Genetic Disease, Methylmalonic Aciduria and Homocystinuria,Cblc Type, Retinopathy
Conditions
Keywords
Cobalamin C defect, methylmalonic aciduria with homocystinuria, Visual function, VEP, ERG, antioxidant drugs
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.
Interventions
DRUGEpi-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.
OTHERPlacebo supplementation
Placebo will be administered in the same formulation as the active comparator
Sponsors
Catholic University of the Sacred Heart
Bambino Gesù Hospital and Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
1 Years to 20 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Visual Function | Baseline, six months, twelve months | 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
| Measure | Time frame | Description |
|---|---|---|
| Change in steady-state luminance Visual Evoked Potentials | Baseline, six months, twelve months | Steady-state luminance VEPs to sinusoidal flicker at the optimal frequency of 8 Hz. |
| Evaluation of neurological function | Baseline, six months, twelve months | Evaluation of neurological function with Gross motor function measure, movement ABC |
Other
| Measure | Time frame | Description |
|---|---|---|
| Biomarkers of redox state | Baseline, six months, twelve months | Glutathione species in blood cells, Antioxidant enzymes expression, redox proteomic studies |
Countries
Italy
Outcome results
None listed