Phase 3 Study of Ataluren in Participants With Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)

Nervous System Diseases Clinical Trial

— ACT DMD  

Official title:

A Phase 3 Efficacy and Safety Study of Ataluren in Patients With Nonsense Mutation Dystrophinopathy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01826487
• Other study ID #: PTC124-GD-020-DMD
• Secondary ID: 2012-004527-20
• Status: Completed
• Phase: Phase 3
• Start date: March 26, 2013
• Est. completion date: August 20, 2015

Study information

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

Clinical Trial Summary

Dystrophinopathy is a disease continuum that includes Duchenne muscular dystrophy, which 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. A specific type of mutation, called a nonsense (premature stop codon) mutation is the cause of dystrophinopathy in approximately 10-15 percent (%) of boys with the disease. Ataluren is an orally delivered, investigational drug that has the potential to overcome the effects of the nonsense mutation. The main goal of this Phase 3 study is to evaluate the effect of ataluren on walking ability. The effect of ataluren on physical function, quality of life, and activities of daily living will be evaluated. This study will also provide additional information on the long-term safety of ataluren.

Description:

This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study to determine the efficacy and safety of ataluren in participants with nmDMD.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 230
• Est. completion date: August 20, 2015
• Est. primary completion date: August 20, 2015
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 7 Years to 16 Years

Eligibility

Inclusion Criteria:

• Ability to provide written informed consent (parental/guardian consent if applicable)/assent per local requirements.

• Phenotypic evidence of dystrophinopathy based on the onset of characteristic clinical symptoms or signs (for example; proximal muscle weakness, waddling gait, and Gowers' maneuver) by 6 years of age, an elevated serum creatinine kinase level, and ongoing difficulty with walking.

• Documentation of the presence of a nonsense point mutation in the dystrophin gene as determined by gene sequencing from a laboratory certified by the College of American Pathologists (CAP), the Clinical Laboratory Improvement Act/Amendment (CLIA) or an equivalent organization.

• Documentation that a blood sample has been drawn for confirmation of the presence of a nonsense mutation in the dystrophin gene.

• Use of systemic corticosteroids (prednisone, prednisolone, or deflazacort) for a minimum of 6 months immediately prior to start of study treatment, with no significant change in dosage or dosing regimen (not related to body weight change) for a minimum of 3 months immediately prior to start of study treatment and a reasonable expectation that dosage and dosing regimen will not change significantly for the duration of the study.

• Valid Screening 6-minute walk distance (6MWD) greater than or equal to (=) 150 meters. Valid Screening 6MWD must have been less than or equal to (=) 80% of predicted for age and height.

• Results of the 2 Baseline 6MWD results must be determined as valid and results of the Day 2 Baseline 6MWD must be within 20% of the Day 1 Baseline 6MWD.

• Baseline 6MWD (mean of valid Day 1 and Day 2 values) must be no more than a 20% change from the valid Screening 6MWD.

• Confirmed screening laboratory values within the central laboratory ranges (hepatic, renal, and serum electrolyte parameters).

• Willingness to abstain from sexual intercourse or employ an approved method of contraception during the period of study drug administration and 6-week follow-up period.

• Willingness and ability to comply with scheduled visits, drug administration plan, study procedures, laboratory tests, and study restrictions.

Exclusion Criteria:

• Treatment with systemic aminoglycoside antibiotics within 3 months prior to start of study treatment.

• Initiation of systemic corticosteroids therapy within 6 months prior to start of study treatment.

• Change in systemic corticosteroid therapy (for example; change in type of drug, dose modification not related to body weight change, schedule modification, interruption, or reinitiation) within 3 months prior to start of study treatment.

• Any change (initiation, change in type of drug, dose modification, schedule modification,interruption, discontinuation, or reinitiation) in prophylaxis/treatment for congestive heart failure (CHF) within 3 months prior to start of study treatment.

• Ongoing use of coumarin-based anticoagulants (for example; warfarin), phenytoin, tolbutamide, or paclitaxel.

• Prior therapy with ataluren.

• Known hypersensitivity to any of the ingredients or excipients of the study drug.

• Exposure to another investigational drug within 3 months prior to start of study treatment.

• History of major surgical procedure within 6 weeks prior to start of study treatment.

• Ongoing immunosuppressive therapy (other than corticosteroids).

• Ongoing participation in any clinical trial (except for studies specifically approved by PTC Therapeutics).

• Expectation of major surgical procedure (for example; scoliosis surgery) during the 12-month treatment period of the study.

• Requirement for daytime ventilator assistance.

• Uncontrolled clinical symptoms and signs of CHF (American College of Cardiology/American Heart Association Stage C or Stage D).

• Prior or ongoing medical condition (for example; concomitant illness, psychiatric condition, behavioral disorder, alcoholism, drug abuse), medical history, physical findings (for example; lower limb injury that may affect 6MWT performance), 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 as per the dose and schedule specified in the arm.
• Placebo
Placebo will be administered as per the 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
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
France	Groupe Hospitalier La Pitie-Salpetriere	Paris
France	Hopital Necker - Enfants Malades	Paris
Germany	University of Essen-Duisburg	Essen
Germany	University Hospital Medical Center Freiburg	Freiburg
Israel	Hadassah University Hospital	Jerusalem
Italy	Policlinico Universitario G. Martino	Messina	Sicily
Italy	Fondazione IRCS Ca Granda Ospedale Maggiore Policlinico di Milano	Milan
Italy	Bambino Gesu Hospital	Rome
Italy	U.O. Complessa di Neuropsichiatria Infantile	Rome
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
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	Boston Children's Hospital	Boston	Massachusetts
United States	Children's Hospital Boston	Boston	Massachusetts
United States	Rush University Medical Center	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	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

Sponsors (1)

Lead Sponsor	Collaborator
PTC Therapeutics

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Brazil,  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
Other	Change From Baseline in Physical Function Total Score as Measured by NSAA at Week 48	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 48
Other	Number of Participants With Change From Baseline in Activities of Daily Living and Disease Status at Week 48, 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 48), 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 worse), 2 (slightly worse), 3 (unchanged), 4 (slightly better), or 5 (much better).	Baseline, Week 48
Other	Change From Baseline in PODCI Transfers/Basic Mobility and Sports/Physical Functioning Scores at Week 48	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 domains were prespecified in the protocol for analysis:Transfers/Basic Mobility domain assesses difficulty experienced in performing routine motor activities in daily life. Sports/Physical Functioning domain assesses difficulty encountered in participating in more active recreational activities. 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 48
Other	Ataluren Plasma Concentration	Plasma samples for the determination of ataluren concentrations were analyzed using a validated high performance liquid chromatography with tandem mass spectrometry (HPLC/MS-MS) method with a lower limit of quantitation of 0.5 micrograms/milliliter (mcg/mL).	Weeks 8, 16, 24, 32, 40, and 48
Other	Study Drug Compliance	Study drug compliance was assessed by quantification of used and unused study drug. Compliance was assessed in terms of the percentage of drug actually taken relative to the amount that should have been taken during the study.	Baseline to Week 48
Primary	Change From Baseline in 6MWD at Week 48	The 6MWD test is a non-encouraged test performed in a 30 meters long flat corridor, where the participant is 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. Participants with confirmed loss of ambulation at a particular visit were assigned a 6MWD result of 0. Baseline and Week 48 6MWD values are each the average of two valid 6MWD values, or a single available value if one was missing.	Baseline, Week 48
Secondary	Time to 10 Percent (%) Persistent Worsening in 6MWD	The 6MWD test is a non-encouraged test performed in a 30 meters long flat corridor, where the participant is 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. Time to 10% persistent worsening in 6MWD was defined as the last time that 6MWD was not 10% worse compared with baseline. Time to 10% persistent worsening in 6MWD <300 meters, >=300 to 400 meters, and >=400 meters was evaluated. For participants who did not have 10% 6MWD worsening or who were removed from study, time to 10% 6MWD worsening was censored at the time of the last 6MWD test. Participants who became non-ambulatory were considered to have 10% worsening.	Baseline to Week 48
Secondary	Change From Baseline in Time to Walk/Run 10 Meters at Week 48	During the test for walking/running 10 meters, the method of walk/run used by the participant was categorized as follows: 1. Unable to walk independently; 2. Unable to walk independently but can walk with support from a person or with assistive device (full leg calipers [knee-ankle-foot orthoses ] or walker); 3. Highly adapted gait, wide-based lordotic gait, cannot increase walking speed; 4. Moderately adapted gait, can pick up speed but cannot run; 5. Able to pick up speed but runs with a double stance phase (that is, cannot achieve both feet off the ground); 6. Runs and gets both feet off the ground (with no double stance phase). 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. A cumulative change from baseline data has been reported.	Baseline, Week 48
Secondary	Change From Baseline in Time to Climb 4 Stairs at Week 48	During the test for stair-climbing, the method of climbing used by the participant was categorized as follows: 1. Unable to up climb 4 standard stairs; 2. Climbs 4 standard stairs "marking time" (climbs one foot at a time, with both feet on a step before moving to next step), using both arms on one or both handrails; 3. Climbs 4 standard stairs "marking time" (climbs one foot at a time, with both feet on a step before moving to next step), using one arm on one handrail; 4. Climbs 4 standard stairs "marking time" (climbs one foot at a time, with both feet on a step before moving to next step), not needing handrail; 5. Climbs 4 standard stairs alternating feet, needs handrail for support; 6. Climbs 4 standard stairs alternating feet, not needing handrail support. A cumulative change from baseline data has been reported.	Baseline, Week 48
Secondary	Change From Baseline in Time to Descend 4 Stairs at Week 48	During the test for stair-descending, the method of descending used by the participant was categorized as follows: 1. Unable to descend 4 standard stairs; 2. Descends 4 standard stairs "marking time" (climbs one foot at a time, with both feet on a step before moving to next step), using both arms on one or both handrails; 3. Descends 4 standard stairs "marking time" (climbs one foot at a time, with both feet on a step before moving to next step), using one arm on one handrail; 4. Descends 4 standard stairs "marking time" (climbs one foot at a time, with both feet on a step before moving to next step), not needing handrail; 5. Descends 4 standard stairs alternating feet, needs handrail for support; 6. Descends 4 standard stairs alternating feet, not needing handrail support. A cumulative change from baseline data has been reported.	Baseline, Week 48
Secondary	Percentage of Participants With Treatment-Emergent Adverse Events (AEs)	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an 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); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. Treatment-emergent adverse event (TEAE) was defined as an adverse event that occurred or worsened in the period extending from first dose of study drug to 6 weeks after the last dose of study drug. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'.	Baseline up to Week 54

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