Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients (PLEO-CMT)

NCT02579759 | Completed Phase 3 Results DMC

• 2 other identifiers: CLN-PXT3003-022015-002378-19
• Study Type: interventional
• Target: 323
• Locations: 8 countries
• Sites: 30

Brief Summary

The purpose of this study is to determine whether PXT3003 is effective and safe in the treatment of Charcot-Marie-Tooth disease - Type 1 A (CMT1A). This double-blind study will assess in parallel groups 2 doses of PXT3003 compared to Placebo in CMT1A patients treated for 15 months.

Conditions

Charcot-Marie-Tooth Disease Type 1A

Keywords

PXT3003

Outcome Measures

Primary Outcomes (1)

• Overall Neuropathy Limitation Scale (ONLS) Total Score

  The primary efficacy variable used in the main analysis is the mean of the available ONLS values at month 12 and month 15. The ONLS is a disability scale that was derived and improved from the Overall Disability Sum Score (ODSS) to measure limitations in the everyday activities of the upper limbs (rated on 5 points) and the lower limbs (rated on 7 points). The total score is a 12-point scale: 0 (no disability) to 12 (maximum disability). Lower values in the ONLS indicate a better clinical condition. Reported values are the values at Baseline (Base) and the average of the available values at Month 12 and Month 15 (Fin).

  From Baseline to Month 15

Secondary Outcomes (7)

• Mean of Ten Meter Walking Test (10MWT)

  From Baseline to Month 15

• Mean of the CMTNS-v2 Sensory Score

  From Baseline to Month 15

• Mean of the CMTNS-v2 Examination Score (CMTES-v2)

  From Baseline to Month 15

• Mean of the Results at the Nine-Hole Peg Test (9-HPT)

  From Baseline to Month 15

• Number of Subjects With at Least One TEAE

  The period between the patient signing the informed consent and 30 days after the end of study (i.e. completion/early discontinuation/last contact as recorded on the 'Study Completion on Early Termination' form up to 15 months)

Other Outcomes (6)

• Mean of the CMTNS-v2 Sensory Symptoms

  From Baseline to Month 15

• Plasma Concentrations of Baclofen at Trough and at 90 Min After Drug Intake

  At Month 12 and Month 15

• Plasma Concentrations of Naltrexone at Trough and at 90 Min After Drug Intake

  At Month 12 and month 15

Study Arms (3)

PXT3003 dose 1

ACTIVE COMPARATOR

Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months

Drug: PXT3003 dose 1

PXT3003 dose 2

ACTIVE COMPARATOR

Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months

Drug: PXT3003 dose 2

placebo

PLACEBO COMPARATOR

Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months

Drug: placebo

Interventions

PXT3003 dose 1 DRUG

Liquid oral solution, 5 ml twice a day, morning and evening with food

Also known as: DOSE 1

PXT3003 dose 1

PXT3003 dose 2 DRUG

Liquid oral solution, 5 ml twice a day, morning and evening with food

Also known as: DOSE 2

PXT3003 dose 2

placebo DRUG

Liquid oral solution, 5 ml twice a day, morning and evening with food

placebo

Eligibility Criteria

• Age: 16 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female, aged from 16 to 65 years;
• Patient with a proven genetic diagnosis of CMT1A;
• Mild-to-moderate severity assessed by Charcot-Marie-Tooth Neuropathy Score (version 2) with a score \>2 and ≤18;
• Muscle weakness in at least foot dorsiflexion;
• Motor nerve conduction of the ulnar nerve of at least 15 m/sec;
• Providing signed written informed consent to participate in the study and willing and able to comply with all study procedures and scheduled visits.

You may not qualify if:

• Any other associated cause of peripheral neuropathy such as diabetes;
• Patient with another significant neurological disease or a concomitant major systemic disease;
• Clinically significant history of unstable medical illness since the last 30 days (unstable angina, cancer…) that may jeopardize the participation in the study;
• Significant hematologic disease, hepatitis or liver failure, renal failure;
• Limb surgery within six months before randomization or planned before trial completion;
• Clinically significant abnormalities on the pre-study laboratory evaluation, physical evaluation, electrocardiogram (ECG);
• Elevated ASAT/ALAT (\> 3 x ULN) and elevated serum creatinine levels (\> 1.25 x ULN);
• History of recent alcohol or drug abuse or non-adherence with treatment or other experimental protocols;
• Patient using unauthorized concomitant treatments 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 a peripheral neuropathy. Patient who can/agrees to stop these medications 4 weeks before randomization and during the whole study duration can be included;
• Female of childbearing potential (apart of patient using adequate contraceptive measures), pregnant or breast feeding;
• Known hypersensitivity to any of the individual components of PXT3003;
• Porphyria as it is a contra indication to baclofen, and it may also induce neuropathy;
• Suspected inability to complete the study follow-up (foreign workers, transient visitors, tourists or any others for whom follow-up evaluation is not assured);
• Limited mental capacity or psychiatric disease rendering the subject unable to provide written informed consent or comply with evaluation procedures;
• Patient who has participated in another trial of investigational drug(s) within the past 30 days;

Sponsors & Collaborators

• Pharnext S.C.A.: lead

Study Sites (30)

Department of Neurology, Cedars-Sinai Medical Center

Los Angeles, California, 90048, United States

Location

Hospital for Special Care, New Britain

New Britain, Connecticut, 06053, United States

Location

Department of Neurology, McKnight Brain Institute

Gainesville, Florida, 32610, United States

Location

University of Kansas Medical Center

Kansas City, Kansas, 66160, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

University of Michigan Health System

Ann Arbor, Michigan, 48109-5322, United States

Location

Department of Neurology, University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Department of Neurology and Psichiatry, Saint Louis University

St Louis, Missouri, 63104-1027, United States

Location

Peripheral Neuropathy Center, Neurological Institue Building, Columbia University Medical Center

New York, New York, 10032, United States

Location

Ohio State University

Columbus, Ohio, 43210, United States

Location

Saint Luke's Rehabilitation Institute

Spokane, Washington, 99202-1330, United States

Location

Departement of Neurology, UZ Leuven

Leuven, Belgium

Location

University Hospital of Quebec

Québec, Quebec, G1J 1Z4, Canada

Location

Centre de Référence des Maladies Neuromusculaires, Hôpital Swynghedauwl, CHU de Lille

Lille, France

Location

Centre de Référence des Neuropathies Périphériques Rares, Hôpital Dupuytren, CHU Limoges

Limoges, France

Location

Service de Neurologie et du Sommeil, CHU Lyon Sud

Lyon, France

Location

Centre de Référence des Maladies Neuromusculaires, Pôle des Neurosciences Clinique, CHU la Timone

Marseille, France

Location

Centre de Référence des Maladies Neuromusculaires; Hôtel Dieu, CHU de Nantes

Nantes, France

Location

Service de Neurologie, Hôpital Kremlin Bicêtre

Paris, France

Location

Department of Neurology and Institute for Neuropathology, University Hospital RWTH Aachen

Aachen, Germany

Location

Department of Clinical Neurophysiology, University Medical Center Göttingen

Göttingen, Germany

Location

Department of Neurology, Ludwig-Maximillian University, Munich

Munich, Germany

Location

Department for Sleep Medicine and Neuromuscular, University Hospital Münster

Münster, Germany

Location

Departement of Neurology, Academic Medical Center

Amsterdam, Netherlands

Location

Department of neurology, Hospital Univesitario de Bellvitge

Barcelona, Spain

Location

Servicio de Neurologia, Hospital Universitario La Paz

Madrid, Spain

Location

Centro de Diagnostico y Tratamiento, Hospital Universitario Virgen del Rocio

Seville, Spain

Location

Servicio de Neurologia, Hospital Univesitari i Politécnic La Fe

Valencia, Spain

Location

Department of Neurology, Salford Royal NHS Foundation Trust

Salford, Manchester, M6 8HD, United Kingdom

Location

Ninewells Hospital and Medical School

Dundee, Scotland, DD1 9SY, United Kingdom

Location

Related Publications (6)

• Attarian S, Vallat JM, Magy L, Funalot B, Gonnaud PM, Lacour A, Pereon Y, Dubourg O, Pouget J, Micallef J, Franques J, Lefebvre MN, Ghorab K, Al-Moussawi M, Tiffreau V, Preudhomme M, Magot A, Leclair-Visonneau L, Stojkovic T, Bossi L, Lehert P, Gilbert W, Bertrand V, Mandel J, Milet A, Hajj R, Boudiaf L, Scart-Gres C, Nabirotchkin S, Guedj M, Chumakov I, Cohen D. An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A. Orphanet J Rare Dis. 2014 Dec 18;9:199. doi: 10.1186/s13023-014-0199-0.

  PMID: 25519680 RESULT

• Chumakov I, Milet A, Cholet N, Primas G, Boucard A, Pereira Y, Graudens E, Mandel J, Laffaire J, Foucquier J, Glibert F, Bertrand V, Nave KA, Sereda MW, Vial E, Guedj M, Hajj R, Nabirotchkin S, Cohen D. Polytherapy with a combination of three repurposed drugs (PXT3003) down-regulates Pmp22 over-expression and improves myelination, axonal and functional parameters in models of CMT1A neuropathy. Orphanet J Rare Dis. 2014 Dec 10;9:201. doi: 10.1186/s13023-014-0201-x.

  PMID: 25491744 RESULT

• Mandel J, Bertrand V, Lehert P, Attarian S, Magy L, Micallef J, Chumakov I, Scart-Gres C, Guedj M, Cohen D. A meta-analysis of randomized double-blind clinical trials in CMT1A to assess the change from baseline in CMTNS and ONLS scales after one year of treatment. Orphanet J Rare Dis. 2015 Jun 13;10:74. doi: 10.1186/s13023-015-0293-y.

  PMID: 26070802 RESULT

• Prukop T, Stenzel J, Wernick S, Kungl T, Mroczek M, Adam J, Ewers D, Nabirotchkin S, Nave KA, Hajj R, Cohen D, Sereda MW. Early short-term PXT3003 combinational therapy delays disease onset in a transgenic rat model of Charcot-Marie-Tooth disease 1A (CMT1A). PLoS One. 2019 Jan 16;14(1):e0209752. doi: 10.1371/journal.pone.0209752. eCollection 2019.

  PMID: 30650121 RESULT

• Hajj R, Prukop T, Wernick S, Ewers D, Brureau A, Cholet N, Laffaire J, Nave KA, Cohen D, Sereda M. Baclofen, Naltrexone and Sorbitol all contribute to the efficacy of PXT3003 in CMT1A Rats. EMJ Neurol, 2019;7[1]:47-49

  RESULT

• Attarian S, Vallat JM, Magy L, Funalot B, Gonnaud PM, Lacour A, Pereon Y, Dubourg O, Pouget J, Micallef J, Franques J, Lefebvre MN, Ghorab K, Al-Moussawi M, Tiffreau V, Preudhomme M, Magot A, Leclair-Visonneau L, Stojkovic T, Bossi L, Lehert P, Gilbert W, Bertrand V, Mandel J, Milet A, Hajj R, Boudiaf L, Scart-Gres C, Nabirotchkin S, Guedj M, Chumakov I, Cohen D. Erratum to: An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A. Orphanet J Rare Dis. 2016 Jul 7;11(1):92. doi: 10.1186/s13023-016-0463-6. No abstract available.

  PMID: 27387831 RESULT

Related Links

• Attarian et al., 2016
• Chumakov et al., 2014
• Mandel et al., 2015
• Prukop et al., 2019
• Attarian et al., Erratum, 2016
• Hajj et al., 2019

MeSH Terms

Conditions

Charcot-Marie-Tooth Disease

Condition Hierarchy (Ancestors)

Hereditary Sensory and Motor Neuropathy; Nervous System Malformations; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn

Limitations and Caveats

Two events occured during the trial due to crytals in Dose 2 formulation: hold of all subjects enrolled in Germany (Jun-17) and discontinuation of Dose 2 arm by the sponsor worldwide due to discovery of crystals in the ICH stability batch in Sep-17.

Results Point of Contact

• Title: Susanne Dorn
• Organization: Pharnext

contact@pharnext.com

+33 (0)1 41 09 22 30

Study Officials

• Shahram Attarian, MD

  CHU La Timone, Marseille, France

  PRINCIPAL INVESTIGATOR

• Peter Young, MD

  University Hospital Munster, Germany

  PRINCIPAL INVESTIGATOR

• Teresa Sevilla, MD

  Hospital Universitari i Politécnic La Fe, Valencia, Spain

  PRINCIPAL INVESTIGATOR

• Marianne De Visser, MD

  Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

  PRINCIPAL INVESTIGATOR

• Philip Van Damme, MD

  UZ Leuven, Belgium

  PRINCIPAL INVESTIGATOR

• Mark Roberts, MD

  Salford Royal NHS Foundation Trust, Manchester, UK

  PRINCIPAL INVESTIGATOR

• Florian Thomas, MD

  Saint-Louis University, Saint-Louis, USA

  PRINCIPAL INVESTIGATOR

• Jack Puymirat, MD

  University Hospital of Quebec

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 28, 2015
• First Posted: October 20, 2015
• Study Start: December 1, 2015
• Primary Completion: March 1, 2018
• Study Completion: August 1, 2018
• Last Updated: February 27, 2020
• Results First Posted: February 27, 2020

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will not share

Locations

BE (1); US (11); FR (6); NL (1); DE (4); ES (4); GB (2); CA (1)