L-Citrulline Dose Finding Safety Study in MELAS

NCT03952234 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: H-43576U54NS078059
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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.

Conditions

MELAS Syndrome

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Establishment of the maximum tolerable dose of L-citrulline in patients with MELAS syndrome by measuring the incidence of dose limiting toxicities (DLTs)

  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.

  Eight weeks

Secondary Outcomes (5)

• Changes in cerebral blood flow effected by the use of citrulline supplementation

  Four weeks

• Changes in cerebrovascular reactivity effected by the use of citrulline supplementation

  Four weeks

• Changes effected by the use of citrulline supplementation in the micromolar concentration of plasma amino acids citrulline, arginine, ornithine, and alanine levels.

  Four weeks

• 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

• Changes effected by the use of citrulline in the concentration of plasma guanidino compounds

  One week

Study Arms (1)

Dose finding safety study

OTHER

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

Interventions

L-Citrulline DRUG

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

Also known as: L-Citrulline powder

Dose finding safety study

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Clinical diagnosis of MELAS (stroke-like events, seizures, exercise intolerance or muscle weakness).
• Subject must be aged 18 to 65 years.
• The m.3243A\>G mutation in the MTTL1 gene.
• Elevated plasma lactate (\>2.2 mmol/L) taken at any point in the screening period (6 months prior to screening visit, including and up to the baseline visit).
• Negative urine pregnancy test, if applicable.
• Score of 26 or higher on the Montreal Cognitive Assessment (MOCA). -

You may not qualify if:

• Evidence of acute illness or physical disability that may interfere with their ability to undergo the study.
• Tobacco use
• 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 at the baseline visit.
• 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.
• \> 2 seizures in week prior to baseline visit.
• Hypotension defined as systolic blood pressure ≤ 90 mm Hg or diastolic blood pressure ≤ 60 mm Hg at the baseline visit.
• Arginine supplementation within one week prior to baseline visit.
• Inability to travel to the study site.
• Subjects with no evidence of neurological disease, muscle weakness, or exercise intolerance.
• Subjects with evidence of moderate to severe renal impairment ( eGFR \< 60 mL/min/1.73 m2 ) at the baseline visit.
• Subjects with poor cognitive ability to provide consent and to understand and report hypoglycemia.
• Unwillingness of sexually active female subjects of childbearing age to practice reliable methods of contraception.
• Intake of drugs that increase NO synthesis, vasodilators, or amino acid supplements that cannot be stopped during the study period.
• Positive urine pregnancy test.
• Score of less than 26 on the Montreal Cognitive Assessment (MOCA). -

Sponsors & Collaborators

• Baylor College of Medicine: lead
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator
• University of South Florida: collaborator
• Columbia University: collaborator

Study Sites (1)

Baylor St. Luke'S Medical Center

Houston, Texas, 77030, United States

Location

Related Publications (7)

• 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.

  PMID: 26851065 BACKGROUND

• El-Hattab AW, Almannai M, Scaglia F. MELAS. 2001 Feb 27 [updated 2018 Nov 29]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK1233/

  PMID: 20301411 BACKGROUND

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

  PMID: 28736735 BACKGROUND

• 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.

  PMID: 25411654 BACKGROUND

• 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. doi: 10.2165/00023210-200620060-00002.

  PMID: 16734497 BACKGROUND

• Hirano M, Pavlakis SG. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): current concepts. J Child Neurol. 1994 Jan;9(1):4-13. doi: 10.1177/088307389400900102.

  PMID: 8151079 BACKGROUND

• 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.

  PMID: 18184842 BACKGROUND

Related Links

• L-citrulline and Metformin in Duchenne's Muscular Dystrophy

MeSH Terms

Conditions

MELAS Syndrome

Interventions

Citrulline

Condition Hierarchy (Ancestors)

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; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; Mitochondrial Diseases

Intervention Hierarchy (Ancestors)

Amino Acids, Diamino; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• FERNANDO SCAGLIA, M.D

  Baylor College of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: L-Citrulline

Study Record Dates

• First Submitted: May 8, 2019
• First Posted: May 16, 2019
• Study Start: April 22, 2021
• Primary Completion: April 30, 2024
• Study Completion: June 1, 2024
• Last Updated: June 26, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)