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

Primary Purpose

Methylmalonic Aciduria and Homocystinuria,Cblc Type, Genetic Disease, Retinopathy

Status
Completed
Phase
Phase 2
Locations
Italy
Study Type
Interventional
Intervention
Epi-743
Placebo supplementation
Sponsored by
Bambino Gesù Hospital and Research Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Methylmalonic Aciduria and Homocystinuria,Cblc Type focused on measuring Cobalamin C defect, methylmalonic aciduria with homocystinuria, Visual function, VEP, ERG, antioxidant drugs

Eligibility Criteria

1 Year - 20 Years (Child, Adult)All SexesDoes not accept 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.

Sites / Locations

  • Bambino Gesù Hospital and Research Institute

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

EPI-743

Placebo supplementation

Arm Description

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

placebo in the same formulation as the active comparator will be administered to patients, assigned to this arm in a randomized design

Outcomes

Primary Outcome Measures

Change in Visual Function
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
Steady-state luminance VEPs to sinusoidal flicker at the optimal frequency of 8 Hz.
Evaluation of neurological function
Evaluation of neurological function with Gross motor function measure, movement ABC

Full Information

First Posted
February 8, 2013
Last Updated
April 22, 2017
Sponsor
Bambino Gesù Hospital and Research Institute
Collaborators
Catholic University of the Sacred Heart
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1. Study Identification

Unique Protocol Identification Number
NCT01793090
Brief Title
EPI-743 in Cobalamin C Defect: Effects on Visual and Neurological Impairment
Official Title
Phase 2, Double-Blind, Placebo Controlled Clinical Trial of EPI-743 in Subjects With Cobalamin C Defect
Study Type
Interventional

2. Study Status

Record Verification Date
April 2017
Overall Recruitment Status
Completed
Study Start Date
January 2013 (Actual)
Primary Completion Date
July 2013 (Actual)
Study Completion Date
February 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Bambino Gesù Hospital and Research Institute
Collaborators
Catholic University of the Sacred Heart

4. Oversight

Data Monitoring Committee
No

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Methylmalonic Aciduria and Homocystinuria,Cblc Type, Genetic Disease, Retinopathy
Keywords
Cobalamin C defect, methylmalonic aciduria with homocystinuria, Visual function, VEP, ERG, antioxidant drugs

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
EPI-743
Arm Type
Active Comparator
Arm Description
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
Arm Title
Placebo supplementation
Arm Type
Placebo Comparator
Arm Description
placebo in the same formulation as the active comparator will be administered to patients, assigned to this arm in a randomized design
Intervention Type
Drug
Intervention Name(s)
Epi-743
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Placebo supplementation
Intervention Description
Placebo will be administered in the same formulation as the active comparator
Primary Outcome Measure Information:
Title
Change in Visual Function
Description
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
Time Frame
Baseline, six months, twelve months
Secondary Outcome Measure Information:
Title
Change in steady-state luminance Visual Evoked Potentials
Description
Steady-state luminance VEPs to sinusoidal flicker at the optimal frequency of 8 Hz.
Time Frame
Baseline, six months, twelve months
Title
Evaluation of neurological function
Description
Evaluation of neurological function with Gross motor function measure, movement ABC
Time Frame
Baseline, six months, twelve months
Other Pre-specified Outcome Measures:
Title
Biomarkers of redox state
Description
Glutathione species in blood cells, Antioxidant enzymes expression, redox proteomic studies
Time Frame
Baseline, six months, twelve months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
20 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Carlo Dionisi-Vici, MD
Organizational Affiliation
Bambino Gesù Hospital and Research Institute
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Giancarlo Iarossi, MD
Organizational Affiliation
Bambino Gesù Hospital and Research Institute
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Daniela Ricci, MD,PhD
Organizational Affiliation
Catholic University of the Sacred Heart
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Diego Martinelli, MD, PhD
Organizational Affiliation
Bambino Gesù Hospital and Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Bambino Gesù Hospital and Research Institute
City
Rome
ZIP/Postal Code
00165
Country
Italy

12. IPD Sharing Statement

Citations:
PubMed Identifier
20632110
Citation
Martinelli D, Deodato F, Dionisi-Vici C. Cobalamin C defect: natural history, pathophysiology, and treatment. J Inherit Metab Dis. 2011 Feb;34(1):127-35. doi: 10.1007/s10545-010-9161-z. Epub 2010 Jul 15.
Results Reference
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PubMed Identifier
18164228
Citation
Nogueira C, Aiello C, Cerone R, Martins E, Caruso U, Moroni I, Rizzo C, Diogo L, Leao E, Kok F, Deodato F, Schiaffino MC, Boenzi S, Danhaive O, Barbot C, Sequeira S, Locatelli M, Santorelli FM, Uziel G, Vilarinho L, Dionisi-Vici C. Spectrum of MMACHC mutations in Italian and Portuguese patients with combined methylmalonic aciduria and homocystinuria, cblC type. Mol Genet Metab. 2008 Apr;93(4):475-80. doi: 10.1016/j.ymgme.2007.11.005. Epub 2007 Dec 27.
Results Reference
background
PubMed Identifier
15944903
Citation
Ricci D, Pane M, Deodato F, Vasco G, Rando T, Caviglia S, Dionisi-Vici C, Mercuri E. Assessment of visual function in children with methylmalonic aciduria and homocystinuria. Neuropediatrics. 2005 Jun;36(3):181-5. doi: 10.1055/s-2005-865609.
Results Reference
background
PubMed Identifier
14706491
Citation
Trisciuzzi MT, Riccardi R, Piccardi M, Iarossi G, Buzzonetti L, Dickmann A, Colosimo C Jr, Ruggiero A, Di Rocco C, Falsini B. A fast visual evoked potential method for functional assessment and follow-up of childhood optic gliomas. Clin Neurophysiol. 2004 Jan;115(1):217-26. doi: 10.1016/s1388-2457(03)00282-7.
Results Reference
background
PubMed Identifier
16602092
Citation
Deodato F, Boenzi S, Santorelli FM, Dionisi-Vici C. Methylmalonic and propionic aciduria. Am J Med Genet C Semin Med Genet. 2006 May 15;142C(2):104-12. doi: 10.1002/ajmg.c.30090.
Results Reference
background
PubMed Identifier
17301081
Citation
Carrozzo R, Dionisi-Vici C, Steuerwald U, Lucioli S, Deodato F, Di Giandomenico S, Bertini E, Franke B, Kluijtmans LA, Meschini MC, Rizzo C, Piemonte F, Rodenburg R, Santer R, Santorelli FM, van Rooij A, Vermunt-de Koning D, Morava E, Wevers RA. SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness. Brain. 2007 Mar;130(Pt 3):862-74. doi: 10.1093/brain/awl389. Epub 2007 Feb 14.
Results Reference
background
PubMed Identifier
16763906
Citation
Dionisi-Vici C, Deodato F, Roschinger W, Rhead W, Wilcken B. 'Classical' organic acidurias, propionic aciduria, methylmalonic aciduria and isovaleric aciduria: long-term outcome and effects of expanded newborn screening using tandem mass spectrometry. J Inherit Metab Dis. 2006 Apr-Jun;29(2-3):383-9. doi: 10.1007/s10545-006-0278-z.
Results Reference
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EPI-743 in Cobalamin C Defect: Effects on Visual and Neurological Impairment

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