EPI-743 for Metabolism or Mitochondrial Disorders
Condition: Mitochondrial Disease; Neurology; Myopathy
MeSH terms: Mitochondrial Diseases
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Background:

        -  Mitochondria are the parts of cells that help produce energy. Metabolism is the process
           by which the body uses energy to help cells grow and reproduce. Metabolic and
           mitochondrial disorders affect the body s ability to produce and store energy. These
           disorders can cause a wide variety of problems, but most often they affect the muscles
           and the brain, where energy requirements are high. Treatment is difficult because the
           exact source of the problem is hard to detect.

        -  EPI-743 is a new drug that is based on vitamin E. Tests have shown that it can help
           improve the function of cells with mitochondrial problems. It may be able to treat
           people with genetic disorders that affect metabolism and mitochondria.

      Objectives:

      - To see if EPI-743 can improve energy production and use in people with mitochondrial or
      metabolic disorders.

      Eligibility:

      - Children between 2 and 11 years of age who have metabolic or mitochondrial problems.

      Design:

        -  Participants will be screened with a physical exam and medical history. Blood and urine
           samples will be collected.

        -  The study will last about 13 months. Participants will have seven 3- to 5-day inpatient
           study visits about 3 months apart.

        -  Participants will take either EPI-743 or a placebo for the first 6 months of the study.
           After 6 months, there will be a 1-month rest period. Then, those who received EPI-743 in
           the first 6 months will take the placebo for the next 6 months. Those who had the
           placebo will take EPI-743.

        -  During each inpatient study visit, participants will have a physical exam. A 24-hour
           urine collection will be obtained. Blood samples will also be taken. Imaging studies and
           other tests may be performed as directed by the study researchers.
    

Detailed description: 
      The clinical manifestations of disorders of energy metabolism and defects in
      oxidation/reduction are similar because the basic defect involves the inability to transfer
      electrons. The same is true for many mitochondrial diseases. Affected patients exhibit a wide
      variety of signs and symptoms, but the most frequent and earliest dysfunctions occur in the
      muscle and brain, where energy requirements are high. The diagnosis of this type of defect is
      problematic because of the nonspecific and protean clinical manifestations of these
      disorders. Treatment is equally challenging, since the exact locus of the primary defect
      generally remains enigmatic. As a consequence, physicians rely upon generic cocktails of
      vitamin co-factors or endogenous intermediates intended to enhance mitochondrial electron
      transport, diminish the damage of reactive oxygen species, and promote energy production. The
      field is such a morass that, in general, it calls for trial-and-error treatment based upon
      empiric data. Edison Pharmaceuticals, Inc, has developed an in vitro assay that utilizes
      patient fibroblasts to model the innate susceptibility to oxidative stress caused by the
      disorders of energy metabolism and oxidation/reduction. The assay system also determines if
      the cells respond with increased viability to an IND drug called EPI-743. We propose a
      clinical trial that enrolls 20 children who meet three criteria. First, they must have a
      disorder that, based upon studies performed in a clinical protocol such as 76-HG-0238
      ("Diagnosis and Treatment of Patients with Inborn Errors of Metabolism and Other Genetic
      Disorders"), is consistent with a defect in energy metabolism or oxidation/reduction. Second,
      their cultured fibroblasts must exhibit a defect in the ability to withstand oxidant stress.
      Third, their fibroblasts must respond to EPI-743 in vitro by showing improved viability under
      conditions of oxidative stress. This protocol is a double-blind, placebo-controlled crossover
      study with 6-month periods of treatment and a two-month washout period. Patients will be
      admitted to the NIH Clinical Center for 2-5 days every 3 months. The primary outcome measure
      will be quality of life based upon the Newcastle Paediatric Mitochondrial Disease Scale
      (NPMDS) for ages 2-11 years; parts IIII

      will be evaluated separately from part IV. Secondary outcome measures will be tailored to
      each patient's laboratory, imaging, and clinical abnormalities. Results while receiving
      EPI-743 will be compared to results while receiving placebo; both repeated measures analyses
      and Student's t test will be employed.
    

Intervention name(s): EPI-743; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): This medication is used to treat disorders of energy metabolism such as mitochondrial diseases. It does not correct the inherited disorder of energy metabolism or mitochondrial diseases. EPI-743 is structurally related to Vitamin E and can be broadly classified as an antioxidant.
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Oxidative Stress; Oxidative Phosphorylation; Mitochondrial Disease