E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary Mitochondrial Disease Resulting from Pathogenic Nuclear DNA Mutations (nPMD) |
Malattia mitocondriale primaria derivante da Mutazioni del DNA nucleare patogeno (nPMD) |
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E.1.1.1 | Medical condition in easily understood language |
Nuclear Primary Mitochondrial Disease (nPMD) |
Malattia mitocondriale primaria nucleare e (nPMD) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
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 | 10027710 |
E.1.2 | Term | Mitochondrial myopathy |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10010331 |
E.1.2 | Term | Congenital, familial and genetic disorders |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10052635 |
E.1.2 | Term | Cytoplasmic disorders congenital |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10052637 |
E.1.2 | Term | Genetic mitochondrial abnormalities NEC |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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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 |
• To evaluate the effect of single daily SC administration of elamipretide for 48 weeks on the: - Distance walked (in meters) on the 6-Minute Walk Test (6MWT) |
valutare l'effetto della singola somministrazione sottocute giornaliera di elamipretide per 48 settimane su: -distanza percorsa in metri nell test di camminata di 6 minuti (6MWT) |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the effect of single daily SC administration of elamipretide for 48 weeks as measured by changes in the: - Total time (in seconds) the Five-Times Sit-to-Stand Test (5XSST) - Total time (in seconds) the Triple Timed Up-and-Go Test (3TUG) - Patient Global Impression (PGI) of Change Scale
• To evaluate the safety and tolerability of single daily SC doses of elamipretide administered for 48 weeks |
• Valutare l'effetto della singola somministrazione sottocutanea giornaliera di elamipretide per 48 settimane, misurato sulle variazioni del: - Tempo totale (in secondi) del test del passaggio dalla posizione seduta alla posizione eretta per cinque volte (Five-Times Sit-to-Stand Test, 5XSST) - Tempo totale (in secondi) del test Timed Up-and-Go in triplicato (3TUG) - Scala della percezione globale del cambiamento da parte del paziente (Patient Global Impression, PGI)
• Valutare la sicurezza e la tollerabilità di dosi singole giornaliere s.c. di elamipretide somministrato per 48 settimane |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Willing and able to provide a signed informed consent form (ICF) prior to participation in any trial-related procedures. 2. Agrees and is able to adhere to the trial requirements for the length of the trial, including administration of assigned treatment. 3. Is =18 years and = 70 years of age at the time of screening. 4. Diagnosed with nPMD with a predominant clinical manifestation of myopathy, which must include progressive external ophthalmoplegia (PEO) and exercise intolerance and/or skeletal muscle weakness, with genetic confirmation of either: a. Nuclear DNA mutation of the mitochondrial replisome (replisome related mutations), which include the following genes: - POLG 1/2 - TWINKLE (C10ORF2) - TYMP - DGUOK - TK2 - RRM2B - RNASEH1 - SSBP - MGME1 - DNA2 - ANT1 (SLC25A4) - SUCLG1 - SUCLA2 - MPV17 or b. Other pathogenic mutations specific to nuclear DNA. 5. Women of childbearing potential must agree to use one of the following methods of birth control from the date they sign the ICF until 28 days after the last dose of IMP: a. Abstinence, when it is in line with the preferred and usual lifestyle of the subject. Subject agrees to use a highly effective method of contraception should they become sexually active. b. Relationships with male partners who have been surgically sterilized by vasectomy (the vasectomy procedure must have been conducted at least 60 days prior to the Screening Visit). c. Barrier method (e.g., condom or occlusive cap) with spermicidal foam/gel/film/cream AND either hormonal contraception (oral, implanted, or injectable) or an intrauterine device or system. Note: Non-childbearing potential is defined as surgical sterilization (e.g., bilateral oophorectomy, hysterectomy, or tubal ligation) or postmenopausal (defined as permanent cessation of menstruation for at least 12 consecutive months prior to the Screening Visit). 6. Male subjects with female partners of childbearing potential must be willing to use a highly effective method of contraception from the date they sign the ICF until 28 days after the last dose of IMP. |
1. Disponibilità e capacità di fornire un ICF firmato prima della partecipazione a qualsiasi procedura correlata allo studio. 2. Capacità e consenso ad aderire ai requisiti della sperimentazione per la durata della stessa, inclusa la somministrazione del trattamento assegnato. 3. Età =18 e =70 anni al momento dello screening. 4. Diagnosi di nPMD con una manifestazione clinica predominante di miopatia, che deve includere oftalmoplegia esterna progressiva (Progressive External Ophthalmoplegia, PEO) e intolleranza all'esercizio e/o debolezza muscolo-scheletrica, con conferma genetica di: a. Mutazione del DNA nucleare del replisoma mitocondriale (mutazione correlata al replisoma), che include i seguenti geni: - POLG 1/2 - TWINKLE (C10ORF2) - TYMP - DGUOK - TK2 - RRM2B - RNASEH1 - SSBP - MGME1 - DNA2 - ANT1 (SLC25A4) - SUCLG1 - SUCLA2 - MPV17 oppure b. Altre mutazioni patogene specifiche del DNA nucleare. 5. Le donne in età fertile devono accettare di utilizzare 1 dei seguenti metodi contraccettivi dalla data di firma dell'ICF fino a 28 giorni dopo l'ultima dose dell'IMP: a. Astinenza, se conforme allo stile di vita usuale e preferito dal soggetto. Il soggetto accetta di utilizzare un metodo contraccettivo altamente efficace nel caso in cui diventi sessualmente attivo. Rapporti con partner di sesso maschile sterilizzati chirurgicamente mediante vasectomia (la vasectomia deve essere stata eseguita almeno 60 giorni prima della visita di screening). c. Metodo di barriera (p. es., preservativo o cappuccio occlusivo) con schiuma/gel/pellicola/crema spermicida E contraccezione ormonale (orale, impiantata o iniettabile) o dispositivo o sistema intrauterino. Nota: le partecipanti sono considerate non potenzialmente fertili se sottoposte a sterilizzazione chirurgica (ad es. ovariectomia bilaterale, isterectomia o legatura delle tube) o in postmenopausa (definita come cessazione permanente delle mestruazioni per almeno 12 mesi consecutivi prima della visita di screening). 6. I soggetti di sesso maschile con partner di sesso femminile potenzialmente fertile devono essere disposti a utilizzare un metodo contraccettivo altamente efficace dalla data di firma dell'ICF fino a 28 giorni dopo l'ultima dose dell'IMP. |
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E.4 | Principal exclusion criteria |
1. Subject is unable to perform the 6MWT, 3TUG, or 5XSST functional tests. The use of a gait assist device is allowed; however, use should remain consistent for the entire duration of the trial. 2. Female subjects who are pregnant, planning to become pregnant, or breastfeeding/lactating. 3. Walks < 200 meters or > 450 meters during the 6MWT (Screening visit only). 4. The estimated glomerular filtration rate (eGFR) is < 30 mL/min/1.73 m2, using the Modification of Diet in Renal Disease (MDRD) Study equation (Screening visit only). 5. Subject has undergone an in-patient hospitalization within 30 days prior to screening or has a planned hospitalization or a surgical procedure during the trial, unless in the opinion of the Investigator it is concluded that it will not impact the outcome measurements of the trial. 6. Subject has clinically significant respiratory disease and/or cardiac disease that would interfere with trial assessments, in the opinion of the Investigator. 7. Subject has had any prior interventional cardiac procedure (e.g., cardiac catheterization, angioplasty/percutaneous coronary intervention, balloon valvuloplasty, etc.) within 3 months prior to screening. 8. Subject has history of or current severe neurologic impairment, severe epilepsy, severe ataxia, or severe neuropathy that may interfere with their ability to complete all trial requirements, in the opinion of the Investigator. 9. Active malignancy or any other cancer from which the subject has been disease-free for < 2 years. Localized squamous or non-invasive basal cell skin carcinomas are allowed, if appropriately treated prior to screening. 10. Subject has had a solid organ transplant. 11. Subject has been previously diagnosed with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection. 12. Subject has a history of a systemic eosinophilic illness and/or an eosinophil count >1,000 cells x106/L at the Screening Visit. 13. Subject is currently participating or has participated in an interventional clinical trial (i.e., investigational product or device, stem cell therapy, gene therapy) within 30 days prior to current trial; or is currently enrolled in a non-interventional clinical trial that, in the opinion of the Investigator, may be potentially confounding to the results of the current trial (e.g., exercise therapy trial). 14. Subject has received elamipretide (MTP-131) within the past one year of the Screening Visit. 15. Subject has a history of active substance abuse during the year prior, in the opinion of the Investigator. 16. Subject has any prior or current medical condition that, in the judgment of the Investigator, would prevent the subject from safely participating in and/or completing all trial assessments and requirements to the best of their ability. |
1. Soggetto non è in grado di eseguire i test funzionali 6MWT, 3TUG o 5XSST. È consentito l'uso di un dispositivo di assistenza alla deambulazione; tuttavia, l'uso deve rimanere costante per l'intera durata della sperimentazione. 2. Soggetti di sesso femminile in gravidanza, che pianificano una gravidanza o che allattano al seno. 3. Soggetto che cammina <200 metri o >450 metri durante il 6MWT (solo visita di screening). 4. Velocità di filtrazione glomerulare stimata (estimated Glomerular Filtration Rate, eGFR) <30 ml/min/1,73 m2, misurata utilizzando l'equazione dello studio sulla modifica della dieta nella malattia renale (Modification of Diet in Renal Disease, MDRD) (solo visita di screening). 5. Ricovero ospedaliero nei 30 giorni precedenti allo screening o ricovero o procedura chirurgica programmati durante lo studio, a meno che, secondo il parere dello sperimentatore, si concluda che ciò non influirà sulle misurazioni degli esiti dello studio. 6. Malattia respiratoria e/o cardiaca clinicamente significativa che, secondo il parere dello sperimentatore, interferirebbe con le valutazioni dello studio. 7. Precedente procedura cardiaca interventistica (ad es. cateterismo cardiaco, angioplastica/intervento coronarico percutaneo, valvuloplastica con palloncino, ecc.) nei 3 mesi precedenti lo screening. 8. Precedente o attuale grave compromissione neurologica, epilessia grave, atassia grave o grave neuropatia che, secondo il parere dello sperimentatore, potrebbe interferire con la capacità del soggetto di soddisfare tutti i requisiti dello studio. 9. Neoplasia maligna attiva o qualsiasi altro tumore da cui il soggetto è libero da <2 anni. Sono ammessi carcinomi cutanei basocellulari non invasivi o squamosi localizzati, se opportunamente trattati prima dello screening. 10. Precedente trapianto di un organo solido. 11. Diagnosi precedente di infezione da virus dell'immunodeficienza umana (HIV), epatite B o epatite C. 12. Anamnesi di malattia eosinofila sistemica e/o conta di eosinofili >1.000 cellule x106/l alla visita di screening. 13. Partecipazione a una sperimentazione clinica interventistica (ad es. su un prodotto o dispositivo sperimentale, una terapia con cellule staminali, una terapia genica) in corso o passata, nei 30 giorni precedenti la sperimentazione in oggetto; o soggetto attualmente arruolato in uno studio clinico non interventistico che, secondo il parere dello sperimentatore, potrebbe potenzialmente interferire con i risultati dello studio in oggetto (ad es., sperimentazione sulla terapia fisica). 14. Trattamento con elamipretide (MTP-131) nell'anno precedente la visita di screening. 15. Antecedenti Storia di abuso di principi attivi nell'anno precedente, secondo il parere dello sperimentatore. 16. Qualsiasi condizione medica precedente o attuale che, secondo il parere dello sperimentatore, impedirebbe al soggetto di partecipare in sicurezza e/o completare tutte le valutazioni e i requisiti della sperimentazione al meglio delle sue capacità. |
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E.5 End points |
E.5.1 | Primary end point(s) |
• To evaluate the effect of single daily SC doses of elamipretide administered for 48 weeks on the: - Distance walked (in meters) on the 6MWT |
• Valutare l'effetto di singole dosi giornaliere sottocutanee di elamipretide somministrato per 48 settimane su Distanza percorsa (in metri) nel test 6MWT |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
6MWT: At all clinical site visits (Screening; Day 1; Week 12; Week 24; Week 36; Week 48; EOT) |
6MWT: a tutte le visite al centro (Screening, Giorno1, Week12, Week24,Week 36; Week 48; EOT) |
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E.5.2 | Secondary end point(s) |
• To evaluate the effect of single daily SC doses of elamipretide administered for 48 weeks on the: - Total time (in seconds) on the Five Times Sit-to-Stand Test (5XSST) - Total time (in seconds) on the Triple Timed Up-and-Go Test (3TUG) - Patient Global Impression of Change (PGI) of Change Scale |
• Valutare l'effetto della singola somministrazione sottocutanea giornaliera di elamipretide per 48 settimane, misurato sulle variazioni del: - Tempo totale (in secondi) del test del passaggio dalla posizione seduta alla posizione eretta per cinque volte (Five-Times Sit-to-Stand Test, 5XSST) - Tempo totale (in secondi) del test Timed Up-and-Go in triplicato (3TUG) - Scala della percezione globale del cambiamento da parte del paziente (Patient Global Impression, PGI)
• Valutare la sicurezza e la tollerabilità di dosi singole giornaliere s.c. di elamipretide somministrato per 48 settimane |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
3TUG, 5XSST, PGI Tests: At all study site visits (Screening; Day 1; Week 12; Week 24; Week 36; Week 48; EOT)
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3TUG, 5XSST, PGI Tests: per tutte le visite al centro (Screening; Day 1; Week 12; Week 24; Week 36; Week 48; EOT) |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Tolerability, Biomarkers assessment etc. |
Tolerability, Biomarkers assessment etc. |
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Denmark |
Finland |
Germany |
Hungary |
Italy |
Netherlands |
Norway |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 27 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 27 |