Assessing Long Term Safety and Tolerability of PXT3003 in Patients With Charcot-Marie-Tooth Disease Type 1A (PLEO-CMT-FU)

International, Multi-center, Open Label, Follow-up Extension Study Assessing the Long-term Safety and Tolerability of PXT3003 in Patients With Charcot-Marie-Tooth Disease Type 1A

All randomised patients with Charcot-Marie-Tooth Type 1A (CMT1A) who completed the primary study CLN-PXT3003-02, i.e. treatment with PXT3003 or placebo, are eligible to continue in the extension study CLN-PXT3003-03.

Period 1: Patients randomised to PXT3003 dose 1 or placebo in the primary study (CLN-PXT3003-02) continued in the extension study on PXT3003 dose 1 (5 mL). Patients randomised to PXT3003 dose 2 (5 mL) in the primary study (CLN-PXT3003-02) continued in the extension study on PXT3003 dose 2 or PXT3003 twice dose 1 (2x5 mL).

Period 2: All patients continue on twice dose 1 (2X5mL).

Study Overview

• Status: Active, not recruiting
• Conditions: Charcot-Marie-Tooth Disease, Type IA
• Intervention / Treatment: Drug: PXT3003

Detailed Description

PXT3003 is a rational design, fixed combination of low-dose (RS) baclofen, naltrexone hydrochloride and D-sorbitol. The use of PXT3003 in a multicenter, randomised, placebo controlled phase II study (CLN-PXT3003-01) was well-tolerated and safe in patients with CMT1A for the three dose-levels investigated (Attarian et al., 2014). The intermediate and high dose of PXT3003 demonstrated an improvement of disability in this patient population.

Subsequently a multicenter, randomised, placebo controlled phase III study (CLN-PXT3003-02) to assess the efficacy and safety of PXT3003 in the treatment of patients with CMT1A was initiated in December 2015. In March 2017 the first patients completed the 15-month treatment with PXT3003 and rolled over into the extension study CLN-PXT3003-03.

During Period 1 (9 months), patients that were randomised to PXT3003 dose 1 or placebo in the primary study (CLN-PXT3003-02) continued in the extension study on PXT3003 dose 1 (5 mL). Patients randomised to PXT3003 dose 2 (5 mL) in the primary study (CLN-PXT3003-02) continued in the extension study on on PXT3003 dose 2 or PXT3003 twice dose 1 (2x5 mL). During Period 2, all patients continue on twice dose 1 (2X5mL).

• Study Type: Interventional
• Enrollment (Actual): 187
• 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
    • Cntre de Reference des Maladies Neuromusculaires, Hopital Swynghedauwl, CHU Lille
  • Limoges, France
    • Centre de Reference des Neuropathies Peripheriques Rare, Hopital Dupuytren, CHU Limoges
  • Lyon, France
    • Service de Neurologie et du Sommeil, CHU Lyon Sud
  • Marseille, France
    • Centre de Reference des Maladie Neuromusculaires, CHU la Timone
  • Nantes, France
    • Centre de Reference des Maladie Neuromusculaires, Hotel Dieu, CHU de Nantes
  • Paris, France
    • Service de Neurologie, Hopital Kremlin Bicetre
• Netherlands
  • Amsterdam, Netherlands
    • Departement of Neurology, Academic Medical Center
• Spain
  • Barcelona, Spain
    • Department of neurology, Hospital Univesitario de Bellvitge
  • Madrid, Spain
    • Servicio de Neurologia, Hospital Universitario La Paz
  • Sevilla, Spain
    • Centro de Diagnostico y Tratamiento, Hospital Universitario Virgen del Rocio
  • Valencia, Spain
    • Servicio de Neurologia, Hospital Universitario i Politécnic La Fe
• United Kingdom
  • Manchester
    • Salford, Manchester, United Kingdom, M6 8HD
      • Department of Neurology, Salford Royal NHS Foundation Trust
• United States
  • California
    • Los Angeles, California, United States, 90048
      • Department of Neurology, Cedars-Sinai Medical Center
  • 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
  • Washington
    • Spokane, Washington, United States, 99202-1330
      • Saint Luke's Rehabilitation Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 67 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria after September 18th 2017:

• Patients previously randomized to study CLN-PXT3003-02 under placebo and dose 1 and having completed 15 months of double-blind treatment in that study, including all procedures required at the Study Termination visit (V6) or
• Patients previously randomized to the initial study CLN-PXT3003-02 under dose 2, prematurely discontinued following sponsor decision, and having performed all procedures required at the Study Termination visit (V6)
• Patients whose V6 was performed within 4 weeks before entering the extension study or if not done must have a new baseline visit (VB)
• Female patients must agree to continue using an approved method of birth control throughout the extension study
• Patients must sign a written informed consent, specific to the extension study, in order to participate in this study. In case of minor children aged 16 to 18 years, both parent' and children's consents should be collected

Inclusion Criteria until September 18th 2017:

• Patients must have completed 15 months of double-blind treatment in the primary study CLN-PXT3003-02, including all procedures required at the Study Termination visit (V6)
• Female patients must agree to continue using an approved method of birth control throughout the extension study
• Patients must sign a written informed consent, specific to the extension study, in order to participate in this study. In case of minor children aged 16 to 18 years, both parent' and children's consents should be collected

Exclusion Criteria:

• Any clinically significant change in health status that, in the opinion of the Investigator, would prevent the subject from participating in this study or successfully completing this study
• Any unauthorized concomitant treatments, as study CLN-PXT3003-02 (e.g. 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 peripheral neuropathy)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: PXT3003 dose 1; Period 1, PXT3003 : Liquid oral solution (0.6 mg/mL baclofen, 0.07 mg/mL naltrexone HCl and 210 mg/mL D-sorbitol), 5 mL bid (taken morning and evening with food) for 9 consecutive months	Drug: PXT3003; Liquid oral solution, twice 5 mL (Dose 1) bid
Active Comparator: PXT3003 dose 2; Period 1, PXT3003: Liquid oral solution (1.2 mg/mL baclofen, 0.14 mg/mL naltrexone HCl and 420 mg/mL D-sorbitol), 5 mL bid (taken morning and evening with food) for 9 consecutive months Period 2, PXT3003: Liquid oral solution (0.6 mg/mL baclofen, 0.07 mg/mL naltrexone HCl and 210 mg/mL D-sorbitol), 10 mL bid (taken morning and evening with food)	Drug: PXT3003; Liquid oral solution, twice 5 mL (Dose 1) bid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of treatment-emergent adverse events (TEAEs) related to PXT3003 during the follow-up in patients with CMT1A	Incidence of treatment-emergent adverse events (TEAEs) related to PXT3003 during the follow-up in patients with CMT1A	9 or 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of all TEAEs and their evaluation of type/nature, severity/intensity, seriousness, duration, relationship to study drug, and outcome	Incidence of all TEAEs and their evaluation of type/nature, severity/intensity, seriousness, duration, relationship to study drug, and outcome	9 or 24 months
Incidence of adverse events leading to withdrawal of study drug	Incidence of adverse events leading to withdrawal of study drug	9 or 24 months
Overall Neuropathy Limitation Scale (ONLS) score, and its arm and leg sub-items	Overall Neuropathy Limitation Scale (ONLS) score, and its arm and leg sub-items	9 or 24 months
Charcot-Marie-Tooth Neuropathy Score - version 2 (CMTNS-V2), and its sub-items	Charcot-Marie-Tooth Neuropathy Score - version 2 (CMTNS-V2), and its sub-items	9 or 24 months
Nine-hole Peg Test (9-HPT)	Nine-hole Peg Test (9-HPT)	9 or 24 months
Quantified Muscular Testing (QMT) by hand grip and foot dorsiflexion dynamometry (mean of both sides)	Quantified Muscular Testing (QMT) by hand grip and foot dorsiflexion dynamometry (mean of both sides)	9 or 24 months
Time to walk 10 meters	Time to walk 10 meters	9 or 24 months
Compound Muscle Action Potential (CMAP) on ulnar nerve	Compound Muscle Action Potential (CMAP) on ulnar nerve	9 or 24 months
Sensory Nerve Action Potential (SNAP) on radial nerve	Sensory Nerve Action Potential (SNAP) on radial nerve	9 or 24 months
Nerve conduction velocity (NCV)	Nerve conduction velocity (NCV)	9 or 24 months
Quality of Life (EQ-5D)	Quality of Life (EQ-5D)	9 or 24 months
Visual analog scale on self-assessment of individualized main impairment in daily activities (defined at baseline with the patient)	Visual analog scale on self-assessment of individualized main impairment in daily activities (defined at baseline with the patient)	9 or 24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Through plasma concentration of PXT3003	Measurement of baclofen, naltrexone and 6-beta-naltrexone plasma concentration at the through	at month 6 and 9
Peak plasma concentration of PXT3003	Measurement of baclofen, naltrexone and 6-beta-naltrexone plasma concentration at the through	at month 6 and 9

Collaborators and Investigators

• Sponsor: Pharnext S.C.A.
• Collaborators: Premier Research Group plc; Eurofins Optimed; Synteract HCR (Syneos Health); Greenphire; Theradis; Amarex
• Investigators: Principal Investigator: Shahram Attarian, MD, CHU la Timone, Marseille, France; Principal Investigator: Teresa Sevilla, MD, Hospital Universitario i Politécnico La F, Valencia, Spain; Principal Investigator: Marianne de Visser, MD, Academic Medical Center, Amsterdam, Netherlands; Principal Investigator: Mark Roberts, MD, Selor Royal NHS Foundation Trust, Manchester, UK; Principal Investigator: Florian Thomas, MD PhD, Seton Hall-Hackensack-Meridian School of Medicine, Hackensack, USA

Study record dates

Study Major Dates

• Study Start (Actual): March 7, 2017
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: December 26, 2016
• First Submitted That Met QC Criteria: January 13, 2017
• First Posted (Estimated): January 18, 2017

Study Record Updates

• Last Update Posted (Actual): February 20, 2024
• Last Update Submitted That Met QC Criteria: February 16, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Peripheral neuropathy; Charcot Marie Tooth Type 1A; PXT3003
• Additional Relevant MeSH Terms: 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; Tooth Diseases; Nerve Compression Syndromes; Charcot-Marie-Tooth Disease; Hereditary Sensory and Motor Neuropathy
• Other Study ID Numbers: CLN-PXT3003-03; 2015-002379-81 (EudraCT Number)

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No