Ataluren for Nonsense Mutation Methylmalonic Acidemia
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ClinicalTrials.gov Identifier: NCT01141075 |
Recruitment Status :
Terminated
(Terminated due to low enrollment and unclear pharmacologic effect in available pharmacodynamic data (not due to any safety concerns).)
First Posted : June 10, 2010
Results First Posted : July 7, 2020
Last Update Posted : July 7, 2020
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Condition or disease | Intervention/treatment | Phase |
---|---|---|
Amino Acid Metabolism, Inborn Errors | Drug: Ataluren | Phase 2 |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 11 participants |
Allocation: | N/A |
Intervention Model: | Single Group Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | A Phase 2 Study of Ataluren (PTC124®) as an Oral Treatment for Nonsense Mutation Methylmalonic Acidemia |
Actual Study Start Date : | July 19, 2010 |
Actual Primary Completion Date : | November 3, 2011 |
Actual Study Completion Date : | November 3, 2011 |

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. |
Drug: Ataluren
Ataluren will be provided as a vanilla-flavored powder to be mixed with water.
Other Name: PTC124 |
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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).
- 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.

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Ages Eligible for Study: | 2 Years and older (Child, Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
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

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01141075
Belgium | |
ZNA Queen Paola Child Hospital and Provincial Centre for Metabolic Disorders | |
Antwerp, Belgium | |
France | |
Hôpital Edouard Herriot | |
Lyon, France | |
Necker-Enfants Malades Hospital | |
Paris, France | |
Germany | |
University Children's Hospital | |
Duesseldorf, Germany | |
Italy | |
Istituti Clinici di Perfezionamento, Milano | |
Milan, Italy | |
Federico II University | |
Naples, Italy | |
University Hospital, Department of Pediatrics | |
Padova, Italy | |
Switzerland | |
University Children's Hospital | |
Zürich, Switzerland | |
United Kingdom | |
Great Ormand Street Hospital | |
London, United Kingdom |
Study Director: | Jay Barth, MD | PTC Therapeutics |
Publications:
Responsible Party: | PTC Therapeutics |
ClinicalTrials.gov Identifier: | NCT01141075 |
Other Study ID Numbers: |
PTC124-GD-012-MMA |
First Posted: | June 10, 2010 Key Record Dates |
Results First Posted: | July 7, 2020 |
Last Update Posted: | July 7, 2020 |
Last Verified: | June 2020 |
Metabolism, Inborn Errors Amino Acid Metabolism, Inborn Errors Genetic Diseases, Inborn Metabolic Diseases |