O. Complessa di Neuropsichiatria Infantile	Rome
Italy	Policlinico Universitario G. Martino	Sicily
Korea, Republic of	Seoul National University Hospital	Seoul
Poland	Medical University of Warsaw	Warsaw
Spain	Hospital Sant Joan de Deu	Barcelona
Spain	Hospital Universitari i Politecnic la Fe	Valencia
Sweden	Queen Silvia Children's Hospital	Goteburg
Sweden	Astrid Lindgren Childrens Hospital	Stockholm
Switzerland	CHUV Lausanne	Lausanne
Turkey	Hacettepe Childrens Hospital	Ankara
Turkey	Erciyes University Faculty of Medicine	Talas/Kayseri
United Kingdom	University College London Institute of Child Health	London
United Kingdom	Royal Manchester Children's Hospital	Manchester
United Kingdom	The Newcastle upon Tyne Hospitals, NHS Foundation Trust	Newcastle upon Tyne
United States	Children's Hospital Colorado - Center for Cancer and Blood Disorders	Aurora	Colorado
United States	Children's Hospital Boston	Boston	Massachusetts
United States	Rush University Medical Center	Chicago	Illinois
United States	Children's Hospital Cincinnati	Cincinnati	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Childrens Medical Center Dallas, Texas	Dallas	Texas
United States	Child Neurology Center of Northwest Florida	Gulf Breeze	Florida
United States	Texas Children's Hospital	Houston	Texas
United States	University of Iowa	Iowa City	Iowa
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	University of California, Los Angeles	Los Angeles	California
United States	University of Minnesota	Minneapolis	Minnesota
United States	Columbia University College of Physicians & Surgeons	New York	New York
United States	The Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	UC Davis Medical Center	Sacramento	California
United States	Washington University School of Medicine, Division of Endocrinology, Metabolism and Lipid Research	Saint Louis	Missouri
United States	University of Utah	Salt Lake City	Utah
United States	Seattle Children's Hospital - Childhood Cancer and Blood Disorders	Seattle	Washington
United States	Stanford University Medical Center	Stanford	California

Sponsors (1)

Lead Sponsor	Collaborator
PTC Therapeutics

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Brazil,  Bulgaria,  Canada,  Chile,  Czechia,  France,  Germany,  Israel,  Italy,  Korea, Republic of,  Poland,  Spain,  Sweden,  Switzerland,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Change From Baseline in Body Temperature at Week 144		Baseline, Week 144

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