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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Catholic University of the Sacred Heart
Information provided by (Responsible Party):
Giancarlo Iarossi, Bambino Gesù Hospital and Research Institute
ClinicalTrials.gov Identifier:
NCT01793090
First received: February 8, 2013
Last updated: April 23, 2014
Last verified: April 2014
  Purpose

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

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by Bambino Gesù Hospital and Research Institute:

Primary Outcome Measures:
  • 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


Secondary Outcome Measures:
  • 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


Other Outcome Measures:
  • 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


Estimated Enrollment: 30
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)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   1 Year to 20 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01793090

Locations
Italy
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
  More Information

Publications:

Responsible Party: Giancarlo Iarossi, MD, Bambino Gesù Hospital and Research Institute
ClinicalTrials.gov Identifier: NCT01793090     History of Changes
Other Study ID Numbers: R-12-92
Study First Received: February 8, 2013
Last Updated: April 23, 2014
Health Authority: Italy: Ethics Committee

Keywords provided by Bambino Gesù Hospital and Research Institute:
Cobalamin C defect
methylmalonic aciduria with homocystinuria
Visual function
VEP
ERG
antioxidant drugs

Additional relevant MeSH terms:
Amino Acid Metabolism, Inborn Errors
Homocystinuria
Brain Diseases
Brain Diseases, Metabolic
Brain Diseases, Metabolic, Inborn
Central Nervous System Diseases
Connective Tissue Diseases
Genetic Diseases, Inborn
Hyperhomocysteinemia
Metabolic Diseases
Metabolism, Inborn Errors
Nervous System Diseases

ClinicalTrials.gov processed this record on October 29, 2014