Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A

Study Overview
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Brief Summary
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The present trial is a randomized, placebo-controlled study evaluating 3 different doses of PXT3003 in patients with CMT1A disease.

Detailed Description
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In addition to the safety and tolerability of the treatment, clinical, electrophysiological and biological endpoints (PMP22 mRNA, skin biopsy histology and plasma biomarkers) will be assessed. Standard laboratory tests and drug plasma concentrations will also be measured. Because of the slow progression of the disease and the nature of the observed symptoms, a minimum duration of 12 months of treatment is required in order to observe a potential improvement in any of the efficacy parameters.

Official Title
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A Phase II, Randomized, Placebo-controlled Trial of the Safety, Efficacy, Pharmacodynamics and Pharmacokinetics of PXT3003 in Patients With Charcot-Marie-Tooth Disease Type 1A.

Conditions
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Charcot-Marie-Tooth Disease, Hereditary Neuropathy With Liability to Pressure Palsies, Genetic Disorders

Intervention / Treatment
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* Drug: PXT3003 Low dose
* Drug: PXT3003 Intermediate Dose
* Drug: PXT3003 High Dose
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: DNA proven CMT1A Muscle weakness in at least foot dorsiflexion (clinical assessment) Age between 18 and 65 years Male or non pregnant, non breastfeeding female CMT neuropathy score at screening ≤ 20 Agrees to perform electrorophysiological studies and two cutaneous biopsies for determination of PMP22 expression and histology 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: Patients with another neurological disease Patients using unauthorized concomitant treatments, ascorbic acid, opioids, levothyroxine and potentially neurotoxic drugs. Patients who can/agree to stop these medications 4 weeks before randomization can be included Patients who have participated in another trial of investigational drug within the past 30 days Concomitant major systemic disease Clinically significant history of unstable medical illness over the last 30 days (unstable angina…) History of significant hematologic, kidney, liver disease, or insulin-dependent diabetes Clinically significant abnormalities on the prestudy laboratory evaluation, physical evaluation, electrocardiogram (ECG) ASAT/ALAT levels above the upper limit of normal (ULN). However, patients with an isolated elevation of either ASAT or ALAT (<1.5 ULN) can be included at investigators discretion if the remaining liver function tests are normal and if ASAT or ALAT value is stable at 2 distinct evaluations in the month prior to inclusion Serum creatinine levels above the upper limit of normal Limited mental capacity or psychiatric disease rendering the subject unable to provide written informed consent or comply with evaluation procedures History of recent alcohol or drug abuse or non-adherence with treatment or other experimental protocols Female of childbearing potential (apart of patient using adequate contraceptive measures), pregnant or breast feeding Suspected inability to complete the study follow-up (foreign workers, transient visitors, tourists or any others for whom follow-up evaluation is not assured) Limb surgery in the six months before randomization or planned before completion of the trial Known hypersensitivity to any of the individual components of PXT3003 Porphyria

Ages Eligible for Study
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Minimum Age: 18 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PXT3003 Low dose<br>Oral Liquid formulation, 1/100, bid, 12 months | Drug: PXT3003 Low dose<br>* Liquid,5 ml, twice a day, 12-month treatment<br>* Other names: Pleocompound PXT3003;|
| Experimental: PXT3003 Intermediate dose<br>Oral Liquid formulation, 1/50, bid, 12 months | Drug: PXT3003 Intermediate Dose<br>* Liquid,5 ml, twice a day, 12-month treatment<br>* Other names: Pleocompound PXT3003;|
| Experimental: PXT3003 High dose<br>Oral Liquid formulation, 1/10, bid, 12 months | Drug: PXT3003 High Dose<br>* Liquid,5 ml, twice a day, 12-month treatment<br>* Other names: Pleocompound PXT3003;|
| Placebo Comparator: Placebo<br>Oral Liquid formulation, bid, 12 months | Other: Placebo<br>* Liquid,5 ml, twice a day, 12-month treatment<br>* Other names: Pleocompound PXT3003;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of PXT3003 | The Primary Objective is to assess the clinical and laboratory safety and tolerability of three doses of PXT3003 administered orally for 12 months to CMT1A patients versus placebo. Number of participants with adverse events in each arm. | Screening, randomization, 1-, 3-, 6-, 9-, 12-month treatment and 1-month follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Obtain Preliminary Data on the Efficacy of PXT3003 on Clinical Scores and Functional Tests | Efficacy scores and functional tests will be assessed CMTNS/CMTES:ONLS, VAS, fatigue, pain, six minute walk test (6MWT), nine-hole peg test, quantified muscular testing (QMT; hand grip and foot dorsiflexion), CGI. For each test or score, change from baseline after 3-,6-, 9- and 12-months of treatment. | Screening, randomization, 3-, 6-, 9- and 12-months treatment | 
| To Assess the Pharmacodynamic Effect of PXT3003 on PMP22 mRNA Levels and Intra-epidermal Axon Density in Cutaneous Biopsy | A cutaneous biopsy (consisting in 2 small punch biopsies) will be performed to assess PMP22 mRNA expression and intra-epidermal axon density. Change from baseline after 12-month of treatment. | Randomization and 12-month treatment | 
| To Assess the Pharmacodynamic Effect of PXT3003 on Selected Neurophysiological Parameters | Electrophysiological examination will be performed to assess sensory and motor responses of the median and ulnar nerves (non-dominant side) including: NCV, compound muscle action potential (CMAP) and SNAP. Change from baseline after 3-,6-, 9- and 12-months of treatment. | Screening, randomization, 3-, 6-, 9- and 12-month treatment | 
| To Assess the Pharmacodynamic Effect of PXT3003 on a Series of Biochemical Biomarkers | Dosages of biochemical biomarkers in plasma. Change from baseline after 3-month of treatment. | Randomization and 3-month treatment | 
| To Assess the Plasma Concentrations of PXT3003 | PXT3003 plasmatic concentrations after one administration (randomization) and after 1-,6-and 12-months of treatment. | Randomization, 1-, 6- and 12-month treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PXT3003, Charcot-Marie-Tooth Disease, Hereditary Motor and Sensory Neuropathies