E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Charcot-Marie-Tooth Disease type 1A |
Maladie de Charcot-Marie-Tooth Type 1A |
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E.1.1.1 | Medical condition in easily understood language |
Charcot-Marie-Tooth Disease type 1A |
Maladie de Charcot-Marie-Tooth Type 1A |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008414 |
E.1.2 | Term | Charcot-Marie-Tooth disease |
E.1.2 | System Organ Class | 100000004850 |
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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 |
The main objective of the study is to assess the long-term safety and tolerability of PXT3003 up to 2 years, and to increase the exposed population receiving PXT3003 for at least 9 months. |
L'objectif principal de l'étude est d'évaluer la sécurité d'emploi à long terme et la tolérance de PXT3003 pendant 2 ans, et d'augmenter la population exposée recevant PXT3003 pendant au moins 9 mois. |
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E.2.2 | Secondary objectives of the trial |
To gather up-to-2-year data to estimate the long term effect of PXT3003 on clinical, functional and electrophysiological endpoints; - To compare the effect of PXT3003 in patients receiving PXT3003 active dose from the start of the primary study to patients assigned to a delayed start (i.e., who received placebo during the primary study) in order to show if PXT3003 slows the progression of the disease - To assess the evolution of potential blood biomarkers and molecular changes in skin biopsy on longer term.
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- Recueillir des données pendant 2 ans pour estimer l'effet à long terme du PXT3003 : paramètres cliniques, fonctionnels et électrophysiologiques ; - Comparer l'effet de PXT3003 chez les patients recevant la dose active de PXT3003 depuis le début de l'étude principale aux patients inclus avec un début différé (c'est-à-dire qui ont reçu un placebo pendant l'étude principale) et ce, afin de montrer si PXT3003 ralentit la progression de la maladie ; - Évaluer l'évolution dans le temps de potentiels biomarqueurs sanguins et de changements moléculaires dans la biopsie cutanée. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
• Skin Biopsy (ancillary sub-study) for molecular biology will be done at the end of the study (9-month visit) • MRI measure (ancillary sub-study) of muscle/fat index in the leg (by MRI quantification of lower limb muscles and fatty muscle infiltration) will be performed at the end of the study (9-month visit).
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• biopsie cutanée (sous-étude ancillaire) pour la biologie moléculaire sera réalisée à la fin de l'étude (visite 9) • IRM des 2 jambes (sous-étude ancillaire) afin de mesurer l'indice muscle/graisse (quantification par IRM de l'infiltration graisseuse des membres inférieurs ) réalisée à la fin de l'étude (visite 9) |
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E.3 | Principal inclusion criteria |
Male or female patients with all of the following inclusion criteria will be considered for randomization: 1. Patient previously randomized to the initial PLEO-CMT study (protocol CLN-PXT3003-02) and having completed 15 months of double-blind treatment in that study, including all procedures required at the Study Termination visit (V6) 2. Patient providing a signed written informed consent to participate in the extension study and willing and able to comply with all study procedures and scheduled visits. 3. Female patients must agree to continue using an approved method of birth control throughout the extension study |
Les patients doivent satisfaire à tous les critères suivants pour la randomisation: 1. Les patients doivent avoir complété 15 mois de traitement en double aveugle dans l'étude principale, CLN-PXT3003-02, y compris toutes les procédures requises lors de la visite de fin d'étude (V6). 2. Les patientes, en âge de procréer, doivent accepter de continuer à utiliser une méthode hautement efficace de contraception tout au long de l'étude d'extension. 3. Les patients doivent signer un consentement éclairé écrit, spécifique à l'étude d'extension, afin de participer à celle-ci. |
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E.4 | Principal exclusion criteria |
Patients with any of the following criteria will be excluded from entry: 1. Presenting any clinically significant change in health status that, in the opinion of the Investigator, would prevent the subject from participating in this study or successfully completing this study. 2. Any unauthorized concomitant treatments, as study CLN-PXT3003-02. |
Les patients seront exclus de l'étude en présence de l'un ou de plusieurs des critères suivants : 1. Tout changement clinique significatif de l'état de santé qui, de l'avis de l'investigateur, empêcherait le patient de participer à cette étude ou de terminer celle-ci. 2. Utilisation de traitement concomitant non-autorisé et attendue, identique à ceux décrit dans CLN-PXT3003-02, étude principale, se référer à l’Appendix 1. |
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E.5 End points |
E.5.1 | Primary end point(s) |
To assess the safety and tolerability of PXT3003 in CMT1A patients during a long term period, the primary endpoint will be the incidence of Treatment-Emergent Adverse Events (TEAEs) Related to the Investigational Product during the follow-up, in patients exposed to PXT3003 for 24 months or 9 months. The incidence of TEAEs in the two groups P / D1-9m and P/ D2-9m will be compared to the first 9-month placebo period in the primary study. The incidence of TEAEs in the two groups D1-24m, D2-24m will be compared to the first 9-month period in the primary study for their corresponding group.
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Pour évaluer la sécurité à l'emploi et la tolérance de PXT3003 chez les patients CMT1A pendant une longue période, le critère d'évaluation principal sera l'incidence des événements indésirables émergeant après traitement (Treatment-Emergent Adverse Event ; TEAE) pendant l'étude d'extension chez des patients exposés à PXT3003 pendant 24 mois ou 9 mois. L'incidence des TEAE dans les deux groupes P/D1-9m et P/D2-9m sera comparée aux 9 premiers mois sous placebo dans l'étude principale. L'incidence des TEAE dans les deux groupes D1-24m, D2-24m sera comparée aux 9 premiers mois sous placebo dans leur groupe respectif. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The incidence of TEAEs in the two groups P/ D1-9m and P / D2-9m will be compared to the first 9-month placebo period in the primary study. The incidence of TEAEs in the two groups D1-24m, D2-24m will be compared to the first 9-month period in the primary study for their corresponding group
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L'incidence des TEAE dans les deux groupes P/D1-9m et P/D2-9m sera comparée aux 9 premiers mois sous placebo dans l'étude principale. L'incidence des TEAE dans les deux groupes D1-24m, D2-24m sera comparée aux 9 premiers mois sous placebo dans leur groupe respectif. |
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E.5.2 | Secondary end point(s) |
Secondary safety endpoints will be: - The incidence of all Treatment-Emergent Adverse Events (TEAEs) and evaluation of their type/nature, severity/intensity, seriousness, duration, relationship to study drug, and outcome; - The incidence of AEs leading to withdrawal of study drug; - The changes in laboratory parameters, ECGs, vital signs and physical examinations;
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D'autres paramètres de safety seront évalués : - Incidence de tous les TEAE. Ils seront évalués par type/nature, sévérité/intensité, gravité, durée, relation au traitement étudié, et résolution. - Incidence des évènements indésirables (Adverse Event ; AE) entraînant l'arrêt du traitement à l'étude ; - Changements des paramètres biologiques, des ECGs, signes vitaux et examens physiques ; |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
For the patients receiving 24 months of active dose along the two successive studies (from groups D1-24m and D2-24m) the clinical response will be assessed by the change from V1/baseline of each endpoint. For the patients who received placebo during the 15-month primary study and active drug during the 9-month extension study (from groups P/D1-9m and P/D2-9m) the clinical response will be assessed after 9 months of PXT3003 treatment by the change from V6/baseline. The Percentage of responders to PXT3003 defined as a patients improving on ONLS at end of treatment (V9) will be assessed in the patients receiving the active dose of PXT3003 during 24 months (from groups D1-24m, D2-24m).
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Pour les patients recevant 24 mois de dose active pendant les deux études successives (soit les groupes D1-24m et D2-24m) la réponse clinique sera évaluée par le changement depuis V1 / baseline des critères d'évaluation. Pour les patients qui ont reçu du placebo pendant 15 mois dans l'étude principale et le traitement à l'étude dans l'extension pendant 9 mois (des groupes P/ D1-9m et P / D2-9m), la réponse clinique sera évaluée après 9 mois de traitement de PXT3003 par le changement depuis V6 / baseline des critères d'évaluation. Le pourcentage de répondeurs au PXT3003 est défini comme des patients ayant amélioré leur score ONLS à la fin du traitement (V9) ; il sera évalué chez les patients ayant reçu la dose active de PXT3003 pendant 24 mois (soit les groupes D1-24m, D2-24m). |
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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 | 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) | 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 | No |
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 | No |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
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 | No |
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 |
Belgium |
Canada |
France |
Germany |
Netherlands |
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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LVLS |
Dernière visite du dernier patient |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
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 | 8 |