EPI-743 for Metabolism or Mitochondrial Disorders

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2015 by National Institutes of Health Clinical Center (CC)
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) )
ClinicalTrials.gov Identifier:
First received: July 14, 2012
Last updated: February 26, 2015
Last verified: February 2015


  • 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.


- To see if EPI-743 can improve energy production and use in people with mitochondrial or metabolic disorders.


- Children between 2 and 11 years of age who have metabolic or mitochondrial problems.


  • 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.

Condition Intervention Phase
Undiagnosed Diseases
Metabolic Disease
Mitochondrial Disorders
Drug: EPI-743
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double-Blind
Primary Purpose: Treatment
Official Title: Therapeutic Trial of EPI -743 In Patients With Disorders of Energy Utilization or Oxidation-Reduction

Resource links provided by NLM:

Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Newcastle Paediatric Mitochondrial Disease [ Time Frame: every 3 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Various bichemcial and clinical measures [ Time Frame: every 3 months ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 20
Study Start Date: June 2012
Estimated Study Completion Date: April 2017
Estimated Primary Completion Date: April 2017 (Final data collection date for primary outcome measure)
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 provides such empiric data. Their system determines the capacity of fibroblasts in culture to withstand oxidative stress; that ability is reduced in 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, which essentially accepts electrons from other intermediary metabolites more efficiently that other therapeutic compounds. 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 one-month washout period. Patients will be admitted to the NIH Clinical Center for 4-5 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. 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.


Ages Eligible for Study:   2 Years to 11 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion criteria involve enrollment in protocol 76-HG-0238, Diagnosis and Treatment of Patients with Inborn Errors of Metabolism and Other Genetic Disorders . In addition, patients must:

  • Be 2-11 years of age
  • Manifest clinical findings of a neuromuscular disease with a component of impaired energy or oxidation/reduction. Typical symptoms would include hypotonia, dystonia, or seizures.
  • Have a disorder that is untreatable or poorly treatable.
  • Have cultured fibroblasts that exhibit reduced viability under conditions of oxidative stress, compared to age matched control fibroblasts.
  • Have cultured fibroblasts that achieve at least 80% viability rescue with EPI-743 at 1micromolar upon exposure to oxidative stress and that have a half maximal effective concentration of EPI-743 of less than or equal to 50 nanomolar.
  • Be willing to abstain from initiating the use of dietary supplements and nonprescribed medications, foods or beverages or bars fortified with coenzyme Q(10), vitamin E, super fortified functional foods or beverages, and idebenone.
  • Be able to travel to the Clinical Center for at least 8 visits.


  • Age < 2 years or > 11 years
  • Diagnosis of mitochondrial diseases benefiting from treatment and at risk from being moved to placebo
  • Allergy to EPI-743 or sesame oil
  • Hepatic insufficiency with liver function tests greater than 3-times the upper limit of normal
  • Renal insufficiency requiring dialysis
  • Significant malabsorption of fats precluding drug absorption
  • Allergy to vitamin E
  • Significant coagulation abnormalities as evidenced by abnormal PT/PTT tests
  • Severe end-organ hypo-perfusion syndrome secondary to cardiac failure resulting in lactic acidosis
  • Pancreatitis
  • Clinical history of bleeding requiring ongoing medical management
  • Abnormal red cell parameters requiring ongoing medical management besides iron supplementation
  • A platelet disorder
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01642056

Contact: Lynne A Wolfe, C.R.N.P. (301) 443-8577 wolfela@mail.nih.gov
Contact: William A Gahl, M.D. (301) 402-2739 gahlw@helix.nih.gov

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Human Genome Research Institute (NHGRI)
Principal Investigator: William A Gahl, M.D. National Human Genome Research Institute (NHGRI)
  More Information

Additional Information:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) )
ClinicalTrials.gov Identifier: NCT01642056     History of Changes
Other Study ID Numbers: 120161, 12-HG-0161
Study First Received: July 14, 2012
Last Updated: February 26, 2015
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Metabolic Disease

Additional relevant MeSH terms:
Metabolic Diseases
Mitochondrial Diseases

ClinicalTrials.gov processed this record on October 06, 2015