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

April 22, 2017 updated by: Giancarlo Iarossi, Bambino Gesù Hospital and Research Institute

Phase 2, Double-Blind, Placebo Controlled Clinical Trial of EPI-743 in Subjects With Cobalamin C Defect

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

30

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Rome, Italy, 00165
        • Bambino Gesù Hospital and Research Institute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

4 months to 18 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Visual Function
Time Frame: 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
Baseline, six months, twelve months

Secondary Outcome Measures

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

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Biomarkers of redox state
Time Frame: Baseline, six months, twelve months
Glutathione species in blood cells, Antioxidant enzymes expression, redox proteomic studies
Baseline, six months, twelve months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Bambino Gesù Hospital and Research Institute

Collaborators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 1, 2013

Primary Completion (Actual)

July 1, 2013

Study Completion (Actual)

February 1, 2017

Study Registration Dates

First Submitted

February 8, 2013

First Submitted That Met QC Criteria

February 13, 2013

First Posted (Estimate)

February 15, 2013

Study Record Updates

Last Update Posted (Actual)

April 25, 2017

Last Update Submitted That Met QC Criteria

April 22, 2017

Last Verified

April 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • R-12-92

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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