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    Summary
    EudraCT Number:2015-002378-19
    Sponsor's Protocol Code Number:CLN-PXT3003-02
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-11-19
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2015-002378-19
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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
    A.3.2Name or abbreviated title of the trial where available
    PLEO-CMT
    A.4.1Sponsor's protocol code numberCLN-PXT3003-02
    A.5.4Other Identifiers
    Name:US INDNumber:122505
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorPHARNEXT SA
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPharnext
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPHARNEXT SA
    B.5.2Functional name of contact pointAgnès Daoust
    B.5.3 Address:
    B.5.3.1Street Address11 rue des peupliers
    B.5.3.2Town/ cityIssy les Moulineaux
    B.5.3.3Post code92130
    B.5.3.4CountryFrance
    B.5.4Telephone number+33141 09 22 51
    B.5.5Fax number+33141 09 22 31
    B.5.6E-mailadaoust@pharnext.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/14/1260
    D.3 Description of the IMP
    D.3.2Product code PXT3003 dose 1
    D.3.4Pharmaceutical form Oral solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRS-BACLOFEN
    D.3.9.1CAS number 1134-47-0
    D.3.9.4EV Substance CodeSUB05667MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.6
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNALTREXONE HYDROCHLORIDE
    D.3.9.1CAS number 16676-29-2
    D.3.9.3Other descriptive nameNALTREXONE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB14629MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.07
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INND-SORBITOL
    D.3.9.1CAS number 50-70-4
    D.3.9.3Other descriptive nameD-SORBITOL
    D.3.9.4EV Substance CodeSUB20837
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number21
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/14/1260
    D.3 Description of the IMP
    D.3.2Product code PXT3003 dose 2
    D.3.4Pharmaceutical form Oral solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRS-BACLOFEN
    D.3.9.1CAS number 1134-47-0
    D.3.9.4EV Substance CodeSUB05667MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.2
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNALTREXONE HYDROCHLORIDE
    D.3.9.1CAS number 16676-29-2
    D.3.9.3Other descriptive nameNALTREXONE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB14629MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.14
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INND-SORBITOL
    D.3.9.1CAS number 50-70-4
    D.3.9.3Other descriptive nameD-SORBITOL
    D.3.9.4EV Substance CodeSUB20837
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number42
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboOral solution
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Charcot-Marie-Tooth Disease - Type 1A
    E.1.1.1Medical condition in easily understood language
    Charcot-Marie-Tooth Disease
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10008414
    E.1.2Term Charcot-Marie-Tooth disease
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the efficacy of PXT3003 compared to Placebo on the disability measured by the ONLS score in CMT1A patients treated for 15 months.
    E.2.2Secondary objectives of the trial
    - To assess the efficacy of PXT3003 compared to Placebo on clinical score and functional tests, electrophysiological parameters, and measures of quality of life;
    - To assess the safety and tolerability of PXT3003 compared to Placebo;
    - To assess plasma concentrations of PXT3003 components (at peak and trough) when administered with 2 different doses;
    - To assess the change over time of potential blood biomarkers;
    - To assess molecular changes in skin biopsy, when this procedure will be possible (ancillary sub-study);
    - To explore potential new imaging biomarkers by calf MRI, when this procedure will be possible (ancillary sub-study)
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Optional ancillary sub-studies are described in the main protocol in section 13. Skin biopsy ad 13.4 Calf MRI.
    Both sub-studies are optional for the participating sites and the investigators will receive separate processing manuals.
    E.3Principal inclusion criteria
    1. Male or female, aged from 16 to 65 years;
    2. Patient with a proven genetic diagnosis of CMT1A;
    3. Mild-to-moderate severity assessed by CMTNS-v2 with a score >2 and ≤18;
    4. Muscle weakness in at least foot dorsiflexion;
    5. Motor nerve conduction of the ulnar nerve of at least 15m/sec;
    6. Providing signed written informed consent to participate in the study and willing and able to comply with all study procedures and scheduled visits.
    E.4Principal exclusion criteria
    1. Any other associated cause of peripheral neuropathy such as diabetes;
    2. Patients with another significant neurological disease or a concomitant major systemic disease;
    3. Clinically significant history of unstable medical illness since the last 30 days (unstable angina, cancer…) that may jeopardize the participation in the study;
    4. Significant hematologic disease, hepatitis or liver failure, renal failure;
    5. Limb surgery within six months before randomization or planned before trial completion;
    6. Clinically significant abnormalities on the pre-study laboratory evaluation, physical evaluation, electrocardiogram (ECG);
    7. Elevated ASAT/ALAT (> 3 x ULN) and elevated serum creatinine levels (> 1.25 x ULN);
    8. History of recent alcohol or drug abuse or non-adherence with treatment or other experimental protocols;
    9. Patients 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; (list provided in appendix 1). Patients who can/agree to stop these medications 4 weeks before randomization and during the whole study duration can be included;
    10. Female of childbearing potential (apart of patients using adequate contraceptive measures), pregnant or breast feeding;
    11. Known hypersensitivity to any of the individual components of PXT3003;
    12. Porphyria as it is a contra indication to baclofen, and it may also induce neuropathy;
    13. Suspected inability to complete the study follow-up (foreign workers, transient visitors, tourists or any others for whom follow-up evaluation is not assured);
    14. Limited mental capacity or psychiatric disease rendering the subject unable to provide written informed consent or comply with evaluation procedures;
    15. Patients who have participated in another trial of investigational drug(s) within the past 30 days;
    16. 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.
    E.5 End points
    E.5.1Primary end point(s)
    Improvement of disability measured by the Overall Neuropathy Limitation Scale (ONLS) score.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline (V1) ; 12 and 15 months of treatment (V5 and V6)
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints
    - Responders Rate to PXT3003 therapy defined as a patients improving on ONLS at end of treatment;
    - The effect of the studied PXT3003 dosages on the following endpoints:
    *Arm and leg sub-items of ONLS;
    *Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNS-v2), including its sub-items;
    *Nine-hole Peg Test (9-HPT) performed on non-dominant hand;
    *Quantified Muscular Testing (QMT) by Hand grip and Foot dorsiflexion dynamometry (mean of both sides);
    *Time to walk 10 meters;
    *Electrophysiological parameters assessing sensory and motor responses of ulnar and radial nerves (non-dominant side) including:
    o Compound Muscle Action Potential (CMAP) on ulnar nerve;
    o Sensory Nerve Action Potential (SNAP) on radial nerve;
    o Nerve conduction velocity (NCV);
    * Quality of life measured by:
    o EuroQol 5-Dimensional Health-related Quality of Life scale (EQ-5D);
    o VAS on self-assessment of the individualized main impairment in daily activities defined at baseline with the patient.

    Secondary safety endpoints

    Safety and tolerability of PXT3003 will be compared to placebo on the following parameters:
    - Incidence of all Treatment Emergent Adverse Events (TEAEs); they will be evaluated by type/nature, severity/intensity, seriousness, duration, relationship to study drug, and outcome;
    - Incidence of related TEAEs (including possibly and probably related TEAEs) with a moderate or severe intensity;
    - Incidence of AE leading to withdrawal of study drug;
    - Incidence of Serious Adverse Events (SAEs);
    - Change in physical examination, vital signs (blood pressure and heart rate), 12-lead ECG, and laboratory data (haematology and blood chemistry).

    Additional exploratory endpoints

    - Plasma concentrations of baclofen, naltrexone and 6ß-naltrexol at trough and at peak
    - Blood biomarkers (tryptophan, alanine, serotonin, T4, free cholesterol) and other biomarkers for research such as Gene expression studies
    - mRNA levels of PMP22 and other putative candidates biomarkers in skin biopsies performed at baseline and at the end of treatment(optional)
    - muscle/fat index in the calf measured by MRI performed at baseline and at the end of treatment.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline ; after 6 months of treatment (V3); after 12 months of treatment (V5); after 15 months of treatment (V6)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United States
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 30
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 30
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 270
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 200
    F.4.2.2In the whole clinical trial 300
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    In order to stimulate the recruitment and motivate patients to be
    enrolled, patients having completed the 15-month study will be eligible
    to receive PXT3003 in a follow-up extension trial for 9 months if they
    are willing to continue the treatment. They will be attributed to active
    drug by a second randomization. This 9-month extension study will
    provide additional long-term data on safety and additional efficacy data
    that could provide some evidence of disease modifying effect.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-01-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-01-18
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-03-22
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