A Phase 2 Study of Ataluren (PTC124®) as an Oral Treatment for Nonsense Mutation Methylmalonic Acidemia
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 11
- 试验地点
- 8
- 主要终点
- Plasma Methylmalonic Acid (MMacid) Levels
研究概览
简要总结
Methylmalonic acidemia (MMA) 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 participants with mutations in the MCM gene, and approximately 20% to >50% of participants with mutations in one of the AdoCbl genes. Ataluren 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 participants with MMA due to a nonsense mutation. The main purpose of this study is to understand whether ataluren can safely decrease MMacid levels.
详细描述
In this study, participants with MMA due to a nonsense mutation will be administered an investigational drug called ataluren. Evaluation procedures to determine if a participant qualifies for the study will be performed within 14 days prior to the start of drug administration. Eligible participants who elect to enroll in the study will then participate in 2 drug administration and follow-up periods. Within the first period, ataluren will be taken 3 times per day with meals for 28 days at doses of 5 milligrams/kilograms (mg/kg) (morning), 5 mg/kg (midday), and 10 mg/kg (evening); there will then be an interval of approximately 21 days without ataluren. Within the second period, ataluren 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. During the study, ataluren activity, safety, and pharmacokinetics will be evaluated, and MMacid levels in blood and urine will be measured periodically.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 2 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Ataluren (Drug)
结局指标
主要结局
Plasma Methylmalonic Acid (MMacid) Levels
时间窗: 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.
次要结局
- Urinary MMacid Levels(Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2)
- Plasma Propionylcarnitine Levels(Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2)
- Urine Methylcitric Acid Levels(Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2)
- Number of Participants With Adverse Events (AEs)(Baseline up to Day 112 (end of study follow-up))
- Number of Participants With Potentially Clinically Significant Laboratory (Hematology and Biochemistry) Abnormal Results(Baseline up to Day 112 (end of study follow-up))
- Number of Participants With a Metabolic Decompensation Episode(Baseline up to Day 112 (end of study follow-up))
- Number of Participants Compliant With Study Treatment(Baseline up to Day 29 of Cycles 1 and 2)
- Ataluren Plasma Exposure(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])