EPI-743 in Cobalamin C Defect: Effects on Visual and Neurological Impairment
Methylmalonic Aciduria and Homocystinuria,Cblc Type
Other: Placebo supplementation
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Phase 2, Double-Blind, Placebo Controlled Clinical Trial of EPI-743 in Subjects With Cobalamin C Defect|
- Change in Visual Function [ Time Frame: Baseline, six months, twelve months ] [ Designated as safety issue: No ]Visual acuity: - Patients age 0-2: Durand acuity cards procedure: Improvement from baseline or nadir by greater than 2 lines when converted to EDTRS values.-Patients age 2-4: LEA Symbols for crowding binocular acuity: Improvement from baseline or nadir by greater than 2 lines when converted to EDTRS values; -Patients age > 4 years: Cambridge acuity cards: Improved from baseline or nadir by greater than 2 lines on the EDTRS acuity testing chart at 4 meters. Eye-hand coordination: -Patients age 0-2: Improvement over baseline of 20% on Griffiths Mental Development Scale subscales D,E; - Patients age > 2: Improvement over baseline of 20% on Movement Assessment Battery for Children
- Change in steady-state luminance Visual Evoked Potentials [ Time Frame: Baseline, six months, twelve months ] [ Designated as safety issue: No ]Steady-state luminance VEPs to sinusoidal flicker at the optimal frequency of 8 Hz.
- Evaluation of neurological function [ Time Frame: Baseline, six months, twelve months ] [ Designated as safety issue: No ]Evaluation of neurological function with Gross motor function measure, movement ABC
- Biomarkers of redox state [ Time Frame: Baseline, six months, twelve months ] [ Designated as safety issue: No ]Glutathione species in blood cells, Antioxidant enzymes expression, redox proteomic studies
|Study Start Date:||January 2013|
|Estimated Study Completion Date:||December 2014|
|Estimated Primary Completion Date:||July 2014 (Final data collection date for primary outcome measure)|
Active Comparator: EPI-743
EPI- 743 in capsule or formulation comprised of USP/NF (United States Pharmacopeia and The National Formulary)Sesame Oil at a potency of 100 mg EPI-743/ 1 mL total volume. Mode of Administration: Oral with meal or G-Tube infusion with food.
Dose: 100mg or 200 mg tid for 12 months, to be continued if clinically effective
EPI- 743 in capsule or formulation comprised of USP/NF Sesame Oil at a potency of 100 mg EPI-743/ 1 mL total volume. Mode of Administration: Oral with meal or G-Tube infusion with food.
Placebo Comparator: Placebo supplementation
placebo in the same formulation as the active comparator will be administered to patients, assigned to this arm in a randomized design
Other: Placebo supplementation
Placebo will be administered in the same formulation as the active comparator
Cobalamin C (Cbl-C) defect is the most common inborn error of cobalamin metabolism causing methylmalonic aciduria and homocystinuria. Cbl-Cdefect is due to impaired activity of MMACHC, a cobalamin trafficking protein, involved in the decyanation of cyanocobalamin as well as in the dealkylation of alkylcobalamins through a glutathione transferase activity. Despite pharmacological treatment with hydroxycobalamin, betaine, folic acid, (and carnitine), long-term outcome in early-onset patients is in most cases unsatisfactory with progression of visual and neurological impairment, mainly expressed in the form of retinal degeneration and/or maculopathy. Moreover, despite some hypotheses have been proposed, the pathophysiological mechanism causing progressive eye and brain damage still remains unclear. Recently, the contribution of oxidative stress has been hypothesized based on in vitro studies showing in Cbl-C fibroblasts a significant increase of reactive oxygen species (ROS) and in vivo studies documenting severe alteration of glutathione species, the main cellular redox buffer.
EPI-743 is a small molecule therapeutic that has demonstrated beneficial effects in diseases characterized by oxidative stress and alterations in glutathione redox balance including Leigh syndrome and other inherited respiratory chain diseases.
Based on the principle that Cbl-C defect causes both in vivo and in vitro perturbations of redox state, the aim of our study is to verify the potential beneficial effects of EPI-743 in preventing/reducing progression of neurological and visual signs, as well as in ameliorating redox abnormalities in Cbl-C patients, in combination with standard therapy.
Primary Endpoints will include the improvement in visual function as assessed by visual acuity and eye-hand coordination and manual dexterity. Secondary Endpoints will be improvement in neurologic function, evaluated by a battery of age-appropriated psychophysical tests, and/or in objective electrophysiological tests such as VEP and ERG, and/or the change in serum markers of redox state. Patient's and parental Quality of life will be regularly assessed prior of treatment start and periodically while on EPI-743.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01793090
|Bambino Gesù Hospital and Research Institute|
|Rome, Italy, 00165|
|Study Chair:||Carlo Dionisi-Vici, MD||Bambino Gesù Hospital and Research Institute|
|Principal Investigator:||Giancarlo Iarossi, MD||Bambino Gesù Hospital and Research Institute|
|Principal Investigator:||Daniela Ricci, MD,PhD||Catholic University of the Sacred Heart|
|Principal Investigator:||Diego Martinelli, MD, PhD||Bambino Gesù Hospital and Research Institute|