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

• ClinicalTrials.gov Identifier: NCT03023540
• Recruitment Status: Active, not recruiting
• First Posted: January 18, 2017
• Last Update Posted: February 20, 2024
• Sponsor: Pharnext S.C.A.
• Collaborators: Synteract HCR (Syneos Health); Premier Research Group plc; Greenphire; Theradis; Amarex; Eurofins Optimed
• Information provided by (Responsible Party): Pharnext S.C.A.

Tracking Information

• First Submitted Date: December 26, 2016
• First Posted Date: January 18, 2017
• Last Update Posted Date: February 20, 2024
• Actual Study Start Date: March 7, 2017
• Estimated Primary Completion Date: December 31, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 16, 2024)

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

Incidence of treatment-emergent adverse events (TEAEs) related to PXT3003 during the follow-up in patients with CMT1A

• Original Primary Outcome Measures (submitted: January 13, 2017): Incidence of treatment-emergent adverse events (TEAEs) related to PXT3003 during the follow-up in patients with CMT1A [ Time Frame: 9 or 24 months ]

Current Secondary Outcome Measures (submitted: February 16, 2024)

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

Original Secondary Outcome Measures (submitted: January 13, 2017)

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

Current Other Pre-specified Outcome Measures (submitted: January 13, 2017)

• Through plasma concentration of PXT3003 [ Time Frame: at month 6 and 9 ]
  Measurement of baclofen, naltrexone and 6-beta-naltrexone plasma concentration at the through
• Peak plasma concentration of PXT3003 [ Time Frame: at month 6 and 9 ]
  Measurement of baclofen, naltrexone and 6-beta-naltrexone plasma concentration at the through

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Assessing Long Term Safety and Tolerability of PXT3003 in Patients With Charcot-Marie-Tooth Disease Type 1A
• Official Title: 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

Brief Summary

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).

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
• Study Phase: Phase 3

Study Design

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Patients who completed the pivotal phase III study CLN-PXT3003-02 are allowed to continue in this open-label study. In Period 1, patients who were randomly assigned to placebo or low-dose PXT3003 in pivotal phase III study were assigned to receive low-dose PXT3003 (5 mL), whereas patients assigned to high-dose PXT3003 continued on that dose (receiving the high-dose PXT3003 (5 mL) or twice the low-dose for each administration (i.e. 10 mL)). The primary objective was to assess safety and tolerability for prolonged exposure to PXT3003, and to evaluate the effect on disability in patients with mild to moderate CMT1A.

In Period 2, all patients are allowed to continue in an open-label fashion to receive high-dose PXT3003 (receiving twice the low-dose for each administration (i.e. 10 mL). The objective is to mainly assess the safety and tolerability in the aforementioned patient population.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Charcot-Marie-Tooth Disease, Type IA

Intervention

Drug: PXT3003

Liquid oral solution, twice 5 mL (Dose 1) bid

Study Arms

• 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
  Intervention: Drug: PXT3003
• 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)

  Intervention: Drug: PXT3003

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 17, 2019): 187
• Original Estimated Enrollment (submitted: January 13, 2017): 323
• Estimated Study Completion Date: December 31, 2024
• Estimated Primary Completion Date: December 31, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 17 Years to 67 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Canada, France, Netherlands, Spain, United Kingdom, United States
• Removed Location Countries: Germany

Administrative Information

• NCT Number: NCT03023540
• Other Study ID Numbers: CLN-PXT3003-03; 2015-002379-81 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Pharnext S.C.A.
• Original Responsible Party: Same as current
• Current Study Sponsor: Pharnext S.C.A.
• Original Study Sponsor: Same as current

Collaborators

• Synteract HCR (Syneos Health)
• Premier Research Group plc
• Greenphire
• Theradis
• Amarex
• Eurofins Optimed

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

• PRS Account: Pharnext S.C.A.
• Verification Date: February 2024