A Study to Assess Dystrophin Levels in Participants With Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)
Study Details
Study Description
Brief Summary
This study is designed to evaluate the ability of ataluren to increase dystrophin protein levels in muscle cells of participants with nmDMD. The study will evaluate the levels of dystrophin before and after 40 weeks of ataluren therapy using muscle biopsies and 2 validated assay methods, electrochemiluminescence (ECL) and immunohistochemistry.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Ataluren Participants will receive ataluren oral suspension 10 milligrams per kilogram (mg/kg) in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening each day for 40 weeks. |
Drug: Ataluren
Ataluren will be administered as per the dose and schedule specified in the arm.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Percent Change From Baseline in Dystrophin Level at Week 40, as Measured by ECL [Baseline, Week 40]
The percent change in dystrophin level from baseline in ambulatory nonsense mutation duchenne muscular dystrophy (nmDMD) participants after treatment with ataluren for 40 weeks was analyzed using quantitative assay (ECL).The least square (LS) mean and 90% confidence interval (CI) were analyzed from a mixed-model repeated measures (MMRM) with factors of muscle locations and visits as fixed effects, and participants as a random effect.
Secondary Outcome Measures
- Percent Change From Baseline in Dystrophin Level at Week 40, as Determined by Immunohistochemistry (IHC) Membrane Stain Density [Baseline, Week 40]
The percent change in dystrophin level from baseline in ambulatory nmDMD participants after 40 weeks of ataluren therapy was determined by IHC membrane stain density. The LS mean and 90% CI were analyzed from an MMRM with factors of muscle locations and visits as fixed effects, and participants as a random effect.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
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.
-
Phenotypic evidence of duchenne muscular dystrophy (DMD) based on the onset of characteristic clinical symptoms or signs (for example, proximal muscle weakness, waddling gait, and Gowers' maneuver) and an elevated serum creatine kinase (CK). Medical documentation of phenotypic evidence of DMD needs to be provided upon request by the Sponsor's medical monitor.
-
Documentation of the presence of a nonsense point mutation in the dystrophin gene as determined by gene sequencing. Review and approval of documentation by sponsor or designee is required prior to enrollment.
-
Willing to undergo muscle biopsy.
Exclusion Criteria:
-
Ongoing intravenous (IV) aminoglycoside or IV vancomycin therapy.
-
Known contra-indication to muscle biopsy (such as bleeding or clotting disorders).
-
Prior or ongoing therapy with ataluren.
-
Known hypersensitivity to any of the ingredients or excipients of the study drug (for example, refined polydextrose, polyethylene glycol 3350, poloxamer 407, mannitol 25C, crospovidone XL10, hydroxyethyl cellulose, colloidal silica, magnesium stearate).
-
Exposure to another investigational drug within 2 months prior to start of study treatment, or ongoing participation in any interventional clinical trial.
-
Requirement for daytime ventilator assistance or any use of invasive mechanical ventilation via tracheostomy. Evening non-invasive mechanical ventilation such as use of bilevel positive airway pressure (Bi-PAP) therapy is allowed.
-
Elevated serum creatinine or cystatin C levels at screening.
-
Prior or ongoing medical condition (for example, concomitant illness, psychiatric condition, behavioral disorder), medical history, physical 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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Phoenix Childrens Hospital | Phoenix | Arizona | United States | 85016 |
| 2 | University of California, Los Angeles (UCLA) | Los Angeles | California | United States | 90025 |
| 3 | University of California (UC) Davis Medical Center | Sacramento | California | United States | 95817 |
| 4 | University of Kansas Medical Center | Kansas City | Kansas | United States | 66160 |
| 5 | University of Minnesota | Minneapolis | Minnesota | United States | 55455 |
| 6 | Columbia University College of Physicians & Surgeons | New York | New York | United States | 10032 |
| 7 | Texas Children's Hospital | Houston | Texas | United States | 77030 |
| 8 | University of Texas Heath Science Center at San Antonio | San Antonio | Texas | United States | 78229-3900 |
| 9 | Children's Hospital of the King's Daughters | Norfolk | Virginia | United States | 23507 |
Sponsors and Collaborators
- PTC Therapeutics
Investigators
- Study Director: Francesco Bibbiani, MD, PTC Therapeutics, Inc.
Study Documents (Full-Text)
More Information
Publications
None provided.- PTC124-GD-045-DMD
- 2019-001767-67
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Ataluren |
|---|---|
| Arm/Group Description | Participants received ataluren oral suspension 10 milligrams per kilogram (mg/kg) in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening each day for 40 weeks. |
| Period Title: Overall Study | |
| STARTED | 20 |
| Received at Least 1 Dose of Study Drug | 20 |
| COMPLETED | 20 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | Ataluren |
|---|---|
| Arm/Group Description | Participants received ataluren oral suspension 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening each day for 40 weeks. |
| Overall Participants | 20 |
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
4.8
(1.77)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
0
0%
|
| Male |
20
100%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |
| Hispanic or Latino |
5
25%
|
| Not Hispanic or Latino |
15
75%
|
| Unknown or Not Reported |
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
0
0%
|
| Asian |
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
| Black or African American |
2
10%
|
| White |
17
85%
|
| More than one race |
1
5%
|
| Unknown or Not Reported |
0
0%
|
Outcome Measures
| Title | Percent Change From Baseline in Dystrophin Level at Week 40, as Measured by ECL |
|---|---|
| Description | The percent change in dystrophin level from baseline in ambulatory nonsense mutation duchenne muscular dystrophy (nmDMD) participants after treatment with ataluren for 40 weeks was analyzed using quantitative assay (ECL).The least square (LS) mean and 90% confidence interval (CI) were analyzed from a mixed-model repeated measures (MMRM) with factors of muscle locations and visits as fixed effects, and participants as a random effect. |
| Time Frame | Baseline, Week 40 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population included all enrolled participants with a valid assessment of dystrophin level at baseline, as measured by ECL. |
| Arm/Group Title | Ataluren |
|---|---|
| Arm/Group Description | Participants received ataluren oral suspension 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening each day for 40 weeks. |
| Measure Participants | 20 |
| Least Squares Mean (90% Confidence Interval) [percent change] |
6.559
|
| Title | Percent Change From Baseline in Dystrophin Level at Week 40, as Determined by Immunohistochemistry (IHC) Membrane Stain Density |
|---|---|
| Description | The percent change in dystrophin level from baseline in ambulatory nmDMD participants after 40 weeks of ataluren therapy was determined by IHC membrane stain density. The LS mean and 90% CI were analyzed from an MMRM with factors of muscle locations and visits as fixed effects, and participants as a random effect. |
| Time Frame | Baseline, Week 40 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population included all enrolled participants with a valid assessment of dystrophin level at baseline, as measured by ECL. |
| Arm/Group Title | Ataluren |
|---|---|
| Arm/Group Description | Participants received ataluren oral suspension 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening each day for 40 weeks. |
| Measure Participants | 20 |
| Least Squares Mean (90% Confidence Interval) [percent change] |
4.914
|
Adverse Events
| Time Frame | Baseline up to Week 40 | |
|---|---|---|
| Adverse Event Reporting Description | Safety Population included all participants who received at least 1 dose of ataluren. | |
| Arm/Group Title | Ataluren | |
| Arm/Group Description | Participants received ataluren oral suspension 10 milligrams per kilogram (mg/kg) in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening each day for 40 weeks. | |
All Cause Mortality |
||
| Ataluren | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/20 (0%) | |
Serious Adverse Events |
||
| Ataluren | ||
| Affected / at Risk (%) | # Events | |
| Total | 2/20 (10%) | |
| Infections and infestations | ||
| COVID-19 | 1/20 (5%) | |
| Injury, poisoning and procedural complications | ||
| Femur fracture | 1/20 (5%) | |
Other (Not Including Serious) Adverse Events |
||
| Ataluren | ||
| Affected / at Risk (%) | # Events | |
| Total | 18/20 (90%) | |
| Gastrointestinal disorders | ||
| Diarrhoea | 6/20 (30%) | |
| Vomiting | 3/20 (15%) | |
| Abdominal pain | 2/20 (10%) | |
| Abdominal pain upper | 1/20 (5%) | |
| Constipation | 1/20 (5%) | |
| Dyspepsia | 1/20 (5%) | |
| Gastrooesophageal reflux disease | 1/20 (5%) | |
| General disorders | ||
| Pyrexia | 2/20 (10%) | |
| Gait inability | 1/20 (5%) | |
| Oedema peripheral | 1/20 (5%) | |
| Infections and infestations | ||
| Ear infection | 2/20 (10%) | |
| Nasopharyngitis | 2/20 (10%) | |
| Upper respiratory tract infection | 2/20 (10%) | |
| COVID-19 | 1/20 (5%) | |
| Conjunctivitis bacterial | 1/20 (5%) | |
| Gastroenteritis | 1/20 (5%) | |
| Influenza | 1/20 (5%) | |
| Pharyngitis streptococcal | 1/20 (5%) | |
| Pneumonia bacterial | 1/20 (5%) | |
| Sinusitis | 1/20 (5%) | |
| Viral upper respiratory tract infection | 1/20 (5%) | |
| Injury, poisoning and procedural complications | ||
| Procedural pain | 6/20 (30%) | |
| Post procedural haemorrhage | 3/20 (15%) | |
| Femur fracture | 1/20 (5%) | |
| Investigations | ||
| Urine output increased | 1/20 (5%) | |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 1/20 (5%) | |
| Musculoskeletal and connective tissue disorders | ||
| Muscle spasms | 1/20 (5%) | |
| Pain in extremity | 1/20 (5%) | |
| Nervous system disorders | ||
| Headache | 1/20 (5%) | |
| Psychiatric disorders | ||
| Aggression | 1/20 (5%) | |
| Behaviour disorder | 1/20 (5%) | |
| Sleep disorder | 1/20 (5%) | |
| Renal and urinary disorders | ||
| Pollakiuria | 1/20 (5%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Cough | 2/20 (10%) | |
| Skin and subcutaneous tissue disorders | ||
| Rash | 2/20 (10%) | |
| Miliaria | 1/20 (5%) | |
| Rash pruritic | 1/20 (5%) | |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The Sponsor can review results and/or communications prior to public release and can embargo communications regarding trial results for a period that is up to 180 days from the time submitted to the sponsor for review. The sponsor may consult with the PI to require changes to the communication or extend the embargo.
Results Point of Contact
| Name/Title | Medical Information |
|---|---|
| Organization | PTC Therapeutics, Inc. |
| Phone | 1-866-562-4620 |
| medinfo@ptcbio.com |
- PTC124-GD-045-DMD
- 2019-001767-67