Nitisinone (NTBC) In Different Age Groups Of Patients With Alkaptonuria
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 8
- 试验地点
- 1
- 主要终点
- Homogentisic Acid Excretion
研究概览
简要总结
Nitisinone is a potent inhibitor of the enzyme that catalyzes the formation of homogentisic acid, and should be an even more logical treatment for alkaptonuria than for tyrosinemia, for which it has been approved by the FDA.The objective of this research is to explore reported age related differences in toxicity of nitisinone and its pharmacokinetic underpinnings and to develop an optimal therapeutic requirement for a targeted population of presymptomatic patients. The additional effect of mixtures of amino acids excluding tyrosine will be explored to take advantage of protein synthesis to avoid elevations of tyrosine that would otherwise limit the optimal dosage of nitisinone. The study is designed to treat patients and find the optimal dosage of nitisinone to obtain maximal reduction in levels of homogentisic acid and maintain safe levels of tyrosine.
The long term objective in the target population of pre-symptomatic patients is the prevention of the characteristic effects on joint cartilage and tendons.
详细描述
Study procedures are designed to:
- Develop a method for nitisinone measurement via tandem mass spectrometry (MS/MS).
- Determine whether differences between adult and children could be erased by employing a dosage regimen based on m2 of body surface area as opposed to per kg of body weight, as we have found in a recent study of dichloroacetate
- Determine optimal dosage for reduction of urinary levels of homogentisic acid and minimal elevation of plasma levels of tyrosine in the target population of pre-symptomatic patients.
- Determine optimal doses of Tyrex to prevent hypertyrosinemia and allow maximal reduction in homogentisic acid.
Baseline studies will include ophthalmologic examinations, echocardiogram, X-rays of all joints, MRI of selected joints when financially plausible; history and physical examinations with emphasis on joints and tendons. Ideally MRI will be repeated at 12 month intervals thereafter. Ophthalmologic exam, x-rays of the kidneys and prostate, and echocardiogram will be repeated approximately every 12 months, depending on the age of the subject and the nitisinone dose. Patients will be seen every 3 months for the first year, then at 6 month intervals to month 36. The timing of the visits may be altered in response to modifications of nitisinone and/or Tyrex doses.
Complete or near complete elimination of homogentisic acid excretion will be sought. Optimal NTBC dosage would be judged to yield plasma concentration of tyrosine less than 1000 mmol/L with the concomitant use of tyrosine free amino acid supplement. Dosage will be escalated or reduced dependent on evidence of accumulation of nitisinone and urinary levels of HGA. The maximum initial dose of nitisinone for adult and adolescent patients will be 0.2/mg/kg/day, younger patients may require a larger dose; the standard dose in hypertyrosinemia is 1mg/kg/day, which will be tentatively used as the maximum dose for all populations.
Patients will be asked to collect first morning or 12 hour urine collections for homogentisic acid and p-hydroxyphenyllactic acids and to monitor levels of tyrosine. Accumulation will be tested for by repeated studies after 3 months of treatment. Trough levels for nitisinone will be collected prior to and 5-7 days after dose increases and/or at months 6, 12, 18, 24 and every 12 months.
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
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of alkaptonuria with documented increased excretion of homogentisic acid
- •Willing and able to provide written, signed informed consent, or age appropriate written assent and written informed consent by a legally authorized representative after the study has been explained, prior to any research-related procedures.
- •Willing and able to be seen in the UCSD Clinical Center for Research or a satellite site for the study visits
- •Possession of insurance coverage for standard of care procedures, clearly stated in the consent forms
排除标准
- •Baseline tyrosine level above 250 mmol/mL
- •Baseline serum creatinine, creatine kinase, or transaminases 2x upper limit of normal
- •Baseline anemia or thrombocytopenia
- •Current participation in another investigational medication trial.
- •Pregnant or lactating women
- •Current keratopathy, contact use or uncontrolled glaucoma
- •History myocardial infarction or arrhythmia
- •History of pulmonary insufficiency
- •Psychiatric illness that may interfere with compliance or communication
- •Current malignancy or hypertension
研究组 & 干预措施
Nitisinone
all subjects will receive open-label nitisinone
干预措施: Nitisinone (Drug)
结局指标
主要结局
Homogentisic Acid Excretion
时间窗: 3-6 months
Urine homogentisic acid (umol/mmol creatinine)
次要结局
- Tyrosine Levels(3-6 months)