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Ataluren for Nonsense Mutation Methylmalonic Acidemia

This study has suspended participant recruitment.
Genzyme, a Sanofi Company
Information provided by:
PTC Therapeutics Identifier:
First received: June 7, 2010
Last updated: October 31, 2011
Last verified: October 2011
Methylmalonic acidemia is a rare genetic disorder caused by mutations in the gene for mitochondrial enzyme methylmalonyl-CoA mutase (MCM) or in one of the genes for adenosylcobalamin (AdoCbl). Lack of these proteins causes toxic elevations of methylmalonic acid (MMacid) in blood, urine, and other tissues. A specific type of mutation, called a nonsense (premature stop codon) mutation, is the cause of the disease in approximately 5 to 20% of patients with mutations in the MCM gene, and approximately 20 to >50% of patients with mutations in one of the AdoCbl genes. Ataluren (PTC124) is an orally delivered, investigational drug that acts to overcome the effects of the premature stop codon, potentially enabling the production of functional MCM/AdoCbl. This study is a Phase 2a trial evaluating the safety and activity of ataluren in patients with methylmalonic acidemia due to a nonsense mutation. The main purpose of this study is to understand whether ataluren can safely decrease MMacid levels.

Condition Intervention Phase
Amino Acid Metabolism, Inborn Errors
Drug: Ataluren (PTC124)
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 2 Study of Ataluren (PTC124®) as an Oral Treatment for Nonsense Mutation Methylmalonic Acidemia

Resource links provided by NLM:

Further study details as provided by PTC Therapeutics:

Primary Outcome Measures:
  • Change in plasma MMacid levels [ Time Frame: Baseline and 4 weeks in each cycle ]

Secondary Outcome Measures:
  • Change in urinary MMacid levels [ Time Frame: Baseline and 4 weeks in each cycle ]
  • Effects of ataluren (PTC124) on additional markers of disease activity [ Time Frame: Baseline and 4 weeks in each cycle ]
  • Safety profile of ataluren (PTC124) as assessed by adverse events and laboratory data [ Time Frame: Baseline and 4 weeks in each cycle ]
  • Compliance with study drug administration [ Time Frame: Baseline and 4 weeks in each cycle ]
  • Ataluren (PTC124) plasma exposure [ Time Frame: Baseline and 4 weeks in each cycle ]

Estimated Enrollment: 24
Study Start Date: June 2010
Estimated Study Completion Date: October 2012
Estimated Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Ataluren (PTC124) Drug: Ataluren (PTC124)
Ataluren (PTC124) will be provided as a vanilla-flavored powder to be mixed with water. Ataluren (PTC124) will be taken 3 times per day, with dosing based on the patient's body weight. Ataluren (PTC124) will be taken at two different dose levels. In Cycle 1, the dose level is 5 mg/kg in the morning, 5 mg/kg at midday, and 10 mg/kg in the evening for 28 days. In Cycle 2, the dose level is 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for 28 days.

Detailed Description:
In this study, patients with methylmalonic acidemia due to a nonsense mutation will be administered an investigational drug called ataluren (PTC124). Evaluation procedures to determine if a patient qualifies for the study will be performed within 14 days prior to the start of drug administration. Eligible patients who elect to enroll in the study will then participate in 2 drug administration and follow-up periods. Within the first period, ataluren (PTC124) 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 approximately 21 days without ataluren (PTC124). Within the second period, ataluren (PTC124) 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 approximately 14 days without ataluren (PTC124). During the study, ataluren (PTC124) activity, safety, and pharmacokinetics will be evaluated, and MMacid levels in blood and urine will be measured periodically.

Ages Eligible for Study:   2 Years and older   (Child, Adult, Senior)
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 MMA based on the presence of characteristic clinical symptoms or signs and an elevated plasma MMacid level (>0.27 μmol/L)
  • Presence of a nonsense mutation in at least 1 allele of the mut, cblA, or cblB gene
  • Glomerular filtration rate ≥30 mL/min/1.73 m², serum aminotransferase values ≤2.5 x the upper limit of normal, serum bilirubin ≤1.5 x the upper limit of normal, plasma 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 methylmalonic acidemia 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01141075

ZNA Queen Paola Child Hospital and Provincial Centre for Metabolic Disorders
Antwerp, Belgium
Hôpital Edouard Herriot
Lyon, France
Necker-Enfants Malades Hospital
Paris, France
University Children's Hospital
Duesseldorf, Germany
Istituti Clinici di Perfezionamento, Milano
Milan, Italy
Federico II University
Naples, Italy
University Hospital, Department of Pediatrics
Padova, Italy
University Children's Hospital
Zürich, Switzerland
United Kingdom
Great Ormand Street Hospital
London, United Kingdom
Sponsors and Collaborators
PTC Therapeutics
Genzyme, a Sanofi Company
Study Director: Jay Barth, MD PTC Therapeutics