L-Citrulline Dose Finding Safety Study in MELAS

• ClinicalTrials.gov Identifier: NCT03952234
• Recruitment Status: Recruiting
• First Posted: May 16, 2019
• Last Update Posted: April 26, 2021
• Sponsor: Baylor College of Medicine
• Collaborators: National Institutes of Health (NIH); University of South Florida; Columbia University
• Information provided by (Responsible Party): Fernando Scaglia, Baylor College of Medicine

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
MELAS Syndrome	Drug: L-Citrulline	Phase 1

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 24 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: L-Citrulline
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase-1, Dose Finding and Safety Study on L- Citrulline Treatment of Nitric Oxide Deficiency in MELAS
• Actual Study Start Date: April 22, 2021
• Estimated Primary Completion Date: April 2023
• Estimated Study Completion Date: April 2023

Arms and Interventions

Arm	Intervention/treatment
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: L-Citrulline; 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; Other Name: L-Citrulline powder

Outcome Measures

Primary Outcome Measures :

1. Establishment of the maximum tolerable dose of L-citrulline in patients with MELAS syndrome by measuring the incidence of dose limiting toxicities (DLTs) [ Time Frame: Eight weeks ]

   Measurement of the incidence of treatment-emergent adverse events in a safety and tolerability phase 1 study.

   The following Dose Limiting

   Toxicities (DLTs) will be measured:

   1. Treatment-related adverse events (AE) at grade 3 or higher, or worsening of baseline status, defined by increase of at least 2 grades, if baseline grade is ≤1. The AEs will be graded based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. Subjects will be specifically monitored for the occurrence of the following adverse events:

      1. Syncope
      2. Dizziness
      3. Blurred Vision
      4. Fatigue
      5. Concentration Impairment
      6. Nausea
      7. Vomiting
      8. Diarrhea
      9. Hypoglycemia
      10. Headache
   2. 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.

Secondary Outcome Measures :

1. Changes in cerebral blood flow effected by the use of citrulline supplementation [ Time Frame: Four weeks ]
   Changes in cerebral blood flow by using arterial spin-labeling (ASL) magnetic resonance imaging (MRI) will be measured in milliliters per 100 grams of tissue per minute at four weeks while on citrulline and compared to measurement at baseline in milliliters per 100 grams of tissue per minute before the use of citrulline
2. Changes in cerebrovascular reactivity effected by the use of citrulline supplementation [ Time Frame: Four weeks ]
   Changes in cerebrovascular reactivity by using arterial spin-labeling (ASL) magnetic resonance imaging (MRI) will be measured in milliliters per 100 grams of tissue per minute at four weeks while on citrulline and compared to measurement in milliliters per 100 grams of tissue per minute at baseline before use of citrulline
3. Changes effected by the use of citrulline supplementation in the micromolar concentration of plasma amino acids citrulline, arginine, ornithine, and alanine levels. [ Time Frame: Four weeks ]
   Concentrations of plasma citrulline, arginine, ornithine, and alanine will be measured at baseline before citrulline supplementation and at four weeks during citrulline supplementation to determine the changes in concentration in micromoles per liter
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) [ Time Frame: Four weeks ]
   Concentrations of plasma lactate and plasma alanine will be measured at baseline before citrulline supplementation and at four weeks during citrulline supplementation to determine the change in concentration in micromoles per liter in plasma alanine and in millimoles per liter in plasma lactate
5. Changes effected by the use of citrulline in the concentration of plasma guanidino compounds [ Time Frame: One week ]
   Concentration of plasma guanidino compounds will be measured at baseline before citrulline supplementation and at one week during citrulline supplementation by using untargeted metabolomics profiling and values will be expressed in Z scores

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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). -

Contacts and Locations

Contacts

Contact: MAY ALI; +1 832-822-1630; maali@bcm.edu

Contact: DIANNE BAURI, N.P.; +1 832-824-6225; dianne.bauri@bcm.edu

Locations

United States, Texas

Baylor St. Luke'S Medical Center; Recruiting

Houston, Texas, United States, 77030

Contact: FERNANDO SCAGLIA, M.D. 832-822-4280 fscaglia@bcm.edu

Contact: Claudia soler, M.D. +1 832-822-4280 claudia.soler-alfonso@bcm.edu

Principal Investigator: FERNANDO SCAGLIA, M.D.

Sub-Investigator: CLAUDIA SOLER, M.D.

Sub-Investigator: STEPHEN KRALIK, M.D.

Sub-Investigator: DIANNE BAURI, N.P.

Sub-Investigator: SAIMA ALI, N.P

Sponsors and Collaborators

Baylor College of Medicine

National Institutes of Health (NIH)

University of South Florida

Columbia University

Investigators

• Principal Investigator: FERNANDO SCAGLIA, M.D; Baylor College of Medicine

More Information

Additional Information:

L-citrulline and Metformin in Duchenne's Muscular Dystrophy 

Publications:

El-Hattab AW, Emrick LT, Hsu JW, Chanprasert S, Almannai M, Craigen WJ, Jahoor F, Scaglia F. Impaired nitric oxide production in children with MELAS syndrome and the effect of arginine and citrulline supplementation. Mol Genet Metab. 2016 Apr;117(4):407-12. doi: 10.1016/j.ymgme.2016.01.010. Epub 2016 Jan 27.

El-Hattab AW, Almannai M, Scaglia F. MELAS. 2001 Feb 27 [updated 2018 Nov 29]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Mirzaa GM, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from http://www.ncbi.nlm.nih.gov/books/NBK1233/

El-Hattab AW, Almannai M, Scaglia F. Arginine and citrulline for the treatment of MELAS syndrome. J Inborn Errors Metab Screen. 2017 Jan;5. doi: 10.1177/2326409817697399. Epub 2017 Mar 24.

El-Hattab AW, Emrick LT, Williamson KC, Craigen WJ, Scaglia F. The effect of citrulline and arginine supplementation on lactic acidemia in MELAS syndrome. Meta Gene. 2013 Oct 15;1:8-14. doi: 10.1016/j.mgene.2013.09.001. eCollection 2013 Dec.

Scaglia F, Northrop JL. The mitochondrial myopathy encephalopathy, lactic acidosis with stroke-like episodes (MELAS) syndrome: a review of treatment options. CNS Drugs. 2006;20(6):443-64. Review. Erratum in: CNS Drugs. 2008;22(1):81.

Hirano M, Pavlakis SG. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): current concepts. J Child Neurol. 1994 Jan;9(1):4-13. Review.

Noguchi T, Yoshiura T, Hiwatashi A, Togao O, Yamashita K, Nagao E, Shono T, Mizoguchi M, Nagata S, Sasaki T, Suzuki SO, Iwaki T, Kobayashi K, Mihara F, Honda H. Perfusion imaging of brain tumors using arterial spin-labeling: correlation with histopathologic vascular density. AJNR Am J Neuroradiol. 2008 Apr;29(4):688-93. doi: 10.3174/ajnr.A0903. Epub 2008 Jan 9.

• Responsible Party: Fernando Scaglia, Professor, Baylor College of Medicine
• ClinicalTrials.gov Identifier: NCT03952234
• Other Study ID Numbers: H-43576
• First Posted: May 16, 2019
• Last Update Posted: April 26, 2021
• Last Verified: April 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Fernando Scaglia, Baylor College of Medicine:

Mitochondrial; Encephalomyopathy; Metabolic strokes; Stroke-like episodes; Citrulline; Nitric Oxide

Additional relevant MeSH terms:

MELAS Syndrome; Mitochondrial Encephalomyopathies; Mitochondrial Myopathies; Muscular Diseases; Musculoskeletal Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Cerebral Small Vessel Diseases; Cerebrovascular Disorders; Neuromuscular Diseases; Vascular Diseases; Cardiovascular Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Mitochondrial Diseases