Clinical trial NCT02579759: Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients (PLEO-CMT)
Official title: International, Multi-center, Randomized, Double-blind, Placebo-controlled Phase III Study Assessing in Parallel Groups the Efficacy and Safety of 2 Doses of PXT3003 in Patients With Charcot-Marie-Tooth Disease Type 1A Treated 15 Months
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Charcot-Marie-Tooth Disease Type 1A
Keywords: PXT3003
Lead sponsor: Pharnext S.C.A.
Sponsor class: OTHER
First posted: 2015-10-20
Enrollment: 323
Sex: ALL
Minimum age (years): 16
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: PXT3003 is a fixed dose combination of (RS)-baclofen, naltrexone hydrochloride and D-sorbitol selected via a Systems Biology approach and developed by Pharnext, with the aim to limit the production of PMP22 and protect/improve axonal function in patients with CMT1A. On September 18th 2017, PXT3003 dose 2 was prematurely discontinued, due to an unexpected investigational medicinal product quality event (failed month 18 stability testing). This resulted in a large proportion of missing data that led us to reconsider the efficacy analysis that was initially planned in the protocol.The independent data safety monitoring committee did not identify any safety concern on September 5th 2017. All patients randomised to dose 2 were requested to undergo the end of study visit, and were offered to enter the extension study (CLN-PXT3003-03).

Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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;
* If a patient from the same family, living in the same household, has already been included in this study, it will not be possible to include another patient from the same family to avoid mixing of therapeutic units; therefore there would be a risk of inversion of the blind treatments which could jeopardize the interpretation of study results.

Primary outcomes:
measure: Overall Neuropathy Limitation Scale (ONLS) Total Score
timeFrame: From Baseline to Month 15
Secondary outcomes:
measure: Mean of Ten Meter Walking Test (10MWT)
timeFrame: From Baseline to Month 15
measure: Mean of the CMTNS-v2 Sensory Score
timeFrame: From Baseline to Month 15
measure: Mean of the CMTNS-v2 Examination Score (CMTES-v2)
timeFrame: From Baseline to Month 15
measure: Mean of the Results at the Nine-Hole Peg Test (9-HPT)
timeFrame: From Baseline to Month 15
measure: Number of Subjects With at Least One TEAE
timeFrame: 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)
measure: Incidence of AE Leading to Withdrawal of Study Drug
timeFrame: 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)
measure: Incidence of SAEs
timeFrame: 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:
measure: Mean of the CMTNS-v2 Sensory Symptoms
timeFrame: From Baseline to Month 15
measure: Plasma Concentrations of Baclofen at Trough and at 90 Min After Drug Intake
timeFrame: At Month 12 and Month 15
measure: Plasma Concentrations of Naltrexone at Trough and at 90 Min After Drug Intake
timeFrame: At Month 12 and month 15
measure: Plasma Concentrations of 6β-naltrexol at Trough and at 90 Min After Drug Intake
timeFrame: At Month 12 and Month 15
measure: Number of Participants With ONLS Therapy Response 1
timeFrame: From Baseline to Month 15
measure: Number of Participants With ONLS Therapy Response 2
timeFrame: From Baseline to Month 15
Locations:
city: Los Angeles
country: United States
facility: Department of Neurology, Cedars-Sinai Medical Center
state: California
city: New Britain
country: United States
facility: Hospital for Special Care, New Britain
state: Connecticut
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: Columbus
country: United States
facility: Ohio State University
state: Ohio
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: Centre de Référence des Maladies Neuromusculaires, Hôpital Swynghedauwl, CHU de Lille
city: Limoges
country: France
facility: Centre de Référence des Neuropathies Périphériques Rares, Hôpital Dupuytren, CHU Limoges
city: Lyon
country: France
facility: Service de Neurologie et du Sommeil, CHU Lyon Sud
city: Marseille
country: France
facility: Centre de Référence des Maladies Neuromusculaires, Pôle des Neurosciences Clinique, CHU la Timone
city: Nantes
country: France
facility: Centre de Référence des Maladies Neuromusculaires; Hôtel Dieu, CHU de Nantes
city: Paris
country: France
facility: Service de Neurologie, Hôpital Kremlin Bicêtre
city: Aachen
country: Germany
facility: Department of Neurology and Institute for Neuropathology, University Hospital RWTH Aachen
city: Göttingen
country: Germany
facility: Department of Clinical Neurophysiology, University Medical Center Göttingen
city: Munich
country: Germany
facility: Department of Neurology, Ludwig-Maximillian University, Munich
city: Münster
country: Germany
facility: Department for Sleep Medicine and Neuromuscular, University Hospital Münster
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 Univesitari i Politécnic La Fe
city: Salford
country: United Kingdom
facility: Department of Neurology, Salford Royal NHS Foundation Trust
state: Manchester
city: Dundee
country: United Kingdom
facility: Ninewells Hospital and Medical School
state: Scotland
Study officials:
affiliation: CHU La Timone, Marseille, France
name: Shahram Attarian, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital Munster, Germany
name: Peter Young, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitari i Politécnic La Fe, Valencia, Spain
name: Teresa Sevilla, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: Marianne De Visser, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: UZ Leuven, Belgium
name: Philip Van Damme, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Salford Royal NHS Foundation Trust, Manchester, UK
name: Mark Roberts, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Saint-Louis University, Saint-Louis, USA
name: Florian Thomas, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital of Quebec
name: Jack Puymirat, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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
citation: 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.