Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients

NCT04762758 | Active Not Recruiting Phase 3 DMC FDA Drug

• 2 other identifiers: CLN-PXT3003-062020-004805-30
• Study Type: interventional
• Target: 350
• Locations: 9 countries
• Sites: 50

Brief Summary

The study will consist of 2 periods: Double-blind Treatment and Open-Label Extension(OLE) Period.

• Double-blind Treatment Period - This will be randomized, double-blind, placebo-controlled part of the study which will be conducted in parallel groups, ie,1 group receiving the active treatment (PXT3003) and the other group receiving placebo. Primary endpoint of the study will be assessed at Month 15.
• Open-label Extension (OLE) Period - All subjects completing Double-blind Treatment Period will be given an opportunity to enter the OLE Period of the study and receive the active treatment (PXT3003). The duration of the OLE Period will be based on Sponsor discretion, ie, Sponsor intends to keep the study open until the study drug PXT3003 is commercially available. During this period, the long-term safety and efficacy of PXT3003 will be assessed as an exploratory objective. Double-blind Treatment Period Objectives: Primary: To evaluate the efficacy of treatment with PXT3003 (a fixed-dose combination of \[RS\]-baclofen, naltrexone hydrochloride \[HCl\], and D-sorbitol) compared to placebo in subjects with Charcot-Marie-Tooth disease type 1A (CMT1A). Secondary: To evaluate the safety and tolerability of PXT3003 treatment in subjects with CMT1A. Exploratory: To characterize the relationship between plasma biomarkers and response to PXT3003 treatment. OLE Period Objective: Exploratory: To evaluate the long-term safety and efficacy of PXT3003.

Conditions

Charcot-Marie-Tooth Disease

Keywords

Charcot Marie Tooth Type 1; Peripheral Neuropathy; PXT3003

Outcome Measures

Primary Outcomes (1)

• modified Overall Neuropathy Limitation Scale (mONLS)

  The modified ONLS is a disability scale that was derived and improved from the Overall Disability Sum Score to measure limitations in the everyday activities of the upper limbs (rated on 5 points) and the lower limbs (rated on 7 points).38 The total score goes from 0 (no disability) to 12 (maximum disability). Lower values in the ONLS indicate a better clinical condition.

  From Baseline to Month 15

Secondary Outcomes (6)

• 10-Meter Walk Test

  From Baseline to Month 15

• Quantified Muscular Testing (QMT) (bilateral foot dorsiflexion dynamometry)

  From Baseline to Month 15

• Patient Global Impression of Severity (PGI-S)

  From Baseline to Month 15

• Patient Global Impression of Change (PGI-C)

  From Baseline to Month 15

• CMTNS-V2

  From Baseline to Month 15

Study Arms (2)

PXT3003

EXPERIMENTAL

Liquid oral solution, 10 mL twice a day, morning and evening with food

Drug: (RS)-baclofen, naltrexone hydrochloride and D-sorbitol

Placebo

PLACEBO COMPARATOR

Liquid oral solution, 10 mL twice a day, morning and evening with food

Drug: Placebo

Interventions

(RS)-baclofen, naltrexone hydrochloride and D-sorbitol DRUG

oral fixed dose combination

Also known as: PXT3003

PXT3003

Placebo DRUG

liquid oral solution

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 and non-pregnant female subjects, aged 16 to 65 years with a genetically proven diagnosis of CMT1A. Notes: a) A report of a genetic test confirming PMP22 duplication and therefore a diagnosis of CMT1A must be available in the subject's record at the clinical site. b) In the absence of a report of a genetic test confirming PMP22 duplication in the subject's medical record, a confirmatory genetic test must be conducted via the central laboratory as part of Screening. c) In the exceptional case wherein subject was randomized into the study without meeting(a) or (b), an unscheduled confirmatory genetic test will be performed. In the event of a negative genetic test result, the subject will be withdrawn from the study.
• Able to provide written informed consent/assent and comply with study procedures.
• Mild-to-moderate severity assessed by a CMTNS-V2 score \>2 and ≤18.
• Muscle weakness in at least foot dorsiflexion on clinical assessment.
• Ulnar nerve motor conduction time of at least 15 m/s.
• If taking prescribed psychoactive drugs(eg, antidepressants, stimulants, tranquilizers, anti-epileptics) for CMT1A, should be on a stable dose for at least 4 weeks prior to randomization, which is not planned to be changed.
• If taking prescribed or 'over-the-counter' analgesic medications (eg, paracetamol/acetaminophen, nonsteroidal anti-inflammatory drugs) for CMT1A, should be on a stable dose for at least 2 weeks prior to randomization, which is not planned to be changed.
• If female, subject must be: (a) surgically sterilized via hysterectomy, bilateral oophorectomy, or bilateral tubal ligation; or (b) of childbearing potential and using a birth control method such as:
• Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
• Oral
• Intravaginal
• Transdermal
• Progestogen-only hormonal contraception associated with inhibition of ovulation:
• Oral
• Injectable

You may not qualify if:

• Subjects previously enrolled in any PXT3003 study.
• Subjects living in the same household and enrolled in a PXT3003 study (due to potential lack of adequate storage for study material, risk of mixing treatments and potential unblinding).
• CMT of any subtype other than 1A.
• ONLS score of 0.
• Known clinically significant motor or sensory abnormalities secondary to a different neurological cause (eg, diabetes, alcohol, vascular, autoimmune, neoplastic, neurodegenerative, human immunodeficiency virus, etc.). Note: subjects with diagnosis of unilateral carpal tunnel syndrome at least 1 year prior to Screening Visit, that is asymptomatic at the time of Screening Visit, will not be excluded from participating in this study.
• Subjects who have had any surgery or have a concomitant disorder (eg, severe arthrosis) that reduces the mobility of the ankle or wrist making it, in the opinion of the investigator, difficult to assess the efficacy of the treatment. Note: subjects with surgical repair of unilateral carpel tunnel syndrome will not be excluded from participating in this study.
• Known peripheral neuropathy, myopathy, or neuromuscular disorder of any other kind. Note: subjects with diagnosis of unilateral carpal tunnel syndrome at least 1year prior to Screening Visit, that is asymptomatic at the time of Screening Visit, will not be excluded from participating in this study.
• Any other clinically significant and/or uncontrolled medical condition that, in the opinion of the investigator, could be a confound, may increase subject's risk, or may preclude successful participation or completion of the study.
• Known hypersensitivity or intolerance to PXT3003( or matching placebo), including any of its active ingredients( baclofen, naltrexone, or sorbitol), and/or any of its excipients( acetate buffer, sodium methyl parahydroxybenzoate, sodium propyl parahydroxybenzoate, or isoamyl acetate).
• Concomitant treatments including but not limited to baclofen, naltrexone, sorbitol (pharmaceutical form), opioids, potent central nervous system depressants (such as barbiturates, long-acting benzodiazepines, and neuroleptics), and potentially neurotoxic drugs such as amiodarone, chloroquine, and chemotherapeutics capable of inducing peripheral neuropathy. Subjects able to stop these medications at least 2 weeks before randomization and for the study duration may be included. Subjects with positive urine drug screen at Baseline Visit will be excluded, except for permitted use of codeine and benzodiazepines.
• History of porphyria.
• Diagnosis or history of substance use disorder by Diagnostic and Statistical Manual of Mental Disorders-5th Edition criteria within the past 12 months.
• Medical or recreational use of marijuana in the 3 months prior to the Screening Visit.
• Active suicidality (eg, any suicide attempts within the past 12 months or any current suicidal intent, including a plan, as assessed by the C SSRS score of "YES" on questions 4 or 5; and/or based on clinical evaluation by the investigator).
• Currently active major depression, as determined by a Beck Depression Inventory-II (BDI-II) score ≥20.

Sponsors & Collaborators

• Pharnext S.C.A.: lead
• Worldwide Clinical Trials: collaborator

Study Sites (50)

Cedars-Sinai Medical Center

Los Angeles, California, 90048, United States

Location

UCLA Department of Psychiatry and Biobehavioral Sciences

Los Angeles, California, 90095, United States

Location

UC Davis Health Department of Physical Medicine and Rehabilitation

Sacramento, California, 95817, United States

Location

Hospital for Special Care

New Britain, Connecticut, 06053, United States

Location

University of Florida Clinical Research Center

Gainesville, Florida, 32610, United States

Location

University of Miami Leonard M. Miller School of Medicine

Miami, Florida, 33136, United States

Location

Advent Health Medical Group Neurology Orlando

Orlando, Florida, 32803, United States

Location

University of Kansas Medical Center Research Institute

Fairway, Kansas, 66205, United States

Location

Massachusetts General Hospital Neuromuscular Diagnostic Center

Boston, Massachusetts, 02114, United States

Location

University of Minnesota Health

Minneapolis, Minnesota, 55414, United States

Location

MU Health Care Neurology and Sleep Disorders Clinic

Columbia, Missouri, 65212, United States

Location

Hackensack Meridian Health Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Colombia University Department of Neurology

New York, New York, 10032, United States

Location

UNC Department of Neurology Peripheral Neuropathy Center

Chapel Hill, North Carolina, 27514, United States

Location

Atrium Health Neurosciences Institute

Charlotte, North Carolina, 28207, United States

Location

The Ohio State University Wexner Medical Center

Columbus, Ohio, 43210, United States

Location

Oregon Neurology

Springfield, Oregon, 97477, United States

Location

National Neuromuscular Research Institute

Austin, Texas, 78759, United States

Location

Neurology Clinic at University of Washington Medical Center

Seattle, Washington, 98195, United States

Location

Providence St. Luke's Rehabilitation Medical Center

Spokane, Washington, 99202, United States

Location

Universitaire Ziekenhuizen Leuven

Leuven, 3000, Belgium

Location

Ottawa Hospital Research Institute- Neuromuscular Research Centre

Ottawa, Ontario, K1Y 4E9, Canada

Location

UHN Toronto General Hospital Krembil Neuroscience Centre

Toronto, Ontario, M5G 2C4, Canada

Location

CIUSS de Saguenay-Lac-Saint-Jean Centre d'etudes Cliniques

Chicoutimi, Quebec, G7H 5H6, Canada

Location

Montreal Neurological Institute and Hospital-Clinical Research Unit

Montreal, Quebec, H3A 2B4, Canada

Location

CHU de Quebec-Universite Laval- Hopital Enfant-Jesus

Québec, Quebec, G1J 1Z4, Canada

Location

Rigshospitalet, University of Copenhagen Copenhagen Neuromuscular Center

Copenhagen, DK-1200, Denmark

Location

Centre de Reference des Maladies Neuromusculaires AOC Service de Neurologie, CHU d'Angers

Angers, 49933, France

Location

Centre de reference des maladies neuromusculaires AOC Hopital Pellegrin CHU de Bordeaux

Bordeaux, 33076, France

Location

CHU de Lille Hôpital Salengro

Lille, 59037, France

Location

Service de Neurologie et Maladies Neuromusculaires, CHU de Marseille - Hopital La Timone

Marseille, 13385, France

Location

Association lnstitut de Myologie Hopital Pitie-Salpetriere Service de Neuro-Myologie

Paris, 75013, France

Location

Centre d'investigation Clinique CHU de Strasbourg Hopital de Hautepierre

Strasbourg, 67098, France

Location

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

Aachen, D-52074, Germany

Location

University Medical Centre Goettingen, Dept. of Clinical Neurology

Göttingen, D-37075, Germany

Location

Friedrich-Baur-Institut, Neurologische Klinik und Poliklinik Ludwig-Maximilians-Universität

München, D-80336, Germany

Location

University Hospital Muenster UKM Department of Neurology

Münster, 48149, Germany

Location

Universitätsklinikum Tübingen Crona Kliniken Neuromuskuläres Zentrum

Tübingen, 72076, Germany

Location

Hadassah Ein Kerem University Medical Center Department of Neurology

Jerusalem, 91120, Israel

Location

Sheba Medical Center

Ramat Gan, 52662, Israel

Location

Tel Aviv Sourasky Medical Center

Tel Aviv, 6423906, Israel

Location

Azienda Ospedaliera Universitaria San Martino Universita Degli Studi di Genova Clinica Neurologica

Genova, 16132, Italy

Location

Azienda Ospedaliera Universitaria Policlinico "G. Martino" di Messina

Messina, 98125, Italy

Location

University of Naples Federico II

Naples, 80131, Italy

Location

Tor Vergata University of Rome

Rome, 00133, Italy

Location

University Hospital GB Rossi UOC Neurologia B, AOUI Verona Department of Neuroscience, Biomedicine and Movement Sciences

Verona, 37134, Italy

Location

Hospital Universitario Clinico San Carlos

Madrid, 28040, Spain

Location

Complejo Hospitalario Universitario de Santiago

Santiago de Compostela, 15706, Spain

Location

Hospital Universitario Virgen del Rocío

Seville, 41013, Spain

Location

Hospital Universitario y Politécnico La Fé

Valencia, 46026, Spain

Location

MeSH Terms

Conditions

Charcot-Marie-Tooth Disease; Peripheral Nervous System Diseases

Interventions

Naltrexone; Sorbitol

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Naloxone; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Sugar Alcohols; Alcohols; Organic Chemicals; Carbohydrates

Study Officials

• Sharam Attarian, MD

  CHU la Timone, Marseille , France

  PRINCIPAL INVESTIGATOR

• Mario Saporta, MD

  University of Miami Miller School of Medicine, USA

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: PXT3003 and its matching placebo will have the same presentation, the same aspect and taste in order to be indistinguishable, and they will be supplied and used in the same conditions.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 17, 2021
• First Posted: February 21, 2021
• Study Start: March 30, 2021
• Primary Completion: April 19, 2024
• Study Completion: April 19, 2024
• Last Updated: April 3, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

DE (5); IT (5); FR (6); ES (4); DK (1); CA (5); BE (1); US (20); IL (3)