| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Charcot-Marie-Tooth Disease type 1A |
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| E.1.1.1 | Medical condition in easily understood language |
| Charcot-Marie-Tooth Disease 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 | 20.0 |
| 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 |
Period 1: 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.
Period 2: For patients continuing after V9, the main objective will be to offer patients the opportunity to access to twice Dose 1 equivalent to Dose 2 of PXT3003, with a regular safety follow-up
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| E.2.2 | Secondary objectives of the trial |
Period 1:
Secondary objectives:
- 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 determine if PXT3003 slows the progression of the disease
- To assess the evolution of potential blood biomarkers and molecular changes in skin biopsy on the longer term.
Period 2: For patients continuing after V9, sefty follow-up and ONLS score follow-up on a 12-month frequency. |
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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).
Period 2
After V9, no sub-study
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| E.3 | Principal inclusion criteria |
Period 1
• Patients under P and D1 must have completed 15 months of double-blind treatment in the primary study CLN-PXT3003-02, including all procedures required at the Study Termination visit (V6) or patients under D2 prematurely discontinued from CLN-PXT3003-02 (due to sponsor decision on September 18th, 2017) must have performed an early V6
• Patients who completed the V6 assessments within 4 weeks prior to extension study or patients who have completed a new baseline visit (VB) if the V6 assessments were not completed in the 4 weeks prior to study entry.
• Female patients must agree to continue using an approved method of birth control throughout the extension study.
• Patients must sign a written informed consent, specific to the extension study, in order to participate in this study. For minor patients, both patient’s and parents’ consent shall be collected.
Period 2
• Patients must sign a written informed consent to continue after V9 to access to study treatment. |
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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, in the 4 weeks preceding study entry, as study CLN-PXT3003-02. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Period 1
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 up to 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.
Period 2
After V9, the incidence of TEAEs related to investigational product will be described. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Period 1: 9 months after the inclusion in the open-label study (either Dose 1 or Dose 2 equivalent to twice Dose 1)
Period 2: every 6 months until the end of the study, when 1st marketing authorization for PXT3003 is obtained (estimated in 2024)
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| E.5.2 | Secondary end point(s) |
Period 1
* Safety endpoints:
- Incidence of all TEAEs and their evaluation of type/nature, severity/intensity, seriousness, duration, relationship to study drug, and outcome;
- Incidence of AE leading to withdrawal of study drug;
- Changes in laboratory parameters, ECGs, vital signs and physical examination
*Efficacy endpoints:
The clinical response will be assessed by the change over time of the following efficacy endpoints:
- the Overall Neuropathy Limitation Scale (ONLS) score, and its arm and leg sub-items;
- the Charcot-Marie-Tooth Neuropathy Score - version 2 (CMTNS-V2), and its sub-items;
- the functional assessments measured by Nine-hole Peg Test (9-HPT), Quantified Muscular Testing (QMT) by hand grip and foot dorsiflexion dynamometry (mean of both sides), and Time to walk 10 meters;
- electrophysiological parameters assessing sensory and motor responses of ulnar and radial nerves (non-dominant side) including Compound Muscle Action Potential (CMAP) on ulnar nerve; Sensory Nerve Action Potential (SNAP) on radial nerve; and Nerve conduction velocity (NCV);
- the EuroQol 5-Dimensional Health-related Quality of Life scale (EQ-5D);
- the individualized main impairment in daily activities (defined at baseline with the patient) by self-assessment on visual analog scale.
For the patients receiving up to 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 patients improving on ONLS at end of treatment (V9) will be assessed in the patients receiving the active dose of PXT3003 up to 24 months (from groups D1-24m, D2-24m).
Period 2
After V9,
- the incidence of all TEAEs and their evaluation of type/nature, severity/intensity, seriousness, duration, relationship to study drug, and
outcome;
- the incidence of related TEAEs
- the incidence of TEAE leading to withdrawal of study drug
- the incidence of Serious TEAE, Related Serious TEAEs and Serious TEAE leading to withdrawal of the study drug
- changes in laboratory parameters, ECG's, vital signs and physical examination will be described.
*Efficacy Endpoints:
After V9, the Overall Neuropathy Limitation Scale (ONLS) score, and its arm and leg sub-items shall be assessed every 12 months and the clinical response will be assessed by the change over time of ONLS
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Period 1: 9 months after the inclusion in the open-label study (either Dose 1 or Dose 2 equivalent to twice Dose 1)
Period 2: every 6 months until the end of the study, when 1st marketing authorization for PXT3003 is obtained (estimated in 2024) |
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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 | 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 | 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 |
| Canada |
| United States |
| France |
| Netherlands |
| Spain |
| Belgium |
| United Kingdom |
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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 | 7 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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