L-arginine Therapy on Endothelium-dependent Vasodilation & Mitochondrial Metabolism in MELAS Syndrome

MELAS Syndrome Clinical Trial

Official title:

Pilot Study to Investigate the Efficacy of L-arginine Therapy on Endothelium-dependent Vasodilation & Mitochondrial Metabolism in MELAS Syndrome.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01603446
• Other study ID #: 1000023405
• Status: Completed
• Phase: Phase 2
• First received: May 18, 2012
• Last updated: December 13, 2013
• Start date: May 2012
• Est. completion date: December 2013

Study information

• Verified date: December 2013
• Source: The Hospital for Sick Children
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Health Canada
• Study type: Interventional

Clinical Trial Summary

MELAS patients suffer from exercise intolerance, weakness, poor vision or blindness, poor growth, developmental delay, and deafness. They also have unique 'stroke-like' episodes (SLEs) which are not due to blockages of large or medium arteries. These 'strokes' are thought to be due to energy failure of very small brain blood vessels combined with energy failure in the mitochondria (cell battery) of the brain cells, especially in the back region of the brain in the vision centre. This leads to visual loss and paralysis. The overall goal of this study is to better understand the mechanism of these SLEs at the level of the brain cells and small blood vessels.

Description:

We will study a family of 3 siblings, each with different severities of MELAS, using safe, non-invasive tests. We will determine whether there is a decrease in the ability of small brain blood vessels to increase blood flow by dilating in response to certain stimuli such as increased blood carbon dioxide levels or in response to brain cell activation in the vision centre by visual stimuli. We will use a technique called BOLD-fMRI which can detect changes in brain blood flow. As exercising muscle also depends on increased blood flow and mitochondrial energy, we will study different measures of aerobic energy metabolism in exercising muscle using cycle exercise testing and special phosphorus-magnetic resonance spectroscopy which measures the changes in the major chemicals of muscle energy metabolism. The dietary amino acid L-arginine is known to dilate blood vessels increasing blood flow and to decrease toxic free radicals that are generated by dysfunctional mitochondria. We will determine the effect of a single dose and a 6 week trial of oral L-arginine, on brain blood vessel reactivity, brain cell activation and muscle aerobic function to see how useful this would be in the treatment of these patients and other mitochondrial disorders which present with strokes.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 7
• Est. completion date: December 2013
• Est. primary completion date: May 2013
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 17 Years to 23 Years

Eligibility

Inclusion Criteria:

Experimental Siblings with MELAS (A3243G) syndrome

• 17-23 years

• Followed Neurometabolic Clinic at the Hospital for Sick Children will be studied.

• Normal electrolytes, glucose, renal and liver functions & no history of gastrointestinal, respiratory or cardiac problems.

Controls

-Aged 17-23- Sex matched to the MELAS subjects

Exclusion Criteria:

Controls

• Experience migraines

• Have a metabolic disorder

• Taking medications predisposing to lactic acidosis or vasodilatation

• Neuromuscular/neurologic condition

• Cardiac or pulmonary disease

• Visual abnormalities

• Hypertension, anemia and prothrombotic state. Control subjects

• Contraindication for MRI (pacemaker, ocular metal, claustrophobia, tattoos) will be excluded from the study.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• MELAS Syndrome
• Syndrome

Intervention

Drug:
• L-Arginine
NOW® L-Arginine powder

Locations

Country	Name	City	State
Canada	The Hospital for Sick Children	Toronto	Ontario

Sponsors (1)

Lead Sponsor	Collaborator
The Hospital for Sick Children

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Muscle function investigation via 31P-Magnetic resonance spectroscopy	We will study exercising quadriceps using our MR-compatible up-down ergometer and our well established aerobic exercise protocol at 65 % of maximal voluntary contraction.	60 to 105 minutes post dose	No
Secondary	Total body maximal aerobic capacity	Maximal incremental cycle ergometry is conducted in our CardioRespiratory Exercise Lab at HSC by our established protocols (26). Serum CK and quantitative AA (for arginine, ornithine and citrulline) will be measured pre- and post- exercise as well as eNO in order to correlate aerobic exercise parameters with serum arg and eNO levels..	60-75 mins post dose	No
Secondary	CerebroVascular Reactivity	Functional MRI-Blood oxygen level dependent (BOLD) of brain	75-105 mins post dose	No
Secondary	Exhaled Nitric Oxide (eNO)	eNO will be measured using single breath on-line measurements for the assessment of lower airway Nitric Oxide	75 mins pre dose, 75 mins post dose	No