Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients (PLEO-CMT)

The purpose of this study is to determine whether PXT3003 is effective and safe in the treatment of Charcot-Marie-Tooth disease - Type 1 A (CMT1A). This double-blind study will assess in parallel groups 2 doses of PXT3003 compared to Placebo in CMT1A patients treated for 15 months.

PXT3003 is a fixed dose combination of (RS)-baclofen, naltrexone hydrochloride and D-sorbitol selected via a Systems Biology approach and developed by Pharnext, with the aim to limit the production of PMP22 and protect/improve axonal function in patients with CMT1A. On September 18th 2017, PXT3003 dose 2 was prematurely discontinued, due to an unexpected investigational medicinal product quality event (failed month 18 stability testing). This resulted in a large proportion of missing data that led us to reconsider the efficacy analysis that was initially planned in the protocol.The independent data safety monitoring committee did not identify any safety concern on September 5th 2017. All patients randomised to dose 2 were requested to undergo the end of study visit, and were offered to enter the extension study (CLN-PXT3003-03).

Eligibility Criteria:
Inclusion Criteria:

* Male or female, aged from 16 to 65 years;
* Patient with a proven genetic diagnosis of CMT1A;
* Mild-to-moderate severity assessed by Charcot-Marie-Tooth Neuropathy Score (version 2) with a score \>2 and ≤18;
* Muscle weakness in at least foot dorsiflexion;
* Motor nerve conduction of the ulnar nerve of at least 15 m/sec;
* Providing signed written informed consent to participate in the study and willing and able to comply with all study procedures and scheduled visits.

Exclusion Criteria:

* Any other associated cause of peripheral neuropathy such as diabetes;
* Patient with another significant neurological disease or a concomitant major systemic disease;
* Clinically significant history of unstable medical illness since the last 30 days (unstable angina, cancer...) that may jeopardize the participation in the study;
* Significant hematologic disease, hepatitis or liver failure, renal failure;
* Limb surgery within six months before randomization or planned before trial completion;
* Clinically significant abnormalities on the pre-study laboratory evaluation, physical evaluation, electrocardiogram (ECG);
* Elevated ASAT/ALAT (\> 3 x ULN) and elevated serum creatinine levels (\> 1.25 x ULN);
* History of recent alcohol or drug abuse or non-adherence with treatment or other experimental protocols;
* Patient using unauthorized concomitant treatments 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 a peripheral neuropathy. Patient who can/agrees to stop these medications 4 weeks before randomization and during the whole study duration can be included;
* Female of childbearing potential (apart of patient using adequate contraceptive measures), pregnant or breast feeding;
* Known hypersensitivity to any of the individual components of PXT3003;
* Porphyria as it is a contra indication to baclofen, and it may also induce neuropathy;
* Suspected inability to complete the study follow-up (foreign workers, transient visitors, tourists or any others for whom follow-up evaluation is not assured);
* Limited mental capacity or psychiatric disease rendering the subject unable to provide written informed consent or comply with evaluation procedures;
* Patient who has participated in another trial of investigational drug(s) within the past 30 days;
* If a patient from the same family, living in the same household, has already been included in this study, it will not be possible to include another patient from the same family to avoid mixing of therapeutic units; therefore there would be a risk of inversion of the blind treatments which could jeopardize the interpretation of study results.