Clinical trial NCT03023540: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Charcot-Marie-Tooth Disease, Type IA
Keywords: Charcot Marie Tooth Type 1A
Peripheral neuropathy
PXT3003
Lead sponsor: Pharnext S.C.A.
Sponsor class: OTHER
Collaborators: name: Synteract HCR (Syneos Health)
name: Premier Research Group plc
name: Greenphire
name: Theradis
name: Amarex
name: Eurofins Optimed
First posted: 2017-01-18
Enrollment: 187
Sex: ALL
Minimum age (years): 17
Maximum age (years): 67
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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).

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)

Primary outcomes:
measure: Incidence of treatment-emergent adverse events (TEAEs) related to PXT3003 during the follow-up in patients with CMT1A
timeFrame: 9 or 24 months
Secondary outcomes:
measure: Incidence of all TEAEs and their evaluation of type/nature, severity/intensity, seriousness, duration, relationship to study drug, and outcome
timeFrame: 9 or 24 months
measure: Incidence of adverse events leading to withdrawal of study drug
timeFrame: 9 or 24 months
measure: Overall Neuropathy Limitation Scale (ONLS) score, and its arm and leg sub-items
timeFrame: 9 or 24 months
measure: Charcot-Marie-Tooth Neuropathy Score - version 2 (CMTNS-V2), and its sub-items
timeFrame: 9 or 24 months
measure: Nine-hole Peg Test (9-HPT)
timeFrame: 9 or 24 months
measure: Quantified Muscular Testing (QMT) by hand grip and foot dorsiflexion dynamometry (mean of both sides)
timeFrame: 9 or 24 months
measure: Time to walk 10 meters
timeFrame: 9 or 24 months
measure: Compound Muscle Action Potential (CMAP) on ulnar nerve
timeFrame: 9 or 24 months
measure: Sensory Nerve Action Potential (SNAP) on radial nerve
timeFrame: 9 or 24 months
measure: Nerve conduction velocity (NCV)
timeFrame: 9 or 24 months
measure: Quality of Life (EQ-5D)
timeFrame: 9 or 24 months
measure: Visual analog scale on self-assessment of individualized main impairment in daily activities (defined at baseline with the patient)
timeFrame: 9 or 24 months
Other outcomes:
measure: Through plasma concentration of PXT3003
timeFrame: at month 6 and 9
measure: Peak plasma concentration of PXT3003
timeFrame: at month 6 and 9
Locations:
city: Los Angeles
country: United States
facility: Department of Neurology, Cedars-Sinai Medical Center
state: California
city: Gainesville
country: United States
facility: Department of Neurology, McKnight Brain Institute
state: Florida
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Health System
state: Michigan
city: Minneapolis
country: United States
facility: Department of Neurology, University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Department of Neurology and Psichiatry, Saint Louis University
state: Missouri
city: New York
country: United States
facility: Peripheral Neuropathy Center, Neurological Institue Building, Columbia University Medical Center
state: New York
city: Spokane
country: United States
facility: Saint Luke's Rehabilitation Institute
state: Washington
city: Leuven
country: Belgium
facility: Departement of Neurology, UZ Leuven
city: Quebec
country: Canada
facility: University Hospital of Quebec
city: Lille
country: France
facility: Cntre de Reference des Maladies Neuromusculaires, Hopital Swynghedauwl, CHU Lille
city: Limoges
country: France
facility: Centre de Reference des Neuropathies Peripheriques Rare, Hopital Dupuytren, CHU Limoges
city: Lyon
country: France
facility: Service de Neurologie et du Sommeil, CHU Lyon Sud
city: Marseille
country: France
facility: Centre de Reference des Maladie Neuromusculaires, CHU la Timone
city: Nantes
country: France
facility: Centre de Reference des Maladie Neuromusculaires, Hotel Dieu, CHU de Nantes
city: Paris
country: France
facility: Service de Neurologie, Hopital Kremlin Bicetre
city: Amsterdam
country: Netherlands
facility: Departement of Neurology, Academic Medical Center
city: Barcelona
country: Spain
facility: Department of neurology, Hospital Univesitario de Bellvitge
city: Madrid
country: Spain
facility: Servicio de Neurologia, Hospital Universitario La Paz
city: Sevilla
country: Spain
facility: Centro de Diagnostico y Tratamiento, Hospital Universitario Virgen del Rocio
city: Valencia
country: Spain
facility: Servicio de Neurologia, Hospital Universitario i Politécnic La Fe
city: Salford
country: United Kingdom
facility: Department of Neurology, Salford Royal NHS Foundation Trust
state: Manchester
Study officials:
affiliation: CHU la Timone, Marseille, France
name: Shahram Attarian, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario i Politécnico La F, Valencia, Spain
name: Teresa Sevilla, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Academic Medical Center, Amsterdam, Netherlands
name: Marianne de Visser, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Selor Royal NHS Foundation Trust, Manchester, UK
name: Mark Roberts, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Seton Hall-Hackensack-Meridian School of Medicine, Hackensack, USA
name: Florian Thomas, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: