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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to find the safest maximum dose of L-Citrulline, an amino acid, for people with MELAS syndrome—a condition that affects energy production in the body and leads to symptoms like stroke-like events, seizures, or muscle weakness. The research will determine how much of this amino acid can be safely used in future studies to potentially improve symptoms. Good candidates for the trial are adults with exercise intolerance or muscle weakness who also have a specific genetic mutation tied to MELAS. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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.

Is there any evidence suggesting that L-Citrulline is likely to be safe for humans?

Research has shown that L-citrulline is generally safe for people. It has been used safely in newborns with certain metabolic disorders, suggesting it is likely safe for adults as well.

L-citrulline, an amino acid and building block of proteins, is already used in other medical treatments without causing serious side effects. Although studies on its use for MELAS syndrome remain in the early stages, its safe use in other conditions is a positive sign.

Before joining any clinical trial, discussing potential risks and benefits with a doctor is important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about L-Citrulline for treating MELAS syndrome because it targets nitric oxide deficiency, a key issue in this mitochondrial disorder. Unlike standard treatments that primarily focus on managing symptoms, L-Citrulline aims to directly address the underlying biochemical problem by boosting nitric oxide production. This approach offers a novel way to potentially improve cellular energy levels and overall patient outcomes.

What evidence suggests that L-Citrulline might be an effective treatment for MELAS?

Research has shown that L-Citrulline might help manage MELAS syndrome, a rare condition affecting cellular energy production. MELAS is linked to low levels of nitric oxide, which helps blood vessels relax and improves blood flow. L-Citrulline is believed to increase nitric oxide levels. Early studies suggest it could alleviate symptoms like muscle weakness and difficulty exercising. Although solid evidence on its effectiveness specifically for MELAS is limited, its ability to boost nitric oxide makes it a promising option for future treatment. Participants in this trial will join a dose-finding safety study to determine the highest acceptable dose of L-Citrulline for individuals with this mitochondrial disorder. ^{1 2 3 6 7}

Who Is on the Research Team?

FERNANDO SCAGLIA, M.D

Principal Investigator

Baylor College of Medicine

Are You a Good Fit for This Trial?

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 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.

You scored 26 or higher on the Montreal Cognitive Assessment (MOCA).

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8617702/

Clinical Characteristics of Mitochondrial Encephalomyopathy ... Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, a maternally inherited mitochondrial disorder, is characterized ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03952234

L-Citrulline Dose Finding Safety Study in MELAS 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 ...

3. mdpi.com mdpi.com/2218-273X/14/12/1524

Diagnosis and Management of Mitochondrial ... Key clinical features include recurrent stroke-like episodes, seizures, lactic acidosis, muscle weakness, exercise intolerance, sensorineural hearing loss, ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5625994/

Mitochondrial Encephalomyopathy With Lactic Acidosis ... MELAS syndrome is a rare inherited disorder that results in waxing and waning nervous system and muscle dysfunction.

5. researchgate.net researchgate.net/publication/7047376_The_Mitochondrial_Myopathy_Encephalopathy_Lactic_Acidosis_withStroke-Like_Episodes_MELAS_Syndrome

The Mitochondrial Myopathy Encephalopathy, Lactic ... MELAS syndrome typically affects a young population, with 75% of cases presenting before 20 years of age, and causes significant morbidity, with ...

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0261561417313699

Citrulline in health and disease. Review on human studies The amino acid L-citrulline (CIT) is safely used from the neonatal period onwards in those with urea cycle defects and carbamyl phosphate synthetase or ...

7. go.drugbank.com go.drugbank.com/conditions/DBCOND0133949

Mitochondrial Encephalomyopathy, Lactic Acidosis and ... Mitochondrial Encephalopathy / Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like Episodes (MELAS) ... Citrulline Dose Finding Safety Study in MELAS.