NCT01793090

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

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

• Status: Completed
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 30 (actual)
• Sponsor: Bambino Gesù Hospital and Research Institute · Academic / Other
• Sex: All
• Age: 1 Year – 20 Years
• Healthy volunteers: Not accepted

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

Interventions

Type	Name	Description
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

Timeline

• Start date: 2013-01-01
• Primary completion: 2013-07-01
• Completion: 2017-02-01
• First posted: 2013-02-15
• Last updated: 2017-04-25

Locations

1 site across 1 country: Italy