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L-Citrulline Dose Finding Safety Study in MELAS

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ClinicalTrials.gov Identifier: NCT03952234
Recruitment Status : Not yet recruiting
First Posted : May 16, 2019
Last Update Posted : May 16, 2019
Sponsor:
Collaborators:
National Institutes of Health (NIH)
University of South Florida
Columbia University
Information provided by (Responsible Party):
Fernando Scaglia, Baylor College of Medicine

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
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
Estimated Study Start Date : June 2019
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : July 2021


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




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



Information from the National Library of Medicine

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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). -

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03952234


Contacts
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Contact: MAY ALI +1 832-822-1630 maali@bcm.edu
Contact: DIANNE BAURI, N.P. +1 832-824-6225 dianne.bauri@bcm.edu

Locations
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United States, Texas
Baylor St. Luke'S Medical Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Baylor College of Medicine
National Institutes of Health (NIH)
University of South Florida
Columbia University
Investigators
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Principal Investigator: FERNANDO SCAGLIA, M.D Baylor College of Medicine

Additional Information:
Publications:

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Responsible Party: Fernando Scaglia, Professor, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT03952234     History of Changes
Other Study ID Numbers: H-43576
First Posted: May 16, 2019    Key Record Dates
Last Update Posted: May 16, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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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
Nitric Oxide
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents