L-Citrulline for MELAS Syndrome

Overseen By DIANNE BAURI, N.P.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Must not be taking: Vasodilators, Amino acid supplements

Disqualifiers: Tobacco use, Renal impairment, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

10 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial aims to find the safest dose of citrulline for adults with MELAS, a condition that affects energy production in cells. Citrulline can help increase nitric oxide levels, improving blood flow and potentially reducing stroke risk. Citrulline has been shown to improve nitric oxide production and may have a better therapeutic effect than arginine in treating MELAS syndrome.

Will I have to stop taking my current medications?

The trial requires that you stop taking drugs that increase NO synthesis, vasodilators, or amino acid supplements during the study period.

What data supports the effectiveness of the drug L-Citrulline for MELAS Syndrome?

Research suggests that L-Citrulline, an amino acid, can improve muscle strength and protein balance, and it is better tolerated than similar supplements like arginine. Additionally, in conditions like lysinuric protein intolerance, citrulline has shown clinical improvement by effectively increasing urea cycle intermediates. ^{1 2 3 4 5}

Is L-Citrulline safe for human use?

L-Citrulline, including its form as citrulline malate, has been studied in humans and is generally considered safe. Studies have shown no significant side effects, and it is well-tolerated, even at higher doses used in exercise performance research. ^{1 2 6 7 8}

How does the drug L-Citrulline differ from other treatments for MELAS syndrome?

L-Citrulline is unique because it increases nitric oxide (NO) production more effectively than L-arginine, potentially improving blood flow and reducing complications like stroke-like episodes in MELAS syndrome. Unlike other treatments, L-Citrulline specifically addresses NO deficiency, which is a key issue in this condition. ^{1 2 7 9 10}

Research Team

FERNANDO SCAGLIA, M.D

Principal Investigator

Baylor College of Medicine

Eligibility Criteria

Adults aged 18-65 with MELAS Syndrome, a specific genetic mutation (m.3243A>G), and elevated plasma lactate can join this trial. They must have cognitive health to pass the MOCA test and not be pregnant or using tobacco. Those with recent seizures, no neurological symptoms, severe kidney issues, or taking certain medications are excluded.

Inclusion Criteria

I am between 18 and 65 years old.

I have been diagnosed with MELAS, experiencing symptoms like stroke-like events, seizures, or muscle weakness.

If you can get pregnant, you must have a negative urine pregnancy test.

Exclusion Criteria

I can understand and report low blood sugar levels.

You have taken arginine supplements within one week before the baseline visit.

If your blood pressure drops significantly when you stand up, you may not be able to participate.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive L-citrulline to establish the maximum tolerable dose and monitor changes in cerebral blood flow and cerebrovascular reactivity

8 weeks

Weekly visits for monitoring and dose adjustments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• L-Citrulline

Trial Overview The study is testing the safety of different doses of L-Citrulline in adults with MELAS Syndrome to find the highest safe dose for future research. Participants will receive increasing amounts of L-Citrulline to establish its maximum tolerable level without significant side effects.

Participant Groups

Group I: Dose finding safety study Experimental Treatment 1 Intervention

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.

L-Citrulline is already approved in United States, European Union for the following indications:

Approved in United States as L-citrulline for:

• Nutritional supplement

Approved in European Union as L-citrulline for:

• Nutritional supplement

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

Columbia University

Collaborator

Trials

1,529

Recruited

2,832,000+

University of South Florida

Collaborator

Trials

433

Recruited

198,000+

National Institute of Neurological Disorders and Stroke (NINDS)

Collaborator

Trials

1,403

Recruited

655,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Findings from Research

L-Citrulline is a valuable biomarker for monitoring intestinal health, as its plasma levels decrease with impaired intestinal function.

Supplementation with L-citrulline is generally better tolerated than arginine and may help improve muscle strength and protein balance, making it a potential therapeutic option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Citrulline, Biomarker of Enterocyte Functional Mass and Dietary Supplement. Metabolism, Transport, and Current Evidence for Clinical Use. Maric, S., Restin, T., Muff, JL., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Kinetic mutations in argininosuccinate synthetase deficiency: characterisation and in vitro correction by substrate supplementation. [2018]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Citrulline, Biomarker of Enterocyte Functional Mass and Dietary Supplement. Metabolism, Transport, and Current Evidence for Clinical Use. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Molecular epidemiology of citrullinemia type I in a risk region of Argentina: a first step to preconception heterozygote detection. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Investigation of citrullinemia type I variants by in vitro expression studies. [2008]

5. United States pubmed.ncbi.nlm.nih.gov

Oral administration of urea cycle intermediates in lysinuric protein intolerance: effect on plasma and urinary arginine and ornithine. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Acute Citrulline-Malate Supplementation and High-Intensity Cycling Performance. [2018]

7. Germany pubmed.ncbi.nlm.nih.gov

Activity of citrulline malate on acid-base balance and blood ammonia and amino acid levels. Study in the animal and in man. [2013]

8. Austria pubmed.ncbi.nlm.nih.gov

Almost all about citrulline in mammals. [2022]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Hypocitrullinemia in patients with MELAS: an insight into the "MELAS paradox". [2013]

10. Brazil pubmed.ncbi.nlm.nih.gov

Arginine and citrulline for the treatment of MELAS syndrome. [2022]