EPI-743 in Cobalamin C Defect: Effects on Visual and Neurological Impairment

Sponsor

Bambino Gesù Hospital and Research Institute (Other)

Overall Status

Completed

CT.gov ID

NCT01793090

Collaborator

Catholic University of the Sacred Heart (Other)

Enrollment

Location

Arms

Actual Duration (Months)

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The aim of the research is to investigate the safety and efficacy of EPI-743 treatment in patients with Cbl-C defect and related visual and neurological impairment. Primary Endpoints will be the improvement in visual function as assessed by visual acuity and eye-hand coordination and manual dexterity. Secondary Endpoints will be the improvement in neurologic function, evaluated by a battery of age-appropriated psychophysical tests, and/or in objective electrophysiological tests such as Visual Evoked potentials (VEP) and Electroretinogram (ERG) and/or the change in serum markers of redox state.

Condition or Disease	Intervention/Treatment	Phase
Methylmalonic Aciduria and Homocystinuria,Cblc Type Genetic Disease Retinopathy	Drug: Epi-743 Other: Placebo supplementation	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

30 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, 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

Actual Study Start Date :

Jan 1, 2013

Actual Primary Completion Date :

Jul 1, 2013

Actual Study Completion Date :

Feb 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
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	Drug: Epi-743 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

Arm

Intervention/Treatment

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

Drug: Epi-743

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

Outcome Measures

Primary Outcome Measures

Change in Visual Function [Baseline, six months, twelve months]
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

Secondary Outcome Measures

Change in steady-state luminance Visual Evoked Potentials [Baseline, six months, twelve months]
Steady-state luminance VEPs to sinusoidal flicker at the optimal frequency of 8 Hz.
Evaluation of neurological function [Baseline, six months, twelve months]
Evaluation of neurological function with Gross motor function measure, movement ABC

Other Outcome Measures

Biomarkers of redox state [Baseline, six months, twelve months]
Glutathione species in blood cells, Antioxidant enzymes expression, redox proteomic studies

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Year to 20 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

genetically confirmed Cbl-C defect;
abstention from antioxidant medications (i.e. coenzyme Q10, idebenone, vitamin E) prior to trial initiation and throughout conduct of trial.

Exclusion Criteria:

allergy to EPI-743 or sesame oil (a screening test will be performed);
abnormal coagulation;
hepatic insufficiency with Liver Function Tests greater than 2-times normal values;
renal insufficiency requiring dialysis;
fat malabsorption precluding drug absorption.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Bambino Gesù Hospital and Research Institute	Rome		Italy	00165

Sponsors and Collaborators

Bambino Gesù Hospital and Research Institute
Catholic University of the Sacred Heart

Investigators

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