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

NCT ID: NCT01793090

Last Updated: 2017-04-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-01-31
• Study Completion Date: 2017-02-28

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.

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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

Group Type: ACTIVE_COMPARATOR

Epi-743

Intervention Type: 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.

Placebo supplementation

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

Group Type: PLACEBO_COMPARATOR

Placebo supplementation

Intervention Type: OTHER

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

Interventions

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.

Intervention Type: DRUG

Placebo supplementation

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

Intervention Type: OTHER

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.

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 20 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Catholic University of the Sacred Heart

OTHER

Sponsor Role: collaborator

Bambino Gesù Hospital and Research Institute

OTHER

Sponsor Role: lead

Responsible Party

Giancarlo Iarossi

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Carlo Dionisi-Vici, MD

Role: STUDY_CHAIR

Bambino Gesù Hospital and Research Institute

Giancarlo Iarossi, MD

Role: PRINCIPAL_INVESTIGATOR

Bambino Gesù Hospital and Research Institute

Daniela Ricci, MD,PhD

Role: PRINCIPAL_INVESTIGATOR

Catholic University of the Sacred Heart

Diego Martinelli, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Bambino Gesù Hospital and Research Institute

Locations

Bambino Gesù Hospital and Research Institute

Rome, , Italy

Countries

Italy

References

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.

Reference Type: BACKGROUND

PMID: 20632110 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18164228 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15944903 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 14706491 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 16602092 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 17301081 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 16763906 (View on PubMed)

Other Identifiers

R-12-92

Identifier Type: -

Identifier Source: org_study_id