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

Genetic Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01793090
• Other study ID #: R-12-92
• Status: Completed
• Phase: Phase 2
• First received: February 8, 2013
• Last updated: April 22, 2017
• Start date: January 2013
• Est. completion date: February 2017

Study information

• Verified date: April 2017
• Source: Bambino Gesù Hospital and Research Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: February 2017
• Est. primary completion date: July 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 20 Years

Eligibility

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.

Related Conditions & MeSH terms

• Amino Acid Metabolism, Inborn Errors
• Genetic Disease
• Homocystinuria
• Methylmalonic Aciduria and Homocystinuria,Cblc Type
• Retinopathy
• Vitamin B 12 Deficiency

Intervention

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.

Other:
• Placebo supplementation
Placebo will be administered in the same formulation as the active comparator

Locations

Country	Name	City	State
Italy	Bambino Gesù Hospital and Research Institute	Rome

Sponsors (2)

Lead Sponsor	Collaborator
Bambino Gesù Hospital and Research Institute	Catholic University of the Sacred Heart

Country where clinical trial is conducted

Italy, 

References & Publications (7)

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. Epub 2007 Feb 14. — View 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. Review. — View Citation

Dionisi-Vici C, Deodato F, Röschinger 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. Review. — View 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. Review. — View Citation

Nogueira C, Aiello C, Cerone R, Martins E, Caruso U, Moroni I, Rizzo C, Diogo L, Leão 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. — View Citation

Ricci D, Pane M, Deodato F, Vasco G, Randò 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Biomarkers of redox state	Glutathione species in blood cells, Antioxidant enzymes expression, redox proteomic studies	Baseline, six months, twelve months
Primary	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	Change in steady-state luminance Visual Evoked Potentials	Steady-state luminance VEPs to sinusoidal flicker at the optimal frequency of 8 Hz.	Baseline, six months, twelve months
Secondary	Evaluation of neurological function	Evaluation of neurological function with Gross motor function measure, movement ABC	Baseline, six months, twelve months