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

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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International, Multi-center, Randomized, Double-blind, Placebo-controlled Phase III Study Assessing in Parallel Groups the Efficacy and Safety of 2 Doses of PXT3003 in Patients With Charcot-Marie-Tooth Disease Type 1A Treated 15 Months

Conditions
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Charcot-Marie-Tooth Disease Type 1A

Intervention / Treatment
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* Drug: PXT3003 dose 1
* Drug: PXT3003 dose 2
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 65 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: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: PXT3003 dose 1<br>Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months | Drug: PXT3003 dose 1<br>* Liquid oral solution, 5 ml twice a day, morning and evening with food<br>* Other names: DOSE 1;|
| Active Comparator: PXT3003 dose 2<br>Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months | Drug: PXT3003 dose 2<br>* Liquid oral solution, 5 ml twice a day, morning and evening with food<br>* Other names: DOSE 2;|
| Placebo Comparator: placebo<br>Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months | Drug: placebo<br>* Liquid oral solution, 5 ml twice a day, morning and evening with food<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Neuropathy Limitation Scale (ONLS) Total Score | The primary efficacy variable used in the main analysis is the mean of the available ONLS values at month 12 and month 15. The ONLS is a disability scale that was derived and improved from the Overall Disability Sum Score (ODSS) to measure limitations in the everyday activities of the upper limbs (rated on 5 points) and the lower limbs (rated on 7 points). The total score is a 12-point scale: 0 (no disability) to 12 (maximum disability). Lower values in the ONLS indicate a better clinical condition. Reported values are the values at Baseline (Base) and the average of the available values at Month 12 and Month 15 (Fin). | From Baseline to Month 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean of Ten Meter Walking Test (10MWT) | This outcome measure is the mean of the available 10MWT values at month 12 and month 15. The 10MWT is a simple to administer, standardized, reliable and valid evaluation of functional exercise capacity and gait that has been used to evaluate neurologic disorders and CMT patients. Lower Time to Walk 10 Meters values indicate a better clinical condition. Reported values are the values at Baseline (Base) and the average of the available values at Month 12 and Month 15 (Fin). | From Baseline to Month 15 | 
| Mean of the CMTNS-v2 Sensory Score | This outcome measure is the mean of the available CMTNS-v2 Sensory Score values at month 12 and month 15. The CMTNS-v2 is a specific scale designed to assess severity of impairment in CMT disease. It is a 36-point scale based on nine items to quantify impairment (sensory symptoms, pin sensibility, vibration and arm and leg strength), activity limitations (motor symptoms arms and legs) and electrophysiological function (amplitudes of ulnar CMAP and SNAP). The CMTNS-v2 goes from 0 (no impairment) to 36 (maximum impairment) whom each sub-items goes from 0 to 4. The CMTNS-v2 Sensory score is summed of items 1+4+5 of CMTNS-v2 (Sensory symptoms, Pinprick sensibility and Vibration). It is a 12-point score: 0 (no impairment) to 12 (maximum impairment). Lower CMTNS-v2 Sensory Score values indicate a better clinical condition. Reported values are the values at Baseline (Base) and the average of the available values at Month 12 and Month 15 (Fin). | From Baseline to Month 15 | 
| Mean of the CMTNS-v2 Examination Score (CMTES-v2) | This outcome measure is the mean of the available CMTNS-v2 Examination Score values at month 12 and month 15. The CMTNS-v2 is a specific scale designed to assess severity of impairment in CMT disease. It is a 36-point scale based on nine items to quantify impairment (sensory symptoms, pin sensibility, vibration and arm and leg strength), activity limitations (motor symptoms arms and legs) and electrophysiological function (amplitudes of ulnar CMAP and SNAP). The CMTNS-v2 goes from 0 (no impairment) to 36 (maximum impairment) whom each sub-items goes from 0 to 4. The CMTES-v2 is summed of item 1 to 7 of the CMTNS-v2 (limited to impairment items and excluding electrophysiological items). It is a 28-point score: 0 (no impairment) to 28 (maximum impairment). Lower CMTES-v2 values indicate a better clinical condition. Reported values are the values at Baseline (Base) and the average of the available values at Month 12 and Month 15 (Fin). | From Baseline to Month 15 | 
| Mean of the Results at the Nine-Hole Peg Test (9-HPT) | This outcome measure is the mean of the available 9-HPT values at month 12 and month 15. The Nine-Hole Peg Test (9HPT) is a simple timed test of fine motor coordination of extremitied in the upper limbs. It measures the time needed by the patient to insert 9 pegs in nine holes and to remove them (normal required time 18 seconds). Lower 9HPT values indicate a better clinical condition. Reported values are the values at Baseline (Base) and the average of the available values at Month 12 and Month 15 (Fin). | From Baseline to Month 15 | 
| Number of Subjects With at Least One TEAE | Safety selection was to include all randomized patients that have received at least one dose of study treatment. Safety and tolerability of PXT3003 were compared to placebo on the incidence of treatment-emergent adverse events (TEAEs); they were evaluated by type/nature, severity/intensity, seriousness, and relationship to study drug. | The period between the patient signing the informed consent and 30 days after the end of study (i.e. completion/early discontinuation/last contact as recorded on the 'Study Completion on Early Termination' form up to 15 months) | 
| Incidence of AE Leading to Withdrawal of Study Drug | Safety and tolerability of PXT3003 were compared to placebo on the incidence of TEAEs leading to withdrawal of study drug. | The period between the patient signing the informed consent and 30 days after the end of study (i.e. completion/early discontinuation/last contact as recorded on the 'Study Completion on Early Termination' form up to 15 months) | 
| Incidence of SAEs | Safety and tolerability of PXT3003 were compared to placebo on the incidence of serious adverse events (SAEs). | The period between the patient signing the informed consent and 30 days after the end of study (i.e. completion/early discontinuation/last contact as recorded on the 'Study Completion on Early Termination' form up to 15 months). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PXT3003