EPI-743 for Metabolism or Mitochondrial Disorders

This study is currently recruiting participants. (see Contacts and Locations)

Verified May 1, 2017 by National Institutes of Health Clinical Center (CC)

Sponsor:

Information provided by (Responsible Party):

National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) )

ClinicalTrials.gov Identifier:

NCT01642056

First received: July 14, 2012

Last updated: May 9, 2017

Last verified: May 1, 2017

History of Changes

Tracking Information

First Received Date ^ICMJE

July 14, 2012

Last Updated Date

May 9, 2017

Start Date ^ICMJE

June 22, 2012

Estimated Primary Completion Date

April 1, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures ^ICMJE

Newcastle Paediatric Mitochondrial Disease [ Time Frame: every 3 months ]

Original Primary Outcome Measures ^ICMJE

Same as current

Change History

Complete list of historical versions of study NCT01642056 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures ^ICMJE

Various bichemcial and clinical measures [ Time Frame: every 3 months ]

Original Secondary Outcome Measures ^ICMJE

Same as current

Current Other Outcome Measures ^ICMJE

Not Provided

Original Other Outcome Measures ^ICMJE

Not Provided

Descriptive Information

Brief Title ^ICMJE

EPI-743 for Metabolism or Mitochondrial Disorders

Official Title ^ICMJE

Therapeutic Trial of EPI -743 In Patients With Disorders of Energy Utilization or Oxidation-Reduction

Brief 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 are admitted to the NIH Clinical Center for 2-5 days every 3 months. The primary outcome measure is quality of life based upon the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) for ages 2-11 years; parts I-III are evaluated separately from part IV. Secondary outcome measures are 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. To date, 10 patients have been enrolled, and three are already in the second arm of the protocol. This study now includes an extension arm, through which all patients are offered open label EPI-743 after completing the crossover trial.

Study Type ^ICMJE

Interventional

Study Phase

Phase 2

Study Design ^ICMJE

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (masked roles unspecified)
Primary Purpose: Treatment

Condition ^ICMJE

Undiagnosed Diseases
Metabolic Disease
Neurology
Myoptahy
Oxidation/Reduction
Mitochondrial Disorders

Intervention ^ICMJE

Drug: EPI-743

Study Arms

Not Provided

Publications *

* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.

Recruitment Information

Recruitment Status ^ICMJE

Recruiting

Estimated Enrollment ^ICMJE

Estimated Completion Date

April 1, 2018

Estimated Primary Completion Date

April 1, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria ^ICMJE

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
Pancreatitis
Clinical history of bleeding requiring ongoing medical management
Abnormal red cell parameters requiring ongoing medical management besides iron supplementation
A platelet disorder

Sex/Gender

Sexes Eligible for Study:

All

Ages

2 Years to 11 Years (Child)

Accepts Healthy Volunteers

Contacts ^ICMJE

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

Listed Location Countries ^ICMJE

United States

Removed Location Countries

Administrative Information

NCT Number ^ICMJE

NCT01642056

Other Study ID Numbers ^ICMJE

120161
12-HG-0161

Has Data Monitoring Committee

Not Provided

U.S. FDA-regulated Product

Not Provided

Plan to Share Data

Not Provided

IPD Description

Not Provided

Responsible Party

National Human Genome Research Institute (NHGRI)

Study Sponsor ^ICMJE

National Human Genome Research Institute (NHGRI)

Collaborators ^ICMJE

Not Provided

Investigators ^ICMJE

Principal Investigator:

William A Gahl, M.D.

National Human Genome Research Institute (NHGRI)

Information Provided By

National Institutes of Health Clinical Center (CC)

Verification Date

May 1, 2017

^ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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