Back to resultsL-Citrulline Dose Finding Safety Study in MELAS
Primary Purpose
MELAS Syndrome
Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
L-Citrulline
Sponsored by
About this trial
This is an interventional treatment trial for MELAS Syndrome focused on measuring Mitochondrial, Encephalomyopathy, Metabolic strokes, Stroke-like episodes, Citrulline, Nitric Oxide
Eligibility Criteria
Inclusion Criteria:
- 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) at the baseline visit.
- Negative urine pregnancy test, if applicable.
- Score of 26 or higher on the Montreal Cognitive Assessment (MOCA). -
Exclusion Criteria:
- 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.
- 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.
- 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 ).
- 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). -
Sites / Locations
- Baylor St. Luke'S Medical CenterRecruiting
Arms of the Study
Arm 1
Arm Type
Other
Arm Label
Dose finding safety study
Arm Description
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.
Outcomes
Primary Outcome Measures
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:
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:
Syncope
Dizziness
Blurred Vision
Fatigue
Concentration Impairment
Nausea
Vomiting
Diarrhea
Hypoglycemia
Headache
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
Changes in cerebral blood flow effected by the use of citrulline supplementation
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
Changes in cerebrovascular reactivity effected by the use of citrulline supplementation
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
Changes effected by the use of citrulline supplementation in the micromolar concentration of plasma amino acids citrulline, arginine, ornithine, and alanine levels.
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
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)
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
Changes effected by the use of citrulline in the concentration of plasma guanidino compounds
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
Full Information
NCT ID
NCT03952234
First Posted
May 8, 2019
Last Updated
July 10, 2023
Sponsor
Baylor College of Medicine
Collaborators
National Institute of Neurological Disorders and Stroke (NINDS), University of South Florida, Columbia University
1. Study Identification
Unique Protocol Identification Number
NCT03952234
Brief Title
L-Citrulline Dose Finding Safety Study in MELAS
Official Title
Phase-1, Dose Finding and Safety Study on L- Citrulline Treatment of Nitric Oxide Deficiency in MELAS
Study Type
Interventional
2. Study Status
Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
April 22, 2021 (Actual)
Primary Completion Date
March 2024 (Anticipated)
Study Completion Date
June 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Baylor College of Medicine
Collaborators
National Institute of Neurological Disorders and Stroke (NINDS), University of South Florida, Columbia University
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
MELAS Syndrome
Keywords
Mitochondrial, Encephalomyopathy, Metabolic strokes, Stroke-like episodes, Citrulline, Nitric Oxide
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Model Description
L-Citrulline
Masking
None (Open Label)
Allocation
N/A
Enrollment
24 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Dose finding safety study
Arm Type
Other
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
L-Citrulline
Other Intervention Name(s)
L-Citrulline powder
Intervention Description
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
Primary Outcome Measure Information:
Title
Establishment of the maximum tolerable dose of L-citrulline in patients with MELAS syndrome by measuring the incidence of dose limiting toxicities (DLTs)
Description
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:
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:
Syncope
Dizziness
Blurred Vision
Fatigue
Concentration Impairment
Nausea
Vomiting
Diarrhea
Hypoglycemia
Headache
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.
Time Frame
Eight weeks
Secondary Outcome Measure Information:
Title
Changes in cerebral blood flow effected by the use of citrulline supplementation
Description
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
Time Frame
Four weeks
Title
Changes in cerebrovascular reactivity effected by the use of citrulline supplementation
Description
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
Time Frame
Four weeks
Title
Changes effected by the use of citrulline supplementation in the micromolar concentration of plasma amino acids citrulline, arginine, ornithine, and alanine levels.
Description
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
Time Frame
Four weeks
Title
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)
Description
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
Time Frame
Four weeks
Title
Changes effected by the use of citrulline in the concentration of plasma guanidino compounds
Description
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
Time Frame
One week
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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). -
Exclusion Criteria:
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). -
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
MAY ALI
Phone
+1 832-822-1630
Email
maali@bcm.edu
First Name & Middle Initial & Last Name or Official Title & Degree
DIANNE BAURI, N.P.
Phone
+1 832-824-6225
Email
dianne.bauri@bcm.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
FERNANDO SCAGLIA, M.D
Organizational Affiliation
Baylor College of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Baylor St. Luke'S Medical Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
FERNANDO SCAGLIA, M.D.
Phone
832-822-4280
Email
fscaglia@bcm.edu
First Name & Middle Initial & Last Name & Degree
Claudia soler, M.D.
Phone
+1 832-822-4280
Email
claudia.soler-alfonso@bcm.edu
First Name & Middle Initial & Last Name & Degree
FERNANDO SCAGLIA, M.D.
First Name & Middle Initial & Last Name & Degree
CLAUDIA SOLER, M.D.
First Name & Middle Initial & Last Name & Degree
STEPHEN KRALIK, M.D.
First Name & Middle Initial & Last Name & Degree
DIANNE BAURI, N.P.
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
26851065
Citation
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.
Results Reference
background
PubMed Identifier
20301411
Citation
El-Hattab AW, Almannai M, Scaglia F. MELAS. 2001 Feb 27 [updated 2018 Nov 29]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from http://www.ncbi.nlm.nih.gov/books/NBK1233/
Results Reference
background
PubMed Identifier
28736735
Citation
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.
Results Reference
background
PubMed Identifier
25411654
Citation
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.
Results Reference
background
PubMed Identifier
16734497
Citation
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. Erratum In: CNS Drugs. 2008;22(1):81.
Results Reference
background
PubMed Identifier
8151079
Citation
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.
Results Reference
background
PubMed Identifier
18184842
Citation
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.
Results Reference
background
Links:
URL
https://clinicaltrials.gov/ct2/show/NCT01995032
Description
L-citrulline and Metformin in Duchenne's Muscular Dystrophy
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