| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Nonsense Mutation Duchenne Muscular Dystrophy |
|
| E.1.1.1 | Medical condition in easily understood language |
| Duchenne Muscular Dystrophy |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10013801 |
| E.1.2 | Term | Duchenne muscular dystrophy |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the effect of ataluren on ambulation and endurance as assessed by the 6-minute walk test (6MWT) |
|
| E.2.2 | Secondary objectives of the trial |
• To determine the effects of ataluren on ambulation and burst activity as assessed by timed function tests
• To determine the effects of ataluren on lower-limb muscle function as assessed by the North Star Ambulatory Assessment (NSAA)
• To assess the safety profile of ataluren
Evaluate the correlation between plasma concentration of ataluren and functional outcomes
● Evaluate the plasma pharmacokinetic (PK) profile of ataluren
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
indicating that the subject (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/ethics committee (IRB/EC) regarding whether one or both
parents must provide consent and the appropriate ages for obtaining
consent and assent from the subject should be followed.
2. Male sex.
3. Age ≥5 years. When Version 3 is implemented or approximately 270
subjects have enrolled in the study, only subjects aged ≥7 to ≤16 who
meet the mITT criteria will be eligible to enroll.
4. Phenotypic evidence of DMD based on the onset of characteristic clinical symptoms or signs (eg, proximal muscle weakness, waddling
gait, and Gowers' maneuver) by 6 years of age and an elevated serum
creatine kinase (CK). Medical documentation of phenotypic evidence of
DMD needs to be provided upon request by the PTC Therapeutics medical
monitor.
5. Documentation of the presence of a nonsense point mutation in the
dystrophin gene as determined by gene sequencing. Note: Review and
approval of documentation by sponsor or designee is required prior to
enrollment.
6. Use of systemic corticosteroids (prednisone/prednisolone or
deflazacort) for a minimum of 12 months immediately prior to start of
study treatment, with no significant change in dosage or dosing regimen
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. Note: Daily, every
other day, high-dose weekend, and intermittent regimens permitted
only. The doses recommended or required are shown in Table 1.
Increases in corticosteroid dose to adjust for increases in body weight
will not exclude a subject from participation.
7. 6MWD ≥150 meters at screening, baseline Day 1, and baseline Day 2.
When Version 3 is implemented or approximately 270 subjects have enrolled
in the study, only subjects who meet the mITT criteria, 6MWD ≥ 300 meters at,
Baseline Day 1 or Day 2, and time to stand from supine ≥ 5 seconds at Baseline Day 1,
will be eligible to enroll. Note: Personal assistance or use of assistive devices for ambulation
(eg, short leg braces, long leg braces, or walkers) will not be permitted during the 6MWT.
8. Results of the two 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.
9. Baseline 6MWD (maximum of valid Day 1 and Day 2 values) must be
no more than a 20% reduction from the valid Screening 6MWD.
10. Ability to perform timed function tests (run/walk 10 meters, climb
4 stairs, descend 4 stairs, stand from supine) within 30 seconds at
screening and baseline.
11. In subjects who are sexually active, willingness to abstain from
sexual intercourse or employ a barrier or medical method of
contraception during the study drug administration and 4 week followup
period.
12. 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 (in particular, the
ability to satisfactorily perform the 6MWT) should be considered |
|
| E.4 | Principal exclusion criteria |
1. Any change (initiation, change in type of drug, dose modification, schedule modification, interruption, discontinuation, or reinitiation) in prophylaxis/treatment for cardiomyopathy within 1 month prior to start of study treatment.
2. Ongoing intravenous (IV) aminoglycoside or IV vancomycin therapy.
3. Prior or ongoing therapy with ataluren.
4. Known hypersensitivity to any of the ingredients or excipients of the study drug [eg, refined polydextrose, polyethylene glycol 3350, poloxamer 407, mannitol 25C, crospovidone XL10, hydroxyethyl cellulose, colloidal silica, magnesium stearate].
5. Exposure to another investigational drug within 6 months prior to start of study treatment, or ongoing participation in any interventional clinical trial. Note: This does not apply to patients receiving deflazacort through an expanded access program.
6. History of major surgical procedure within 12 weeks prior to start of study treatment, or expectation of major surgical procedure (eg, scoliosis surgery) during the 72-week placebo controlled treatment period.
7. Ongoing immunosuppressive therapy (other than corticosteroids).
8. Requirement for daytime ventilator assistance or any use of invasive mechanical ventilation via tracheostomy. Note: Evening non-invasive mechanical ventilation such as use of bi level positive airway pressure (Bi-PAP) therapy is allowed.
9. Uncontrolled clinical symptoms and signs of congestive heart failure (American College of Cardiology/American Heart Association Stage C or Stage D) [Hunt 2001].
10. Elevated serum creatinine or cystatin C at screening. Note: If the initial test result is abnormal, it is permissible to re-test serum creatinine or cystatin C and randomize the subject if the re test result is normal.
11. Positive for hepatitis B core antibody or hepatitis C antibody at screening.
12. Prior or ongoing medical condition (eg, concomitant illness, psychiatric condition, behavioral disorder, alcoholism, drug abuse), medical history, physical findings (eg, lower-limb injury that may affect 6MWT performance), ECG findings, or laboratory abnormality that, in the investigator’s opinion, could adversely affect the safety of the subject, makes it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of this study is slope of change in 6-minute walk distance (6MWD) over 72 weeks. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Screening, every 12 weeks for double-blind period, every 24 weeks for open-label period |
|
| E.5.2 | Secondary end point(s) |
Double-Blind Treatment Period:
• Change from baseline to Week 72 in 6MWD
• Composite of average change in times to run/walk 10 meters, climb 4 stairs, and descend 4 stairs at Week 72
• Change from baseline to Week 72 in time to run/walk 10 meters
• Change from baseline to Week 72 in time to climb 4 stairs
• Change from baseline to Week 72 in time to descend 4 stairs
• Change from baseline to Week 72 in NSAA total score
• Time to loss of ambulation over 72 weeks
• Time to loss of stair-climbing over 72 weeks
• Time to loss of stair-descending over 72 weeks
• Risk of loss of NSAA items over 72 weeks
• Ataluren safety profile characterized by type, frequency, severity, and relationship to study drug of any adverse events (AEs), or of abnormalities of laboratory tests, vital signs, physical examinations, or electrocardiograms (ECGs)
Open-Label Treatment Period:
• Slope of change in 6MWD over 144 weeks
• Change from baseline to Week 144 in 6MWD
• Composite of average change in times to run/walk 10 meters, climb 4 stairs, and descend 4 stairs at Week 144
• Change from baseline to Week 144 in time to run/walk 10 meters
• Change from baseline to Week 144 in time to climb 4 stairs
• Change from baseline to Week 144 in time to descend 4 stairs
• Change from baseline to Week 144 in NSAA total score
• Time to loss of ambulation over 144 weeks
• Time to loss of stair-climbing over 144 weeks
• Time to loss of stair-descending over 144 weeks
• Risk of loss of NSAA items over 144 weeks
• Ataluren safety profile characterized by type, frequency, severity, and relationship to study drug of any AEs, or of abnormalities of laboratory tests, vital signs, physical examinations, or ECGs
Plasma PK at pre-morning dose and 2 hours post-morning dose at Week 144
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Screening, every 12 weeks for double-blind period, every 24 weeks for open-label period |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Brazil |
| Bulgaria |
| Canada |
| China |
| Hong Kong |
| India |
| Japan |
| Korea, Republic of |
| Malaysia |
| Mexico |
| Poland |
| Russian Federation |
| Taiwan |
| Thailand |
| Turkey |
| United States |
| Jordan |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 25 |
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