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

Primary Purpose

Charcot-Marie-Tooth Disease, Type IA

Status

Active

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

PXT3003

About this trial

This is an interventional treatment trial for Charcot-Marie-Tooth Disease, Type IA focused on measuring Charcot Marie Tooth Type 1A, Peripheral neuropathy, PXT3003

Eligibility Criteria

16 Years - 67 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

Department of Neurology, Cedars-Sinai Medical Center
Department of Neurology, McKnight Brain Institute
University of Kansas Medical Center
Brigham and Women's Hospital
University of Michigan Health System
Department of Neurology, University of Minnesota
Department of Neurology and Psichiatry, Saint Louis University
Peripheral Neuropathy Center, Neurological Institue Building, Columbia University Medical Center
Saint Luke's Rehabilitation Institute
Departement of Neurology, UZ Leuven
University Hospital of Quebec
Cntre de Reference des Maladies Neuromusculaires, Hopital Swynghedauwl, CHU Lille
Centre de Reference des Neuropathies Peripheriques Rare, Hopital Dupuytren, CHU Limoges
Service de Neurologie et du Sommeil, CHU Lyon Sud
Centre de Reference des Maladie Neuromusculaires, CHU la Timone
Centre de Reference des Maladie Neuromusculaires, Hotel Dieu, CHU de Nantes
Service de Neurologie, Hopital Kremlin Bicetre
Departement of Neurology, Academic Medical Center
Department of neurology, Hospital Univesitario de Bellvitge
Servicio de Neurologia, Hospital Universitario La Paz
Centro de Diagnostico y Tratamiento, Hospital Universitario Virgen del Rocio
Servicio de Neurologia, Hospital Universitario i Politécnic La Fe
Department of Neurology, Salford Royal NHS Foundation Trust

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

PXT3003 dose 1

PXT3003 dose 2

Arm Description

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

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)

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

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

Nine-hole Peg Test (9-HPT)

Quantified Muscular Testing (QMT) by hand grip and foot dorsiflexion dynamometry (mean of both sides)

Time to walk 10 meters

Compound Muscle Action Potential (CMAP) on ulnar nerve

Sensory Nerve Action Potential (SNAP) on radial nerve

Nerve conduction velocity (NCV)

Quality of Life (EQ-5D)

Visual analog scale on self-assessment of individualized main impairment in daily activities (defined at baseline with the patient)

Full Information

NCT ID

NCT03023540

First Posted

December 26, 2016

Last Updated

March 9, 2021

Sponsor

Pharnext SA

Collaborators

SynteractHCR, Syneos Health, Premier Research Group plc

1. Study Identification

Unique Protocol Identification Number

NCT03023540

Brief Title

Assessing Long Term Safety and Tolerability of PXT3003 in Patients With Charcot-Marie-Tooth Disease Type 1A

Acronym

PLEO-CMT-FU

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2021

Overall Recruitment Status

Active, not recruiting

Study Start Date

March 7, 2017 (Actual)

Primary Completion Date

December 31, 2024 (Anticipated)

Study Completion Date

December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Pharnext SA

Collaborators

SynteractHCR, Syneos Health, Premier Research Group plc

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Charcot-Marie-Tooth Disease, Type IA

Keywords

Charcot Marie Tooth Type 1A, Peripheral neuropathy, PXT3003

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

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)

Allocation

Non-Randomized

Enrollment

187 (Actual)

8. Arms, Groups, and Interventions

Arm Title

PXT3003 dose 1

Arm Type

Active Comparator

Arm Description

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

Arm Title

PXT3003 dose 2

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

PXT3003

Intervention Description

Liquid oral solution, 5 mL (Dose 1 or Dose 2) bid OR 10 mL (Dose 1) bid

Primary Outcome Measure Information:

Title

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

Time Frame

9 or 24 months

Secondary Outcome Measure Information:

Title

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

Title

Incidence of adverse events leading to withdrawal of study drug

Time Frame

9 or 24 months

Title

Overall Neuropathy Limitation Scale (ONLS) score, and its arm and leg sub-items

Time Frame

9 or 24 months

Title

Charcot-Marie-Tooth Neuropathy Score - version 2 (CMTNS-V2), and its sub-items

Time Frame

9 or 24 months

Title

Nine-hole Peg Test (9-HPT)

Time Frame

9 or 24 months

Title

Quantified Muscular Testing (QMT) by hand grip and foot dorsiflexion dynamometry (mean of both sides)

Time Frame

9 or 24 months

Title

Time to walk 10 meters

Time Frame

9 or 24 months

Title

Compound Muscle Action Potential (CMAP) on ulnar nerve

Time Frame

9 or 24 months

Title

Sensory Nerve Action Potential (SNAP) on radial nerve

Time Frame

9 or 24 months

Title

Nerve conduction velocity (NCV)

Time Frame

9 or 24 months

Title

Quality of Life (EQ-5D)

Time Frame

9 or 24 months

Title

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

Other Pre-specified Outcome Measures:

Title

Through plasma concentration of PXT3003

Description

Measurement of baclofen, naltrexone and 6-beta-naltrexone plasma concentration at the through

Time Frame

at month 6 and 9

Title

Peak plasma concentration of PXT3003

Description

Measurement of baclofen, naltrexone and 6-beta-naltrexone plasma concentration at the through

Time Frame

at month 6 and 9

10. Eligibility

Sex

All

Minimum Age & Unit of Time

16 Years

Maximum Age & Unit of Time

67 Years

Accepts Healthy Volunteers

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)

Overall Study Officials: