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

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

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.

Study Overview

• Status: Completed
• Conditions: Charcot-Marie-Tooth Disease Type 1A
• Intervention / Treatment: Drug: PXT3003 dose 1; Drug: PXT3003 dose 2; Drug: placebo

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 323
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium
    • Departement of Neurology, UZ Leuven
• Canada
  • Quebec, Canada, G1J 1Z4
    • University Hospital of Quebec
• France
  • Lille, France
    • Centre de Référence des Maladies Neuromusculaires, Hôpital Swynghedauwl, CHU de Lille
  • Limoges, France
    • Centre de Référence des Neuropathies Périphériques Rares, Hôpital Dupuytren, CHU Limoges
  • Lyon, France
    • Service de Neurologie et du Sommeil, CHU Lyon Sud
  • Marseille, France
    • Centre de Référence des Maladies Neuromusculaires, Pôle des Neurosciences Clinique, CHU la Timone
  • Nantes, France
    • Centre de Référence des Maladies Neuromusculaires; Hôtel Dieu, CHU de Nantes
  • Paris, France
    • Service de Neurologie, Hopital Kremlin Bicetre
• Germany
  • Aachen, Germany
    • Department of Neurology and Institute for Neuropathology, University Hospital RWTH Aachen
  • Göttingen, Germany
    • Department of Clinical Neurophysiology, University Medical Center Göttingen
  • Munich, Germany
    • Department of Neurology, Ludwig-Maximillian University, Munich
  • Münster, Germany
    • Department for Sleep Medicine and Neuromuscular, University Hospital Münster
• Netherlands
  • Amsterdam, Netherlands
    • Departement of Neurology, Academic Medical Center
• Spain
  • Barcelona, Spain
    • Department of neurology, Hospital Univesitario de Bellvitge
  • Madrid, Spain
    • Servicio de Neurología, Hospital Universitario La Paz
  • Sevilla, Spain
    • Centro de Diagnostico y Tratamiento, Hospital Universitario Virgen del Rocio
  • Valencia, Spain
    • Servicio de Neurologia, Hospital Univesitari i Politécnic La Fe
• United Kingdom
  • Manchester
    • Salford, Manchester, United Kingdom, M6 8HD
      • Department of Neurology, Salford Royal NHS Foundation Trust
  • Scotland
    • Dundee, Scotland, United Kingdom, DD1 9SY
      • Ninewells Hospital and Medical School
• United States
  • California
    • Los Angeles, California, United States, 90048
      • Department of Neurology, Cedars-Sinai Medical Center
  • Connecticut
    • New Britain, Connecticut, United States, 06053
      • Hospital for Special Care, New Britain
  • Florida
    • Gainesville, Florida, United States, 32610
      • Department of Neurology, McKnight Brain Institute
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-5322
      • University of Michigan Health System
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Department of Neurology, University of Minnesota
  • Missouri
    • Saint Louis, Missouri, United States, 63104-1027
      • Department of Neurology and Psichiatry, Saint Louis University
  • New York
    • New York, New York, United States, 10032
      • Peripheral Neuropathy Center, Neurological Institue Building, Columbia University Medical Center
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Washington
    • Spokane, Washington, United States, 99202-1330
      • Saint Luke's Rehabilitation Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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).

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean of the CMTNS-v2 Sensory Symptoms	This outcome measure is the mean of the available CMTNS-v2 Sensory Symptoms 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 Symptoms is the first item of the CMTNS-v2. It is a 4-point score: 0 (no impairment) to 4 (maximum impairment). Lower CMTNS-v2 Sensory Symptoms 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
Plasma Concentrations of Baclofen at Trough and at 90 Min After Drug Intake	Plasma concentration of PXT3003 components were measured at trough (prior to dose) and 90 minutes after drug intake. The mean plasma values of the baseline correspond to half of the administered dose.	At Month 12 and Month 15
Plasma Concentrations of Naltrexone at Trough and at 90 Min After Drug Intake	Plasma concentration of PXT3003 components were measured at trough (prior to dose) and 90 minutes after drug intake. The mean plasma values of the baseline correspond to half of the administered dose.	At Month 12 and month 15
Plasma Concentrations of 6β-naltrexol at Trough and at 90 Min After Drug Intake	Plasma concentration of PXT3003 components were measured at trough (prior to dose) and peak (90 minutes post dose). The mean plasma values of the baseline correspond to half of the administered dose.	At Month 12 and Month 15
Number of Participants With ONLS Therapy Response 1	ONLS Therapy Response 1 was defined as the number of participants (responders) with an improvement on final ONLS Total Score of at least one point. A higher response rate indicate a better clinical condition.	From Baseline to Month 15
Number of Participants With ONLS Therapy Response 2	ONLS Therapy Response 2 was defined as the number of participants with no deterioration (responders) on final ONLS Total Score. A higher response rate indicates a better clinical condition.	From Baseline to Month 15

Collaborators and Investigators

• Sponsor: Pharnext SA
• Investigators: Principal Investigator: Shahram Attarian, MD, CHU la Timone, Marseille, France; Principal Investigator: Peter Young, MD, University Hospital Münster, Germany; Principal Investigator: Teresa Sevilla, MD, Hospital Universitari i Politècnic La Fe, Valencia, Spain; Principal Investigator: Marianne De Visser, MD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); Principal Investigator: Philip Van Damme, MD, UZ Leuven, Belgium; Principal Investigator: Mark Roberts, MD, Salford Royal NHS Foundation Trust, Manchester, UK; Principal Investigator: Florian Thomas, MD, Saint-Louis University, Saint-Louis, USA; Principal Investigator: Jack Puymirat, MD, University Hospital of Quebec

Publications and helpful links

General Publications

• Attarian S, Vallat JM, Magy L, Funalot B, Gonnaud PM, Lacour A, Pereon Y, Dubourg O, Pouget J, Micallef J, Franques J, Lefebvre MN, Ghorab K, Al-Moussawi M, Tiffreau V, Preudhomme M, Magot A, Leclair-Visonneau L, Stojkovic T, Bossi L, Lehert P, Gilbert W, Bertrand V, Mandel J, Milet A, Hajj R, Boudiaf L, Scart-Gres C, Nabirotchkin S, Guedj M, Chumakov I, Cohen D. An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A. Orphanet J Rare Dis. 2014 Dec 18;9:199. doi: 10.1186/s13023-014-0199-0. Erratum In: Orphanet J Rare Dis. 2016;11(1):92.
• Chumakov I, Milet A, Cholet N, Primas G, Boucard A, Pereira Y, Graudens E, Mandel J, Laffaire J, Foucquier J, Glibert F, Bertrand V, Nave KA, Sereda MW, Vial E, Guedj M, Hajj R, Nabirotchkin S, Cohen D. Polytherapy with a combination of three repurposed drugs (PXT3003) down-regulates Pmp22 over-expression and improves myelination, axonal and functional parameters in models of CMT1A neuropathy. Orphanet J Rare Dis. 2014 Dec 10;9:201. doi: 10.1186/s13023-014-0201-x.
• Mandel J, Bertrand V, Lehert P, Attarian S, Magy L, Micallef J, Chumakov I, Scart-Gres C, Guedj M, Cohen D. A meta-analysis of randomized double-blind clinical trials in CMT1A to assess the change from baseline in CMTNS and ONLS scales after one year of treatment. Orphanet J Rare Dis. 2015 Jun 13;10:74. doi: 10.1186/s13023-015-0293-y.
• Prukop T, Stenzel J, Wernick S, Kungl T, Mroczek M, Adam J, Ewers D, Nabirotchkin S, Nave KA, Hajj R, Cohen D, Sereda MW. Early short-term PXT3003 combinational therapy delays disease onset in a transgenic rat model of Charcot-Marie-Tooth disease 1A (CMT1A). PLoS One. 2019 Jan 16;14(1):e0209752. doi: 10.1371/journal.pone.0209752. eCollection 2019.
• Hajj R, Prukop T, Wernick S, Ewers D, Brureau A, Cholet N, Laffaire J, Nave KA, Cohen D, Sereda M. Baclofen, Naltrexone and Sorbitol all contribute to the efficacy of PXT3003 in CMT1A Rats. EMJ Neurol, 2019;7[1]:47-49
• Attarian S, Vallat JM, Magy L, Funalot B, Gonnaud PM, Lacour A, Pereon Y, Dubourg O, Pouget J, Micallef J, Franques J, Lefebvre MN, Ghorab K, Al-Moussawi M, Tiffreau V, Preudhomme M, Magot A, Leclair-Visonneau L, Stojkovic T, Bossi L, Lehert P, Gilbert W, Bertrand V, Mandel J, Milet A, Hajj R, Boudiaf L, Scart-Gres C, Nabirotchkin S, Guedj M, Chumakov I, Cohen D. Erratum to: An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A. Orphanet J Rare Dis. 2016 Jul 7;11(1):92. doi: 10.1186/s13023-016-0463-6. No abstract available.

Helpful Links

• Attarian et al., 2016
• Chumakov et al., 2014
• Mandel et al., 2015
• Prukop et al., 2019
• Attarian et al., Erratum, 2016
• Hajj et al., 2019

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2015
• Primary Completion (Actual): March 1, 2018
• Study Completion (Actual): August 1, 2018

Study Registration Dates

• First Submitted: September 28, 2015
• First Submitted That Met QC Criteria: October 16, 2015
• First Posted (Estimate): October 20, 2015

Study Record Updates

• Last Update Posted (Actual): February 27, 2020
• Last Update Submitted That Met QC Criteria: February 13, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: PXT3003
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Neuromuscular Diseases; Stomatognathic Diseases; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Nervous System Malformations; Polyneuropathies; Disease; Tooth Diseases; Nerve Compression Syndromes; Charcot-Marie-Tooth Disease; Hereditary Sensory and Motor Neuropathy
• Other Study ID Numbers: CLN-PXT3003-02; 2015-002378-19 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No