Assessing Long Term Safety and Tolerability of PXT3003 in Patients With Charcot-Marie-Tooth Disease Type 1A

Study Overview
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Brief Summary
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All randomised patients with Charcot-Marie-Tooth Type 1A (CMT1A) who completed the primary study CLN-PXT3003-02, i.e. treatment with PXT3003 or placebo, are eligible to continue in the extension study CLN-PXT3003-03. Period 1: Patients randomised to PXT3003 dose 1 or placebo in the primary study (CLN-PXT3003-02) continued in the extension study on PXT3003 dose 1 (5 mL). Patients randomised to PXT3003 dose 2 (5 mL) in the primary study (CLN-PXT3003-02) continued in the extension study on PXT3003 dose 2 or PXT3003 twice dose 1 (2x5 mL). Period 2: All patients continue on twice dose 1 (2X5mL).

Detailed Description
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PXT3003 is a rational design, fixed combination of low-dose (RS) baclofen, naltrexone hydrochloride and D-sorbitol. The use of PXT3003 in a multicenter, randomised, placebo controlled phase II study (CLN-PXT3003-01) was well-tolerated and safe in patients with CMT1A for the three dose-levels investigated (Attarian et al., 2014). The intermediate and high dose of PXT3003 demonstrated an improvement of disability in this patient population. Subsequently a multicenter, randomised, placebo controlled phase III study (CLN-PXT3003-02) to assess the efficacy and safety of PXT3003 in the treatment of patients with CMT1A was initiated in December 2015. In March 2017 the first patients completed the 15-month treatment with PXT3003 and rolled over into the extension study CLN-PXT3003-03. During Period 1 (9 months), patients that were randomised to PXT3003 dose 1 or placebo in the primary study (CLN-PXT3003-02) continued in the extension study on PXT3003 dose 1 (5 mL). Patients randomised to PXT3003 dose 2 (5 mL) in the primary study (CLN-PXT3003-02) continued in the extension study on on PXT3003 dose 2 or PXT3003 twice dose 1 (2x5 mL). During Period 2, all patients continue on twice dose 1 (2X5mL).

Official Title
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International, Multi-center, Open Label, Follow-up Extension Study Assessing the Long-term Safety and Tolerability of PXT3003 in Patients With Charcot-Marie-Tooth Disease Type 1A

Conditions
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Charcot-Marie-Tooth Disease, Type IA

Intervention / Treatment
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* Drug: PXT3003


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria after September 18th 2017: Patients previously randomized to study CLN-PXT3003-02 under placebo and dose 1 and having completed 15 months of double-blind treatment in that study, including all procedures required at the Study Termination visit (V6) or Patients previously randomized to the initial study CLN-PXT3003-02 under dose 2, prematurely discontinued following sponsor decision, and having performed all procedures required at the Study Termination visit (V6) Patients whose V6 was performed within 4 weeks before entering the extension study or if not done must have a new baseline visit (VB) 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. In case of minor children aged 16 to 18 years, both parent' and children's consents should be collected Inclusion Criteria until September 18th 2017: Patients 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) 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. In case of minor children aged 16 to 18 years, both parent' and children's consents should be collected Exclusion Criteria: 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 Any unauthorized concomitant treatments, as study CLN-PXT3003-02 (e.g. including but not limited to baclofen, naltrexone,sorbitol (pharmaceutical form), opioids, levothyroxin, and potentially neurotoxic drugs such as amiodarone, chloroquine, cancer drugs susceptible to induce peripheral neuropathy)

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 67 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients who completed the pivotal phase III study CLN-PXT3003-02 are allowed to continue in this open-label study. In Period 1, patients who were randomly assigned to placebo or low-dose PXT3003 in pivotal phase III study were assigned to receive low-dose PXT3003 (5 mL), whereas patients assigned to high-dose PXT3003 continued on that dose (receiving the high-dose PXT3003 (5 mL) or twice the low-dose for each administration (i.e. 10 mL)). The primary objective was to assess safety and tolerability for prolonged exposure to PXT3003, and to evaluate the effect on disability in patients with mild to moderate CMT1A. In Period 2, all patients are allowed to continue in an open-label fashion to receive high-dose PXT3003 (receiving twice the low-dose for each administration (i.e. 10 mL). The objective is to mainly assess the safety and tolerability in the aforementioned patient population.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: PXT3003 dose 1<br>Period 1, PXT3003 : Liquid oral solution (0.6 mg/mL baclofen, 0.07 mg/mL naltrexone HCl and 210 mg/mL D-sorbitol), 5 mL bid (taken morning and evening with food) for 9 consecutive months | Drug: PXT3003<br>* Liquid oral solution, 5 mL (Dose 1 or Dose 2) bid OR 10 mL (Dose 1) bid<br>|
| Active Comparator: PXT3003 dose 2<br>Period 1, PXT3003: Liquid oral solution (1.2 mg/mL baclofen, 0.14 mg/mL naltrexone HCl and 420 mg/mL D-sorbitol), 5 mL bid (taken morning and evening with food) for 9 consecutive months Period 2, PXT3003: Liquid oral solution (0.6 mg/mL baclofen, 0.07 mg/mL naltrexone HCl and 210 mg/mL D-sorbitol), 10 mL bid (taken morning and evening with food) | Drug: PXT3003<br>* Liquid oral solution, 5 mL (Dose 1 or Dose 2) bid OR 10 mL (Dose 1) bid<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events (TEAEs) related to PXT3003 during the follow-up in patients with CMT1A |  | 9 or 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of all TEAEs and their evaluation of type/nature, severity/intensity, seriousness, duration, relationship to study drug, and outcome |  | 9 or 24 months | 
| Incidence of adverse events leading to withdrawal of study drug |  | 9 or 24 months | 
| Overall Neuropathy Limitation Scale (ONLS) score, and its arm and leg sub-items |  | 9 or 24 months | 
| Charcot-Marie-Tooth Neuropathy Score - version 2 (CMTNS-V2), and its sub-items |  | 9 or 24 months | 
| Nine-hole Peg Test (9-HPT) |  | 9 or 24 months | 
| Quantified Muscular Testing (QMT) by hand grip and foot dorsiflexion dynamometry (mean of both sides) |  | 9 or 24 months | 
| Time to walk 10 meters |  | 9 or 24 months | 
| Compound Muscle Action Potential (CMAP) on ulnar nerve |  | 9 or 24 months | 
| Sensory Nerve Action Potential (SNAP) on radial nerve |  | 9 or 24 months | 
| Nerve conduction velocity (NCV) |  | 9 or 24 months | 
| Quality of Life (EQ-5D) |  | 9 or 24 months | 
| Visual analog scale on self-assessment of individualized main impairment in daily activities (defined at baseline with the patient) |  | 9 or 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Charcot Marie Tooth Type 1A, Peripheral neuropathy, PXT3003