EPI-743 for Metabolism or Mitochondrial Disorders

Tracking Information
First Submitted Date ICMJE	July 14, 2012
First Posted Date ICMJE	July 17, 2012
Last Update Posted Date	July 6, 2018
Study Start Date ICMJE	September 1, 2012
Estimated Primary Completion Date	October 31, 2018 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: July 14, 2012)	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; (submitted: July 14, 2012)	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, 20 patients have been enrolled, 19 have completed the two blinded arms of the study, one has died, and 5 patients have withdrawn. This study now includes an extension arm, through which all patients are offered open label EPI-743 after completing the crossover trial. Eight patients are currently enrolled in this Extension arm.
Study Type ICMJE	Interventional
Study Phase	Phase 2
Study Design ICMJE	Allocation: Randomized; Intervention Model: Crossover Assignment; 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 *	Rodriguez MC, MacDonald JR, Mahoney DJ, Parise G, Beal MF, Tarnopolsky MA. Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders. Muscle Nerve. 2007 Feb;35(2):235-42.; Gahl WA, Tifft CJ. The NIH Undiagnosed Diseases Program: lessons learned. JAMA. 2011 May 11;305(18):1904-5. doi: 10.1001/jama.2011.613.
* 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	Active, not recruiting
Actual Enrollment ICMJE; (submitted: July 14, 2012)	20
Original Estimated Enrollment ICMJE	Same as current
Estimated Study Completion Date	January 1, 2019
Estimated Primary Completion Date	October 31, 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; 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
Sex/Gender	Sexes Eligible for Study: All
Ages	2 Years to 11 Years (Child)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
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	Studies a U.S. FDA-regulated Drug Product: Yes
IPD Sharing Statement	Not Provided
Responsible Party	National Institutes of Health Clinical Center (CC) ( 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)
PRS Account	National Institutes of Health Clinical Center (CC)
Verification Date	February 28, 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP