Methylmalonic Aciduria and Homocystinuria,Cblc TypePhase 2NCT01793090
EPI-743 in Cobalamin C Defect: Effects on Visual and Neurological Impairment
A Phase 2 study testing Epi-743 in people with Methylmalonic Aciduria and Homocystinuria,Cblc Type and Genetic Disease, run by Bambino Gesù Hospital and Research Institute at 1 site in Italy.
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. Read more about this study
- Who is it for?
- Ages 1 year to 20 years
- Conditions the study is for
- Methylmalonic Aciduria and Homocystinuria,Cblc Type, Genetic Disease, Retinopathy
- What is being tested?
- Epi-743
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 30 participants
- Where
- 1 siteItaly
- Study dates
- Jan 2013to Feb 2017
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year to 20 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Phase 2, Double-Blind, Placebo Controlled Clinical Trial of EPI-743 in Subjects With Cobalamin C Defect
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.
Read the 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.
- Being tested
- Epi-743, Placebo supplementation
- Keywords
- Cobalamin C defect, methylmalonic aciduria with homocystinuria, Visual function, VEP, ERG, antioxidant drugs
- Medical subject headings
- Methylmalonic acidemia with homocystinuria, Genetic Diseases, Inborn, Retinal Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Epi-743Drug
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 supplementationOther
Placebo will be administered in the same formulation as the active comparator
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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 Receives: Other: Placebo supplementation |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: Baseline, six months, twelve months
Secondary outcomes (2)
Change in steady-state luminance Visual Evoked Potentials
Steady-state luminance VEPs to sinusoidal flicker at the optimal frequency of 8 Hz.
Measured: Baseline, six months, twelve months
Evaluation of neurological function
Evaluation of neurological function with Gross motor function measure, movement ABC
Measured: Baseline, six months, twelve months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Feb 2013 (estimated)
- Study startJan 2013
- Primary completionJul 2013
- Study completionFeb 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (7)Papers the sponsor has linked to this study.
- Other trials for Methylmalonic Aciduria and Homocystinuria,Cblc TypeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- Bambino Gesù Hospital and Research Institute
- Sponsor type
- University, hospital or other
- Collaborators
- Catholic University of the Sacred Heart
- Responsible party
- Principal investigator, Giancarlo Iarossi, Bambino Gesù Hospital and Research Institute
- Investigators
- Carlo Dionisi-Vici, MD, Study chair, Bambino Gesù Hospital and Research InstituteGiancarlo Iarossi, MD, Principal investigator, Bambino Gesù Hospital and Research InstituteDaniela Ricci, MD,PhD, Principal investigator, Catholic University of the Sacred HeartDiego Martinelli, MD, PhD, Principal investigator, Bambino Gesù Hospital and Research Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01793090
- Sponsor's protocol ID
- R-12-92
- Status last verified
- Apr 2017
- First submitted
- 8 Feb 2013
- Last updated
- 25 Apr 2017
- Results posted
- No
- Data monitoring committee
- No
Publications
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.
PubMed 20632110Nogueira 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.
PubMed 18164228Ricci 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.
PubMed 15944903Trisciuzzi 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.
PubMed 14706491Deodato 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.
PubMed 16602092Carrozzo 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.
PubMed 17301081Dionisi-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.
PubMed 16763906
Study at a glance
From the registry record, last updated by the sponsor on 25 Apr 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 2, Double-Blind, Placebo Controlled Clinical Trial of EPI-743 in Subjects With Cobalamin C Defect
- ClinicalTrials.gov ID
- NCT01793090
- Acronym / sponsor ID
- R-12-92
- Keywords
- Cobalamin C defect, methylmalonic aciduria with homocystinuria, Visual function, VEP, ERG, antioxidant drugs
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- Bambino Gesù Hospital and Research InstituteUniversity, hospital or other
- Collaborators
- Catholic University of the Sacred Heart
- Study start
- Jan 2013 (actual)
- Primary completion
- Jul 2013 (actual)
- Study completion
- Feb 2017 (actual)
- First posted
- 15 Feb 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| EPI-743 | Active comparator | Drug: Epi-743EPI- 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 |
| Placebo supplementation | Placebo comparator | Other: Placebo supplementationplacebo in the same formulation as the active comparator will be administered to patients, assigned to this arm in a randomized design |
Who may qualify
- Ages
- 1 year to 20 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (2 listed)
- 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.
Key exclusion criteria (5 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Epi-743EPI- 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. | Drug | EPI-743 |
| Placebo supplementationPlacebo will be administered in the same formulation as the active comparator | Other | Placebo supplementation |
Primary outcome
Change in Visual Function
Time frame: 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
2 secondary outcomes
Change in steady-state luminance Visual Evoked Potentials
Time frame: Baseline, six months, twelve months
Evaluation of neurological function
Time frame: Baseline, six months, twelve months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Apr 2017.
- Background: PubMed 20632110Martinelli 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.
- Background: PubMed 18164228Nogueira 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.
- Background: PubMed 15944903Ricci 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.
- Background: PubMed 14706491Trisciuzzi 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.
- Background: PubMed 16602092Deodato 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.
- Background: PubMed 17301081Carrozzo 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.
- Background: PubMed 16763906Dionisi-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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Carlo Dionisi-Vici, MD study chair
Bambino Gesù Hospital and Research Institute
Giancarlo Iarossi, MD principal investigator
Bambino Gesù Hospital and Research Institute
Daniela Ricci, MD,PhD principal investigator
Catholic University of the Sacred Heart
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Epi-743 in people with Methylmalonic Aciduria and Homocystinuria,Cblc Type and Genetic Disease, run by Bambino Gesù Hospital and Research Institute at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 25 Apr 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Visual Function (time frame: Baseline, six months, twelve months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01793090, which also lists 7 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Apr 2017.