Study of Idebenone in the Treatment of Mitochondrial Encephalopathy Lactic Acidosis & Stroke-like Episodes

MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes), a
progressive and often devastating multisystem disorder, is most commonly associated with
mitochondrial DNA point mutation at nucleotide 3243. Seizures, cognitive deterioration, and
neurobehavioral abnormalities are frequent features of this disease which typically shortens
life expectancy. Idebenone, an ATP production modulator and antioxidant, improves
neurological function in Friedreich's ataxia, a disease also associated with mitochondrial
dysfunction.

Given that there is no effective treatment for MELAS, we propose a Phase II proof of concept
trial of idebenone to: study its preliminary efficacy in patients with MELAS and the A3243G
mtDNA mutation, and to study its safety and tolerability in this patient group.

We propose to evaluate 21 patients with the A3243G mitochondrial DNA mutation and MELAS
(defined by a history of either seizures or stroke). Patients will receive idebenone (900
mg/day or 2250 mg/day) or matching placebo for one month. The primary outcome measure is
cerebral lactate levels measured by Magnetic Resonance Spectroscopy (MRS), a biomarker
associated with disease worsening. This study will help the investigators to determine if
there is sufficient signal to proceed to efficacy studies. Also it will provide additional
information on the safety and tolerability of two different doses of idebenone in MELAS.

Inclusion Criteria:

- Diagnosis of MELAS with confirmed A3243G mtDNA mutation, or evidence of central
nervous system involvement (cognitive problems, migraines, memory loss)

- Cerebral lactate level equal to or greater than 5.0 i.u. at baseline

- Patients at least 8 and < 65 years of age at baseline

- Patients with a body weight > 37 kg/82 lbs at baseline

- Stable co-medication/vitamins/supplements within 1 month prior to baseline

- Patients who in the opinion of the investigator are able to comply with the
requirements of the study, including swallowing the study medication

- Negative urine pregnancy test at screening and baseline (female patients of
childbearing potential)

Exclusion Criteria:

- Contraindication to MRS (e.g. metal implant, claustrophobia)

- Stroke like event within 2 months prior to baseline

- Treatment with idebenone at any dose, or coenzyme Q10 at doses above 100mg/d within 1
month prior to baseline

- Inadequate contraception use

- Pregnancy and/or breast-feeding

- Clinically significant abnormalities of clinical hematology or biochemistry
including, but not limited to, elevations greater than 1.5 times the upper limit of
normal of aspartate aminotransferase (AST), alanine aminotransferase (ALT) or
creatinine

- Current abuse of drugs or alcohol

- Participation in a trial of another investigational drug within the last month

- Other factor that, in the investigator's opinion, excludes the patient from entering
the study