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

• Mean Change in Venous Lactate Concentration [ Time Frame: Up to 4 weeks from baseline ]
  To compare the efficacy of 1 month treatment with 2 different doses of idebenone with that of placebo on venous lactate concentration
• Mean Change in Score on the Fatigue Severity Scale (FSS) [ Time Frame: Baseline and Week 4 ]

  To assess changes following 1 month treatment with 2 different doses of idebenone with that of placebo in fatigue as assessed by the Fatigue Severity Scale (FSS).

  Scale score minimum is 9 (least fatigue) and maximum is 63 (maximum fatigue). Scores of 36 or less indicate possibility that patient may not be suffering from fatigue, while scores 36 and over suggest suffering from fatigue

• To compare the efficacy of 1 month treatment with 2 different doses of idebenone with that of placebo on venous lactate concentration [ Time Frame: 1 month ]
• To assess changes following 1 month treatment with 2 different doses of idebenone with that of placebo in fatigue as assessed by the Fatigue Severity Scale (FSS) [ Time Frame: 1 month ]
• To assess changes following 1 month treatment with 2 different doses of idebenone with that of placebo in daily activities as assessed by the Quality of Life questionnaires SF36 for adults and PedsQL for children and adolescents [ Time Frame: 1 month ]
• To assess safety and tolerability following 1 month treatment with 2 different doses of idebenone with that of placebo [ Time Frame: 1 month ]

MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes), a progressive and often devastating multisystem disorder, is most commonly associated with mitochondrial Deoxyribonucleic acid (mtDNA) 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, the investigators 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.

The investigators 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.

• Drug: Idebenone
  900 mg/day for 1 month
  Other Name: active drug
• Drug: Idebenone
  2250 mg/day for 1 month
  Other Name: active drug
• Other: Placebo
  Placebo - No idebenone
  Other Name: No active drug

• Experimental: Idebenone 900 mg/day
  Idebenone 900 mg/day
  Intervention: Drug: Idebenone
• Experimental: Idebenone 2250 mg/day
  Idebenone 2250 mg/day
  Intervention: Drug: Idebenone
• Placebo Comparator: placebo
  Placebo
  Intervention: Other: Placebo

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