EPI-743 for Metabolism or Mitochondrial Disorders

• Status: Completed
• Trial end date: 2019-09-24
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National Human Genome Research Institute (NHGRI)

Criteria

• INCLUSION CRITERIA:

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.

EXCLUSION CRITERIA:

• 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

• Ventilator-dependence

• Chronic pancreatitis

• Clinical history of bleeding requiring ongoing medical management

• Abnormal red cell parameters requiring ongoing medical management besides iron supplementation

• A platelet disorder

• Neutrophils less than 500 mm3