- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01141075
Ataluren for Nonsense Mutation Methylmalonic Acidemia
A Phase 2 Study of Ataluren (PTC124®) as an Oral Treatment for Nonsense Mutation Methylmalonic Acidemia
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
-
Antwerp, Belgium
- ZNA Queen Paola Child Hospital and Provincial Centre for Metabolic Disorders
-
-
-
-
-
Lyon, France
- Hôpital Edouard Herriot
-
Paris, France
- Necker-Enfants Malades Hospital
-
-
-
-
-
Duesseldorf, Germany
- University Children's Hospital
-
-
-
-
-
Milan, Italy
- Istituti Clinici di Perfezionamento, Milano
-
Naples, Italy
- Federico II University
-
Padova, Italy
- University Hospital, Department of Pediatrics
-
-
-
-
-
Zürich, Switzerland
- University Children's Hospital
-
-
-
-
-
London, United Kingdom
- Great Ormand Street Hospital
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Major Inclusion Criteria:
- Ability to provide written informed consent (parental/guardian consent if applicable)/assent (if applicable)
- Age ≥2 years
- Phenotypic evidence of methylmalonic acidemia (MMA) based on the presence of characteristic clinical symptoms or signs and an elevated plasma MMacid level (>0.27 micromole/liter (umol/L)
- Presence of a nonsense mutation in at least 1 allele of the mutase (mut), Cobalamin A (cblA), or Cobalamin B (cblB) gene
- Glomerular filtration rate ≥30 milliliters (mL)/minutes/1.73 meters squared (m^2), serum aminotransferase values ≤2.5*the upper limit of normal, serum bilirubin ≤1.5*the upper limit of normal, plasma adrenocorticotropic (ACTH) within normal limits
- Willingness and ability to comply with scheduled visits, drug administration plan, study restrictions, and study procedures
Major Exclusion Criteria:
- Known hypersensitivity to any of the ingredients or excipients of the study drug
- Any change in chronic treatment for MMA within 2 months prior to start of screening laboratory assessments
- Episode of metabolic decompensation within 1 month prior to start of Screening laboratory assessments
- History of organ transplantation
- Ongoing dialysis for renal dysfunction
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: NA
- Interventional Model: SINGLE_GROUP
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
EXPERIMENTAL: Ataluren
Cycle 1: Ataluren treatment will be taken 3 times per day with meals for 28 days at doses of 5 mg/kg (morning), 5 mg/kg (midday), and 10 mg/kg (evening); there will then be an interval of 21 up to 42 days without treatment. Cycle 2: Ataluren treatment will be taken 3 times per day with meals for 28 days at doses of 10 mg/kg (morning), 10 mg/kg (midday), and 20 mg/kg (evening); there will then be an interval of 14 days without treatment. |
Ataluren will be provided as a vanilla-flavored powder to be mixed with water.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Plasma Methylmalonic Acid (MMacid) Levels
Time Frame: Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
|
Normal plasma MMacid level is <0.27 micromole/liters (umol/L).
Plasma samples for MMacid levels were collected after a 2- to 4-hour fast.
Plasma MMacid levels were measured by a standard gas chromatography/mass spectroscopy (GC/MS) stable-isotope dilution method.
Individual participant values in plasma MMacid levels at Baseline and end-to-treatment (Day 28 and Day 29 [last day of dosing]) in each cycle were recorded.
|
Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Urinary MMacid Levels
Time Frame: Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
|
The normal urinary MMacid level is <4 millimole/mole (mmol/mol) creatinine.
Urinary samples for MMacid levels were collected after a 2- to 4-hour fast.
Urinary MMacid levels were measured by a standard GC/MS stable-isotope dilution method.
|
Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
|
Plasma Propionylcarnitine Levels
Time Frame: Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
|
Plasma samples for propionylcarnitine levels were evaluated to detect disease activity.
The level of propionylcarnitine was measured using gas chromatography and LC/MS-MS.
An increase in propionylcarnitine values indicates greater disease activity.
|
Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
|
Urine Methylcitric Acid Levels
Time Frame: Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
|
Urine methylcitric acid levels were evaluated to detect disease activity.
An increase in methylcitric acid values indicates greater disease activity.
|
Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
|
Number of Participants With Adverse Events (AEs)
Time Frame: Baseline up to Day 112 (end of study follow-up)
|
An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug.
Severity was rated by the Investigator on a scale of mild, moderate and severe, with severe as an AE that prevents usual activities.
Relationship of AE to treatment was determined by the Investigator.
Serious AEs include 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 the participant and required medical intervention to prevent the previously listed serious outcomes.
A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
|
Baseline up to Day 112 (end of study follow-up)
|
Number of Participants With Potentially Clinically Significant Laboratory (Hematology and Biochemistry) Abnormal Results
Time Frame: Baseline up to Day 112 (end of study follow-up)
|
Hematological and biochemistry data graded according to Common Terminology Criteria for Adverse Events (CTCAE) severity grade (Grade 1 [mild], Grade 2 [moderate], Grade 3 [severe], Grade 4 [life-threatening], or Grade 5 [fatal]).
Life-threatening (Grade 4) or severe (Grade 3) laboratory abnormalities were considered clinically significant.
Recurrent or persistent moderate (Grade 2) abnormalities were also considered clinically significant in certain circumstances.
Hematology assessments: white blood cell count with differential, hemoglobin, hematocrit, other red cell parameters, and platelet count.
Biochemistry assessments: sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, magnesium, calcium, phosphorus, uric acid, glucose, total protein, albumin, bilirubin (direct and indirect), aspartate aminotransferase, alanine aminotransferase, glutamyl transferase, creatine kinase, lactate dehydrogenase, alkaline phosphatase, total cholesterol, and triglycerides.
|
Baseline up to Day 112 (end of study follow-up)
|
Number of Participants With a Metabolic Decompensation Episode
Time Frame: Baseline up to Day 112 (end of study follow-up)
|
A metabolic decompensation episode is characterized by vomiting, hypotonia, and alteration of consciousness associated with metabolic acidosis and hyperammonemia.
|
Baseline up to Day 112 (end of study follow-up)
|
Number of Participants Compliant With Study Treatment
Time Frame: Baseline up to Day 29 of Cycles 1 and 2
|
For each participant, compliance was described in terms of the proportion of drug actually taken relative to the amount that should have been taken during the time the participant was on study (both Cycle 1 and Cycle 2).
|
Baseline up to Day 29 of Cycles 1 and 2
|
Ataluren Plasma Exposure
Time Frame: Baseline on Day 0 of Cycles 1 and 2 [0 (predose), 1, 2, 3, and 4 hours postdose of the morning dose and 0 (predose) of the midday dose]; Day 28 of Cycles 1 and 2 [0 (predose), 1, 2, 3, and 4 hours postdose of the morning, midday, and evening doses]
|
Validated quantitative methods employing high performance liquid chromatography with tandem mass spectroscopy (HPLC-MS-MS) were used to determine plasma concentrations of unchanged ataluren.
The median and full range of the total of all of the ataluren plasma concentrations collected at Baseline and at Day 28 are reported.
|
Baseline on Day 0 of Cycles 1 and 2 [0 (predose), 1, 2, 3, and 4 hours postdose of the morning dose and 0 (predose) of the midday dose]; Day 28 of Cycles 1 and 2 [0 (predose), 1, 2, 3, and 4 hours postdose of the morning, midday, and evening doses]
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Study Director: Jay Barth, MD, PTC Therapeutics
Publications and helpful links
General Publications
- 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.
- 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.
Helpful Links
Study record dates
Study Major Dates
Study Start (ACTUAL)
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- PTC124-GD-012-MMA
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Amino Acid Metabolism, Inborn Errors
-
National Taiwan University HospitalCompletedAromatic L-amino Acid Decarboxylase DeficiencyTaiwan
-
National Human Genome Research Institute (NHGRI)RecruitingInborn Errors of Metabolism | Methylmalonic Acidemia | Organic AcidemiaUnited States
-
ModernaTX, Inc.RecruitingMethylmalonic AcidemiaUnited States, Spain, Canada, Netherlands, France, Australia, United Kingdom
-
LogicBio Therapeutics, IncAlexion Pharmaceuticals, Inc.TerminatedMethylmalonic AcidemiaUnited States
-
ModernaTX, Inc.RecruitingPropionic AcidemiaUnited States, Canada, United Kingdom
-
HemoShear TherapeuticsPrometrika, LLC; AllStripes Research Inc.; Genome MedicalTerminatedPropionic Acidemia | Methylmalonic AcidemiaUnited States, Canada, United Kingdom
-
HemoShear TherapeuticsTerminatedPropionic Acidemia | Methylmalonic AcidemiaUnited States, Saudi Arabia, Australia
-
King Abdullah International Medical Research CenterCompletedPropionic Acidemia | Methylmalonic AcidemiaSaudi Arabia
-
Mendel TuchmanUniversity of Colorado, Denver; Children's Hospital of Philadelphia; University... and other collaboratorsTerminatedPropionic Acidemia | Methylmalonic AcidemiaUnited States
-
ModernaTX, Inc.RecruitingPropionic AcidemiaUnited States, Spain, Netherlands, France, United Kingdom, Australia, Canada, Italy
Clinical Trials on Ataluren
-
PTC TherapeuticsCystic Fibrosis FoundationCompletedCystic FibrosisUnited States, France, Belgium, Spain, Canada, Germany, Israel, Italy, Netherlands, Sweden, United Kingdom
-
PTC TherapeuticsTerminatedNervous System Diseases | Genetic Diseases, Inborn | Genetic Diseases, X-Linked | Musculoskeletal Diseases | Muscular Diseases | Neuromuscular Diseases | Muscular Dystrophies | Muscular Disorders, Atrophic | Muscular Dystrophy, DuchenneUnited States, Spain, Korea, Republic of, Belgium, France, Canada, Australia, United Kingdom, Israel, Italy, Germany, Brazil, Bulgaria, Chile, Czechia, Poland, Sweden, Switzerland, Turkey
-
PTC TherapeuticsEnrolling by invitationDuchenne Muscular DystrophyUnited States, Canada
-
PTC TherapeuticsCompletedDuchenne Muscular DystrophyUnited States
-
PTC TherapeuticsGenzyme, a Sanofi CompanyTerminatedDuchenne Muscular DystrophyUnited States
-
PTC TherapeuticsGenzyme, a Sanofi CompanyTerminatedDuchenne Muscular Dystrophy | Becker Muscular DystrophyUnited States, Belgium, Australia, Canada, France, Germany, Israel, Italy, Spain, Sweden, United Kingdom
-
PTC TherapeuticsCompletedDuchenne Muscular DystrophyUnited States
-
PTC TherapeuticsCompletedDuchenne Muscular Dystrophy | Becker Muscular DystrophyUnited States, Germany, Spain, Sweden, Canada, Italy, Australia, Belgium, France, Israel, United Kingdom
-
PTC TherapeuticsCompletedNonsene Mutation Duchenne Muscular DystrophyUnited States
-
PTC TherapeuticsCompletedDuchenne Muscular DystrophyUnited States