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

NCT01793090 | Completed Phase 2

• 1 other identifier: R-12-92
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

Cobalamin C defect; methylmalonic aciduria with homocystinuria; Visual function; VEP; ERG; antioxidant drugs

Outcome Measures

Primary Outcomes (1)

• 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

  Baseline, six months, twelve months

Secondary Outcomes (2)

• Change in steady-state luminance Visual Evoked Potentials

  Baseline, six months, twelve months

• Evaluation of neurological function

  Baseline, six months, twelve months

Other Outcomes (1)

• Biomarkers of redox state

  Baseline, six months, twelve months

Study Arms (2)

EPI-743

ACTIVE COMPARATOR

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

Placebo supplementation

PLACEBO COMPARATOR

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

Interventions

Epi-743 DRUG

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.

EPI-743

Placebo supplementation OTHER

Placebo will be administered in the same formulation as the active comparator

Placebo supplementation

Eligibility Criteria

• Age: 1 Year - 20 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Bambino Gesù Hospital and Research Institute: lead
• Catholic University of the Sacred Heart: collaborator

Study Sites (1)

Bambino Gesù Hospital and Research Institute

Rome, 00165, Italy

Location

Related Publications (7)

• 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.

  PMID: 20632110 BACKGROUND

• 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.

  PMID: 18164228 BACKGROUND

• 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.

  PMID: 15944903 BACKGROUND

• 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.

  PMID: 14706491 BACKGROUND

• 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.

  PMID: 16602092 BACKGROUND

• 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.

  PMID: 17301081 BACKGROUND

• 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.

  PMID: 16763906 BACKGROUND

MeSH Terms

Conditions

Methylmalonic acidemia with homocystinuria; Genetic Diseases, Inborn; Retinal Diseases

Interventions

alpha-tocotrienol quinone

Condition Hierarchy (Ancestors)

Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Eye Diseases

Study Officials

• Carlo Dionisi-Vici, MD

  Bambino Gesù Hospital and Research Institute

  STUDY CHAIR

• 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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: February 8, 2013
• First Posted: February 15, 2013
• Study Start: January 1, 2013
• Primary Completion: July 1, 2013
• Study Completion: February 1, 2017
• Last Updated: April 25, 2017

Record last verified: 2017-04

Locations

IT (1)