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

Sponsor

Pharnext SA (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03023540

Collaborator

SynteractHCR (Industry), Syneos Health (Other), Premier Research Group plc (Industry)

187

Enrollment

Locations

Arms

93.8

Anticipated Duration (Months)

8.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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).

Condition or Disease	Intervention/Treatment	Phase
Charcot-Marie-Tooth Disease, Type IA	Drug: PXT3003	Phase 3

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 Design

Study Type:

Interventional

Actual Enrollment :

187 participants

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.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

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

Actual Study Start Date :

Mar 7, 2017

Anticipated Primary Completion Date :

Dec 31, 2024

Anticipated Study Completion Date :

Dec 31, 2024

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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

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 [9 or 24 months]
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 [9 or 24 months]
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) [9 or 24 months]
Time to walk 10 meters [9 or 24 months]
Compound Muscle Action Potential (CMAP) on ulnar nerve [9 or 24 months]
Sensory Nerve Action Potential (SNAP) on radial nerve [9 or 24 months]
Nerve conduction velocity (NCV) [9 or 24 months]
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) [9 or 24 months]

Other Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

16 Years to 67 Years

Sexes Eligible for Study:

All

Accepts 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Department of Neurology, Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
2	Department of Neurology, McKnight Brain Institute	Gainesville	Florida	United States	32610
3	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
4	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
5	University of Michigan Health System	Ann Arbor	Michigan	United States	48109-5322
6	Department of Neurology, University of Minnesota	Minneapolis	Minnesota	United States	55455
7	Department of Neurology and Psichiatry, Saint Louis University	Saint Louis	Missouri	United States	63104-1027
8	Peripheral Neuropathy Center, Neurological Institue Building, Columbia University Medical Center	New York	New York	United States	10032
9	Saint Luke's Rehabilitation Institute	Spokane	Washington	United States	99202-1330
10	Departement of Neurology, UZ Leuven	Leuven		Belgium
11	University Hospital of Quebec	Quebec		Canada	G1J 1Z4
12	Cntre de Reference des Maladies Neuromusculaires, Hopital Swynghedauwl, CHU Lille	Lille		France
13	Centre de Reference des Neuropathies Peripheriques Rare, Hopital Dupuytren, CHU Limoges	Limoges		France
14	Service de Neurologie et du Sommeil, CHU Lyon Sud	Lyon		France
15	Centre de Reference des Maladie Neuromusculaires, CHU la Timone	Marseille		France
16	Centre de Reference des Maladie Neuromusculaires, Hotel Dieu, CHU de Nantes	Nantes		France
17	Service de Neurologie, Hopital Kremlin Bicetre	Paris		France
18	Departement of Neurology, Academic Medical Center	Amsterdam		Netherlands
19	Department of neurology, Hospital Univesitario de Bellvitge	Barcelona		Spain
20	Servicio de Neurologia, Hospital Universitario La Paz	Madrid		Spain
21	Centro de Diagnostico y Tratamiento, Hospital Universitario Virgen del Rocio	Sevilla		Spain
22	Servicio de Neurologia, Hospital Universitario i Politécnic La Fe	Valencia		Spain
23	Department of Neurology, Salford Royal NHS Foundation Trust	Salford	Manchester	United Kingdom	M6 8HD

Sponsors and Collaborators

Pharnext SA
SynteractHCR
Syneos Health
Premier Research Group plc

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