E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Melas Syndrome and PDH deficency enchephalopathy |
Sindrome di Melas, Encefalopatia da deficit di PDH |
|
E.1.1.1 | Medical condition in easily understood language |
Mitochondrial disease |
malattia mitocondrilae |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10053872 |
E.1.2 | Term | MELAS syndrome |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10053872 |
E.1.2 | Term | MELAS syndrome |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10062950 |
E.1.2 | Term | Leigh syndrome |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to investigate the efficiency and safety of PB in patients with PDH deficiency and MELAS . |
Verificare la tollerabilità del PB nei pazienti con Encefalopatia da PDH e pazienti MELAS |
|
E.2.2 | Secondary objectives of the trial |
The secondary objectives are to identify novel biomarkers for these two diseases and to evaluate whether the clinical/biochemical efficacy detected in patients correlates with the response observed in the skin fibroblasts of PDH deficiency/MELAS patients and in cybrids from MELAS patients incubated with PB. |
Verificare l’efficacia del PB sulla base di dati biochimici e clinici nei pazienti con Encefalopatia da PDH e pazienti MELAS; Valutare la correlazione dei dati biochimici e clinici con la risposta al PB nei fibroblasti dei pazienti PDH e nei cibridi dei pazienti MELAS e identificare nuovi biomarker per questi due gruppi di malattie |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
The inclusion criteria are: 1. Age between 3 and 65 years old 2. Confirmed molecular diagnosis: mutations in PDHA1 and m.3 243A>G mtDNA point mutation 3. Plasma lactic acid =2100 umol/l (normal value . 580-2100) 4. Availability of brain MRI and MRSI at baseline (pre-treatment); 5. Availability of PDH residual activity in cultured fibroblasts in PDH1A patients at baseline (pre-treatment) 6. Written informed consent (and assent when applicable) obtained from subject or subject’s legal representative and ability for subject to comply with the requirements of the study. |
1. Età compresa tra i 3 ed i 65 anni 2.Diagnosi molecolare (mutazione in PDHA1 o mutazione m.3243A>G nel DNA mitocondriale per i pz MELAS ) 3.Lattato plasmatico>2100 Umol/l (vn 580-2100) 4.Disponibilità della RM encefalo e della spettroscopiaprima dell’inizio del trattamento (baseline) 5.Disponibilità del dato di attività della PDH nei fibroblasti dei pz con Encefalopatia da difetto della PDH alla baseline 6. Disponibilità del consenso informato scritto |
|
E.4 | Principal exclusion criteria |
The exclusion criteria will be: 1) Comorbidity with other chronic diseases. 2) Other experimental treatment in the previous 6 months. 3) Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study 4) At Screening, the estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2. 5) At Screening presence of history of liver failure. 6) Subject has undergone an in-patient hospitalization within the 30 days prior to the Baseline Visit or has a planned hospitalization or a surgical procedure during the trial. 7) Subject has a history of active substance abuse during the year before the Baseline Visit, in the opinion of the Investigator. 8) Subject has any prior or current medical condition that, would prevent the subject from safely participating in and/or completing all trial requirements . 9) The patient will be excluded from the study if he presents a hart insufficiency ( FE < 40% ) severe renal failure (GRF GFR between 29 and 15 ml/min) clinical conditions in which sodium retention is found with edema, fructose intolerance, glucose / galactose malabsorption or saccharose or isomaltase enzyme deficiencies. 10) Hypersensitivity to the drug or to the excipients. 11) Not able to obtain written informed consent (and assent when applicable) from subject or subject’s legal representative and ability for subject to comply with the requirements of the study. |
Criteri di esclusione: 1. Comorbidità con altre patologie croniche, 2.Pazienti sottoposti ad altre terapie sperimentali nei 6 mesi precedenti .. 3. Paziente in gravidanza o in allattamento, o non disposto a praticare il controllo delle nascite durante la partecipazione allo studio 4. Allo screening (eGFR) < 30 mL/min/1.73 m2 5. Allo screening anamnesi positiva per epatopatia 6. Soggetto che ha subito un ricovero ospedaliero entro i 30 giorni precedenti la visita di base o ha un ricovero ospedaliero pianificato o una procedura chirurgica durante lo studio. 7. Anamnesi positiva per abuso di sostanza stupefacenti o alcolitici 8.Condizione medica precedente o attuale che, impedirebbe al soggetto di partecipare in sicurezza e / o completare lo studio. 9. Grave insufficienza cardiaca (FE <40%), una grave insufficienza renale (GRF GFR tra 29 e 15 ml / min) o condizioni cliniche per cui ha ritenzione di sodio con edema, intolleranza al fruttosio, glucosio / malassorbimento di galattosio o carenze di enzimi saccarosio o isomaltasi. 10. Ipersensibilità al farmaco o ai suoi eccipienti 11. Non in grado di fornire il consenso informato scritto (o l'assenso quando applicabile) o impossibilità di ottenere il consenso dal rappresentante legale del soggetto e incapacità del soggetto di conformarsi ai requisiti dello studio. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of the study is the reduction of lactic acidosis. |
Riduzione della concentrazione di acido lattico plasmatico . |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
All along the trial |
Tutto il tempo della sperimentazione |
|
E.5.2 | Secondary end point(s) |
A. Clinical efficiency of PB B. To evaluate the biochemical efficiency of PB, |
Efficacia clinica del PB Efficacia biochimica del PB |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
All along the trial |
Tutta la durata della sperimentazione |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
non esiste comparatore |
No comparison |
|
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
LVLS |
La sperimentazione si riterrà conclusa con l'ultima visita di follow up dell'ultimo paziente incluso |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |