L-Citrulline Dose Finding Safety Study in MELAS
关键词
抽象
描述
The human body is made of many cells and each cell contains many mitochondria. Mitochondria are called the powerhouses of the cell, because they produce the energy needed for a cell to be healthy and function the way it is meant to.
Diseases of the mitochondria affect the way the tissues and cells of the body make and use energy, and can affect almost all the different organs of the body like the brain and the muscles.
MELAS syndrome is one of the mitochondrial diseases; patients with this disease have different complications including stroke like episodes, headache, muscle weakness, fatigue, and hearing loss. One of the factors contributing to complications seen in patients with MELAS syndrome, in particular the stroke like episodes, is decreased amount of an element called nitric oxide. This element is made in the bodies from an amino acid called arginine. Amino acids are the building blocks of proteins. Proteins make the muscles in the bodies, and they are present in meat, chicken and fish.
In this study, the highest acceptable dose of an amino acid called citrulline will be established in participants who have a mitochondrial disorder. Previous research conducted by several groups including Baylor College of Medicine has determined that there is a deficiency of a compound called nitric oxide in patients affected with MELAS.
The lack of nitric oxide could cause constriction of blood vessels in the brain making it easier for these patients to have a metabolic stroke. The amino acid citrulline is a foundation for nitric oxide. In earlier studies, the investigator has found that there is more production of nitric oxide in the body when participants affected with MELAS take L-citrulline.
日期
| 最后验证: | 06/30/2020 |
| 首次提交: | 05/07/2019 |
| 提交的预估入学人数: | 05/14/2019 |
| 首次发布: | 05/15/2019 |
| 上次提交的更新: | 07/16/2020 |
| 最近更新发布: | 07/19/2020 |
| 实际学习开始日期: | 09/30/2020 |
| 预计主要完成日期: | 09/30/2022 |
| 预计完成日期: | 10/31/2022 |
状况或疾病
干预/治疗
Drug: Dose finding safety study
相
手臂组
| 臂 | 干预/治疗 |
|---|---|
| Other: Dose finding safety study In this study, the highest acceptable dose of an amino acid called citrulline will be established in people who have a mitochondrial disorder. Previous research conducted by several groups including our center at Baylor College of Medicine has determined that there is a deficiency of a compound called nitric oxide in people affected with MELAS. | Drug: Dose finding safety study To determine the safest maximum dose of L-Citrulline which could be used as a potential treatment for adults with disorder of energy metabolism called MELAS |
资格标准
| 有资格学习的年龄 | 18 Years 至 18 Years |
| 有资格学习的性别 | All |
| 接受健康志愿者 | 是 |
| 标准 | Inclusion Criteria: 1. Clinical diagnosis of MELAS (stroke‐like events, seizures, or both). 2. Subject must be aged 18 to 65 years. 3. The m.3243A>G mutation in the MTTL1 gene. 4. Elevated plasma lactate (>2.2 mmol/L) at the baseline visit. 5. Negative urine pregnancy test, if applicable. 6. Score of 26 or higher on the Montreal Cognitive Assessment (MOCA). - Exclusion Criteria: 1. Evidence of acute illness or physical disability that may interfere with their ability to undergo the study. 2. Tobacco use 3. Orthostatic hypotension defined as a decrease in systolic blood pressure of 20 mm Hg, or a decrease in diastolic blood pressure of 10 mm Hg, between one and three minutes of standing when compared with blood pressure from the sitting or supine position. 4. Presence of the following signs or symptoms in the past 12 months at grade 3 or higher based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03: hypotension, syncope, dizziness, blurred vision, fatigue, concentration impairment, nausea, vomiting, diarrhea, hypoglycemia, or headache. 5. > 2 seizures in week prior to baseline visit. 6. Hypotension defined as systolic blood pressure ≤ 90 mm Hg or diastolic blood pressure ≤ 60 mm Hg. 7. Arginine supplementation within one month prior to baseline visit. 8. Inability to travel to the study site. 9. Subjects with no evidence of neurological disease. 10. Subjects with evidence of moderate to severe renal impairment ( eGFR < 60 mL/min/1.73 m2 ). 11. Subjects with poor cognitive ability to provide consent and to understand and report hypoglycemia. 12. Unwillingness of sexually active female subjects of childbearing age to practice reliable methods of contraception. 13. Intake of drugs that increase NO synthesis, vasodilators, or amino acid supplements that cannot be stopped during the study period. 14. Positive urine pregnancy test. 15. Score of less than 26 on the Montreal Cognitive Assessment (MOCA). - |
结果
主要结果指标
1. Establishment of the maximum tolerable dose of L‐citrulline in patients with MELAS syndrome by measuring the incidence of dose limiting toxicities (DLTs) [Eight weeks]
次要成果指标
1. Changes in cerebral blood flow effected by the use of citrulline supplementation [Four weeks]
2. Changes in cerebrovascular reactivity effected by the use of citrulline supplementation [Four weeks]
3. Changes effected by the use of citrulline supplementation in the micromolar concentration of plasma amino acids citrulline, arginine, ornithine, and alanine levels. [Four weeks]
4. Changes effected by the use of citrulline in the micromolar concentration of plasma alanine and in the concentration of plasma lactate (expressed in millimole per liter) [Four weeks]
5. Changes effected by the use of citrulline in the concentration of plasma guanidino compounds [One week]
