MELAS SyndromePhase 2NCT01603446
L-arginine Therapy on Endothelium-dependent Vasodilation & Mitochondrial Metabolism in MELAS Syndrome
A Phase 2 study testing L-Arginine in people with MELAS Syndrome, run by The Hospital for Sick Children at 1 site in Canada.
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. Read more about this study
- Who is it for?
- Ages 17 to 23 yearsHealthy volunteers can take part
- Conditions the study is for
- MELAS Syndrome
- What is being tested?
- L-Arginine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 7 participants
- Where
- 1 siteCanada
- Study dates
- May 2012to Dec 2013
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 17 to 23 years
- All sexes
- Healthy volunteers accepted
- Child, Adult
Who may be able to join
- 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
Who cannot join
- Controls
- Experience migraines
- Have a metabolic disorder
- Taking medications predisposing to lactic acidosis or vasodilatation
- Neuromuscular/neurologic condition
- Cardiac or pulmonary disease
Show all 9Show fewer
- Visual abnormalities
- Hypertension, anemia and prothrombotic state. Control subjects
- Contraindication for MRI (pacemaker, ocular metal, claustrophobia, tattoos) will be excluded from the study.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Pilot Study to Investigate the Efficacy of L-arginine Therapy on Endothelium-dependent Vasodilation & Mitochondrial Metabolism in MELAS Syndrome.
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.
Read the detailed 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.
- Conditions
- MELAS Syndrome
- Being tested
- L-Arginine
- Keywords
- pediatric, MELAS, mechanism of action of L-arginine
- Medical subject headings
- MELAS Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
L-ArginineDrug
NOW® L-Arginine powder
| Study group | Role | What they receive |
|---|---|---|
| MELAS Patients | Experimental | Three siblings with MELAS (A3243G) syndrome (1 male; 2 females) aged 17-23 years, followed or previously followed in the Neurometabolic Clinic at the Hospital for Sick Children will be studied. Receives: Drug: L-Arginine |
| Control Group | No intervention | Four age- and sex-matched controls and female controls will be matched according to phase in menstrual cycle corresponding with their age-matched MELAS subjects |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 60 to 105 minutes post dose
Secondary outcomes (3)
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..
Measured: 60-75 mins post dose
CerebroVascular Reactivity
Functional MRI-Blood oxygen level dependent (BOLD) of brain
Measured: 75-105 mins post dose
Exhaled Nitric Oxide (eNO)
eNO will be measured using single breath on-line measurements for the assessment of lower airway Nitric Oxide
Measured: 75 mins pre dose, 75 mins post dose
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 May 2012 (estimated)
- Study startMay 2012
- Primary completionMay 2013
- Study completionDec 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for MELAS SyndromeStudies of the same condition, open and under way.
- More trials run by The Hospital for Sick ChildrenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 7 participants (actual)
Sponsor and investigators
- Lead sponsor
- The Hospital for Sick Children
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Ingrid Tein, The Hospital for Sick Children
- Investigators
- Ingrid Tein, MD, Principal investigator, The Hospital for Sick Children
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01603446
- Sponsor's protocol ID
- 1000023405
- Status last verified
- Dec 2013
- First submitted
- 18 May 2012
- Last updated
- 17 Dec 2013
- Results posted
- No
- Data monitoring committee
- No
Publications
Rodan LH, Poublanc J, Fisher JA, Sobczyk O, Mikulis DJ, Tein I. L-arginine effects on cerebrovascular reactivity, perfusion and neurovascular coupling in MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) syndrome. PLoS One. 2020 Sep 3;15(9):e0238224. doi: 10.1371/journal.pone.0238224. eCollection 2020.
PubMed 32881886Rodan LH, Wells GD, Banks L, Thompson S, Schneiderman JE, Tein I. L-Arginine Affects Aerobic Capacity and Muscle Metabolism in MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-Like Episodes) Syndrome. PLoS One. 2015 May 20;10(5):e0127066. doi: 10.1371/journal.pone.0127066. eCollection 2015.
PubMed 25993630
Study at a glance
From the registry record, last updated by the sponsor on 17 Dec 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pilot Study to Investigate the Efficacy of L-arginine Therapy on Endothelium-dependent Vasodilation & Mitochondrial Metabolism in MELAS Syndrome.
- ClinicalTrials.gov ID
- NCT01603446
- Acronym / sponsor ID
- 1000023405
- Conditions
- MELAS Syndrome
- Keywords
- pediatric, MELAS, mechanism of action of L-arginine
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 7 participants (actual)
- Lead sponsor
- The Hospital for Sick ChildrenUniversity, hospital or other
- Study start
- May 2012
- Primary completion
- May 2013 (actual)
- Study completion
- Dec 2013 (actual)
- First posted
- 22 May 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| MELAS Patients | Experimental | Drug: L-ArginineThree siblings with MELAS (A3243G) syndrome (1 male; 2 females) aged 17-23 years, followed or previously followed in the Neurometabolic Clinic at the Hospital for Sick Children will be studied. |
| Control Group | No intervention | –Four age- and sex-matched controls and female controls will be matched according to phase in menstrual cycle corresponding with their age-matched MELAS subjects |
Who may qualify
- Ages
- 17 to 23 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (9 listed)
- Controls
- Experience migraines
- Have a metabolic disorder
- Taking medications predisposing to lactic acidosis or vasodilatation
- Neuromuscular/neurologic condition
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| L-ArginineNOW® L-Arginine powder | Drug | MELAS Patients |
Primary outcome
Muscle function investigation via 31P-Magnetic resonance spectroscopy
Time frame: 60 to 105 minutes post dose
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.
3 secondary outcomes
Total body maximal aerobic capacity
Time frame: 60-75 mins post dose
CerebroVascular Reactivity
Time frame: 75-105 mins post dose
Exhaled Nitric Oxide (eNO)
Time frame: 75 mins pre dose, 75 mins post dose
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Dec 2013.
- Derived from this study: PubMed 32881886Rodan LH, Poublanc J, Fisher JA, Sobczyk O, Mikulis DJ, Tein I. L-arginine effects on cerebrovascular reactivity, perfusion and neurovascular coupling in MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) syndrome. PLoS One. 2020 Sep 3;15(9):e0238224. doi: 10.1371/journal.pone.0238224. eCollection 2020.
- Derived from this study: PubMed 25993630Rodan LH, Wells GD, Banks L, Thompson S, Schneiderman JE, Tein I. L-Arginine Affects Aerobic Capacity and Muscle Metabolism in MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-Like Episodes) Syndrome. PLoS One. 2015 May 20;10(5):e0127066. doi: 10.1371/journal.pone.0127066. eCollection 2015.
Related trials for MELAS Syndrome
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Not yet recruitingPhase 1/2
A Basket Clinical Study to Assess Glycerol Tributyrate in Patients With Mitochondrial Encephalopathy, Lactic Acidosis, Stroke-like Episodes (MELAS) or Leber's Hereditary Optic Neuropathy-Plus (LHON-Plus)
MELAS Syndrome, Lebers Hereditory Optic Neuropathy With Extra Ocular Symptoms (LHON-Plus)
RecruitingObservational study
Global Registry and Natural History Study for Mitochondrial Disorders
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North American Mitochondrial Disease Consortium Patient Registry and Biorepository (NAMDC)
Mitochondrial Disorders, Mitochondrial Genetic Disorders
RecruitingObservational study
Natural History Study - Mitochondrial Disease
MELAS or m.3243 A>G Mitochondrial DNA Mutation Carrier
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ingrid Tein, MD principal investigator
The Hospital for Sick Children
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing L-Arginine in people with MELAS Syndrome, run by The Hospital for Sick Children at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Dec 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Muscle function investigation via 31P-Magnetic resonance spectroscopy (time frame: 60 to 105 minutes post dose). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01603446, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Dec 2013.