7416: L-Citrulline treatment of nitric oxide deficiency in MELAS: a Phase I dose-finding and safety study

Summary

The main purpose of this study is to determine the safest maximum dose of an amino acid, citrulline, which will be used as potential treatment for adult patients with a disorder of energy metabolism called Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS). Once established, this dose will be used in a future clinical trial.

For Diseases

Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS).

Background

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 our bodies from an amino acid called arginine. Amino acids are the building blocks of proteins. Proteins make the muscles in our bodies, and they are present in meat, chicken and fish.

About this 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.

The lack of nitric oxide could cause constriction of blood vessels in the brain making it easier for these people to have a metabolic stroke. The amino acid citrulline is a foundation for nitric oxide. In earlier studies, we have found that there is more production of nitric oxide in the body when people take L-citrulline.

Study Drug: The drug you will receive in this study is called oral L-citrulline. Daily dosage will be divided into 4 equal amounts and you will take the study medication 4 times as day.

Study procedures include: During the study, there will be 6 doctor visits. The baseline, week 1, week four and follow-up visit will take place at the Baylor St Luke’s Medical Center Clinical Research Center (BSLMC CRC). The week 2 and week 3 visits will take place either in your home or at the Baylor Clinic Clinical Research Center.

Renal Function Evaluation: At baseline, you will undergo a blood draw to measure blood urea, creatinine, cystatin C, and estimated glomerular filtration rate (eGFR) to determine the function of your kidneys. Approximately 1 ml of blood will be collected.

Blood Pressure Measurement: At baseline, weeks 1-4, and at the follow-up visit your blood pressure will be measured twice; once while in the lying up position and a second time while standing.

ASL MRI: At baseline and at week 4 you will undergo the Arterial Spin-Labeling (ASL) Magnetic Resonance Imaging (MRI) procedure, which is a brain imaging test that is noninvasive, requiring no intravenous contrast administration. A baseline MRI will be performed and then you be administered 1 gram acetazolamide (ACZ), a drug that crosses the blood-brain barrier and acts as a cerebral vasodilator agent, intravenously. The second MRI will take place 15 minutes after the intravenous administration of ACZ.

Urine Guanidino Compounds Measurement: At baseline and at week 1 you will provide the researchers with a urine sample for the purpose of measuring these compounds derived from citrulline.

Physician Adverse Event Assessment: At baseline, weeks 1-4, and at the follow-up visit you will be assessed by a physician to determine if you have encounter any Adverse Events (AEs) from the study drug.

Blood Draw for Blood Glucose Measurement (Venipuncture): At baseline, weeks 1-4, and at the follow-up visit you will undergo a blood draw to measure blood glucose (sugar) level. Approximately 1 ml of blood will be collected. You will be also given a sugar monitoring device (glucometer) to monitor blood sugar at home if you have symptoms of low blood sugar. The study doctor will explain to you and your caregiver how to use the glucometer.

Blood Draw for Comprehensive Metabolic Panel and a Complete Blood Count with Differential: At baseline, you will undergo a blood draw to measure a comprehensive metabolic panel (electrolytes and liver function tests). This test will also include a blood glucose measurement and therefore, there will be no separate blood sugar measurement during this visit. Approximately 2 ml of blood will be collected. Blood will also be drawn to measure a complete blood count with differential to evaluate the number of your red blood cells, white blood cells, and platelets. Approximately 1 ml of blood will be collected. 

Blood Draw for Plasma Guanidino Compounds, Plasma lactate, Renal (kidney) Function Tests, and Plasma Amino Acids (Venipuncture): At baseline and week 1 you will undergo a blood draw to measure plasma amino acids, plasma lactate, renal function tests, and plasma guanidino compounds (compounds derived from L-citrulline). Approximately six milliliters of blood will be drawn from you. Plasma lactate and plasma amino acids will be obtained also at week four. At the baseline visit, we will need to draw blood 6 times (at 0, 0.5,1,2, 4 and 6 hours). This will be done through a catheter that we will keep in your vein to draw blood from.

Seizure Diary: You will be given a seizure diary to be filled out. It will be collected from you at weeks 1-4 and at the follow-up visit. The seizure diary is a simple spreadsheet for you to record the date, time and characteristics of a seizure.

Blood Glucose Diary: You will be given a blood sugar diary to be filled out. It will be collected from you at weeks 1-4 and at the follow-up visit. The blood sugar diary is a simple spreadsheet for you to record the blood sugar values in specific times as indicated or if you experience any symptoms of having a low blood sugar, then you will record time of testing and blood sugar value.

Blood Pressure Diary: You will be given a blood pressure diary to be filled out. It will be collected from you at weeks 1-4 and at the follow-up visit. The blood pressure diary is a simple spreadsheet for you to record the blood pressure values in specific times as indicated or if you experience any symptoms of low blood pressure, then you will record time of testing and blood sugar value.

Headache Calendar: You will be given a headache diary to be filled and will be collected from you at weeks 1-4 and at the follow-up visit. The headache calendar allows for you to record the date, approximate time, severity, and frequency of headaches, as well as whether any medication was used to alleviate headache symptoms.

Gastrointestinal (GI) Diary: You will be given a GI diary to be filled and will be collected from you at weeks 1-4 and at the follow-up visit. The GI diary is a simple spreadsheet for you to record the date, time and characteristics of any GI symptoms including vomiting and diarrhea.

Neurologic Assessment: At baseline and at the follow-up visit a member of the study team will administer a neurologic assessment called “Newcastle Mitochondrial Disease Assessment Scale (NMDAS) “. This will involve some questions and physical exam. 

Weekly Monitoring: Starting 1 week after baseline, the study team will call participants to ensure blood pressure and blood sugar monitoring is being done correctly. This call may be done via phone, skype or facetime.

Target Enrollment

To be eligible to participate, you must:

1. Have a clinical diagnosis of MELAS (stroke-like events, seizures, exercise intolerance, fatigue, or any combination of these);
2. Be an adult aged 18 to 65;
3. Have the m.3243A>G mutation in MTTL1 gene
4. Have elevated lactate (>2.2 mmol/L) level in blood at the baseline visit

You are not eligible to participate if:

1. Evidence of acute illness or physical disability that may interfere with your ability to undergo the study.
2. You use tobacco.
3. You have 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, within three minutes of standing when compared with blood pressure from the sitting or supine position.
4. You have a presence of the following grade 3 Adverse Events in the past 12 months: Hypotension (low blood pressure), Syncope (loss of consciousness), Dizziness, Blurred Vision, Fatigue, Concentration impairment, Nausea, Vomiting, diarrhea, Hypoglycemia (low blood sugar), or Headache.
5. You have more than 2 seizures in the week prior to baseline visit.
6. You have hypotension defined as systolic blood pressure ≤ 90 mm Hg or diastolic blood pressure ≤ 60 mm Hg.
7. You have received arginine or citrulline supplementation one week prior to baseline visit.
8. You are unable to travel to the study site.
9. You do not have evidence of neurological or muscular disease or both.
10. You do not have evidence of moderate to severe kidney impairment (eGFR < 60 mL/min/1.73 m² ).
11. You have poor cognitive ability to provide consent and to understand and report low blood sugars. .
12. You are a sexually active female with reproductive capacity who will not practice reliable methods of contraception.
13. You are taking drugs that increase the production of nitric oxide, vasodilators, or amino acid supplements that cannot be stopped during the study period.

How to participate

In order to participate in a study, you must personally contact the study coordinator by phone or by e-mail. Please use the information to the right to ask about participation.