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

Sponsor
Pharnext SA (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT04762758
Collaborator
Worldwide Clinical Trials (Other)
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Study Details

Study Description

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 1A. This double-blind study will assess in parallel groups 1 dose of PXT3003 compared to Placebo in CMT1A patients treated for 15 months.

Condition or Disease Intervention/Treatment Phase
  • Drug: (RS)-baclofen, naltrexone hydrochloride and D-sorbitol
  • Drug: Placebo
Phase 3

Detailed Description

This international, multi-center, randomized, double-blind, placebo-controlled, Phase III clinical study is designed to evaluate PXT3003 versus placebo in male and non-pregnant female subjects with genetically confirmed CMT1A of mild-to-moderate severity (CMTNS-V2 score >2 and ≤18) aged 16 to 65 years.

The study will be conducted in approximately 52 sites worldwide. Genetically confirmed CMT1A subjects will be screened (approximately 500 subjects assuming a 30% screen failure rate) and randomized in a 1:1 ratio to receive either oral PXT3003 daily or matching placebo for 15 months. A total of approximately 350 subjects will be enrolled. Visits will take place at Screening (up to -35 days), Baseline (Day 1), and Months 3, 6, 9, 12, and 15. Randomization will occur at the Baseline (Day 1) Visit. Telephone contacts (TC) will take place at Weeks 2 or 3, Month 1 and 2, and then monthly between subsequent in-person visits. A Safety follow-up visit will be conducted at Month 16.

Subjects will receive in-clinic dosing of study medication at visits on Day 1 and Months 6, 12, and 15. Study medication will be dispensed for outpatient dosing on Day 1 and Months 3, 6, 9, and 12. During outpatient dosing, subjects will complete the Study Medication Diary using an application on their tablet, phone, or computer. The Study Medication Diary will be evaluated, along with returned unused study medication, as part of study drug compliance at visits at Months 3, 6, 9, 12, and 15.

The primary outcome measure (mONLS) and the 10-Meter Walk Test (10mWT), along with the Columbia Suicide Severity Rating Scale (C-SSRS) will be evaluated at each post-Screening visit. The other secondary outcome measures, exploratory outcome, and safety/tolerability assessments will be evaluated as per Schedule of Activities (SOA). A Safety Follow-Up Visit will take place 30 days (Month 16) after the active treatment period ends (Month 15). A Data Safety and Monitoring Board (DSMB) will meet on a scheduled basis throughout the study to review safety data and will reconvene on an ad hoc basis as necessary.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
350 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Masking Description:
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.
Primary Purpose:
Treatment
Official Title:
A Multi-center, Randomized, Double-blind, Placebo Controlled Phase III Study to Assess the Efficacy, Safety, and Tolerability of PXT3003 in Charcot-Marie-Tooth Type 1A (CMT1A)
Actual Study Start Date :
Mar 30, 2021
Anticipated Primary Completion Date :
Oct 31, 2023
Anticipated Study Completion Date :
Mar 31, 2024

Arms and Interventions

Arm Intervention/Treatment
Experimental: PXT3003

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

Drug: (RS)-baclofen, naltrexone hydrochloride and D-sorbitol
oral fixed dose combination
Other Names:
  • PXT3003
  • Placebo Comparator: Placebo

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

    Drug: Placebo
    liquid oral solution

    Outcome Measures

    Primary Outcome Measures

    1. modified Overall Neuropathy Limitation Scale (mONLS) [From Baseline to Month 15]

      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.

    Secondary Outcome Measures

    1. 10-Meter Walk Test [From Baseline to Month 15]

      The 10mWT is simple to administer, standardized, and valid performance evaluation of functional mobility and gait that has been proven reliable in neurologic disorders, including CMT. Results recorded are the time to walk 10 meters and the number of steps performed.

    2. Quantified Muscular Testing (QMT) (bilateral foot dorsiflexion dynamometry) [From Baseline to Month 15]

      QMT is used to evaluate motor strength in CMT1A.The following muscles will be evaluated: tibialis anterior (right and left). The best value on three consecutive and reproducible tests will be collected in the electronic Case Record Form (eCRF) for each muscle.

    3. Patient Global Impression of Severity (PGI-S) [From Baseline to Month 15]

      The PGI-S is a validated tool that is used to rate the severity of a specific condition. Subjects will rate their health status over the past week. The PGI-S is a 1-item questionnaire on a 5-point scale and subjects will be asked to rate the severity of their condition from "None" (Score = 1) to "Very Severe" (Score = 5). Assessments obtained over the course of the study will be compared to baseline, prior to initiation of treatment.

    4. Patient Global Impression of Change (PGI-C) [From Baseline to Month 15]

      The PGI-C scale is a validated generic tool for assessment of overall change in the severity of illness following treatment. Subjects will rate how they feel now compared with how they felt before receiving study drug on a 7-point scale where 1 is "Very much improved" and 7 is "Very much worse".

    5. CMTNS-V2 [From Baseline to Month 15]

      CMTNS is a specific scale designed to assess severity of impairment in CMT disease. Although not completely validated, it provides a single and reliable measure of CMT severity. It is a 36-point scale based on 9 items: 5 of them quantify impairment (sensory symptoms, pin sensibility, vibration, arm, and leg strength), 2 activity limitations (motor symptoms arms and legs) and 2 electrophysiological data (amplitudes of ulnar compound muscle action potential and sensory nerve action potential). Increased scores indicate a worsening of the function: the scores categorize a disability as mild (0 to10), moderate (11 to 20) and severe (21 to 36). A modified version 2 (CMTNS-V2) was issued in 2011 to attempt to reduce floor and ceiling effects and to standardize patient assessment.

    6. QMT (hand grip) [From Baseline to Month 15]

      QMT is used to evaluate motor strength in CMT1A. The following muscles will be evaluated: hand grip (right and left). The best value on three consecutive and reproducible tests will be collected in the eCRF for each muscle.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    16 Years to 65 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. Male and non-pregnant female subjects, aged 16 to 65 years with a genetically proven diagnosis of CMT1A.

    2. Able to provide written informed consent/assent and comply with study procedures.

    3. Mild-to-moderate severity assessed by a CMTNS-V2 score >2 and ≤18.

    4. Muscle weakness in at least foot dorsiflexion on clinical assessment.

    5. Ulnar nerve motor conduction time of at least 15 m/s.

    6. 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.

    7. 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.

    8. 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

    • Implantable

    • Intrauterine device

    • Intrauterine hormone-releasing system

    • Bilateral tubal occlusion

    • Vasectomized partner

    • Sexual abstinence or (c) Of non-childbearing potential (i.e., no menses for ≥ 12 consecutive months without any other underlying medical cause)

    1. If male, the subject must have had a vasectomy or must use a reliable method of birth control with their partner or total abstinence from sexual intercourse. The subject must agree to continue using their selected method of birth control with their sexual partner during the study and for 120 days after study completion.
    Exclusion Criteria:
    1. Subjects previously enrolled in any PXT3003 study.

    2. 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).

    3. CMT of any subtype other than 1A.

    4. ONLS score of 0.

    5. 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.

    6. 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.

    7. 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.

    8. 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.

    9. 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).

    10. 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.

    11. History of porphyria.

    12. Diagnosis or history of substance use disorder by Diagnostic and Statistical Manual of Mental Disorders-5th Edition criteria within the past 12 months.

    13. Medical or recreational use of marijuana in the 3 months prior to the Screening Visit.

    14. 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).

    15. Currently active major depression, as determined by a Beck Depression Inventory-II (BDI-II) score ≥20.

    16. Currently lactating, pregnant, or planning on becoming pregnant during the study.

    17. Alanine aminotransferase or aspartate aminotransferase levels greater than 2 times the upper limit of normal.

    18. Significant renal impairment as determined by glomerular filtration rate of less than 50 mL/min.

    19. Subject has participated in an investigational drug or device study within 30 days prior to the Screening Visit or plans to participate in an investigational drug or device study during the course of this study.

    20. Subject is a dependent and/or relative of the Sponsor or Principal Investigator.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Cedars-Sinai Medical Center Los Angeles California United States 90048
    2 UCLA Department of Psychiatry and Biobehavioral Sciences Los Angeles California United States 90095
    3 UC Davis Health Department of Physical Medicine and Rehabilitation Sacramento California United States 95817
    4 Hospital for Special Care New Britain Connecticut United States 06053
    5 University of Florida Clinical Research Center Gainesville Florida United States 32610
    6 University of Miami Leonard M. Miller School of Medicine Miami Florida United States 33136
    7 Advent Health Medical Group Neurology Orlando Orlando Florida United States 32803
    8 University of Kansas Medical Center Research Institute Fairway Kansas United States 66205
    9 Massachusetts General Hospital Neuromuscular Diagnostic Center Boston Massachusetts United States 02114
    10 University of Minnesota Health Minneapolis Minnesota United States 55414
    11 MU Health Care Neurology and Sleep Disorders Clinic Columbia Missouri United States 65212
    12 Hackensack Meridian Health Hackensack University Medical Center Hackensack New Jersey United States 07601
    13 Colombia University Department of Neurology New York New York United States 10032
    14 UNC Department of Neurology Peripheral Neuropathy Center Chapel Hill North Carolina United States 27514
    15 Atrium Health Neurosciences Institute Charlotte North Carolina United States 28207
    16 The Ohio State University Wexner Medical Center Columbus Ohio United States 43210
    17 Oregon Neurology Springfield Oregon United States 97477
    18 Austin Neuromuscular Center Austin Texas United States 78759
    19 Neurology Clinic at University of Washington Medical Center Seattle Washington United States 98195
    20 Providence St. Luke's Rehabilitation Medical Center Spokane Washington United States 99202
    21 Universitaire Ziekenhuizen Leuven Leuven Belgium 3000
    22 Ottawa Hospital Research Institute- Neuromuscular Research Centre Ottawa Ontario Canada K1Y 4E9
    23 UHN Toronto General Hospital Krembil Neuroscience Centre Toronto Ontario Canada M5G 2C4
    24 CIUSS de Saguenay-Lac-Saint-Jean Centre d'etudes Cliniques Chicoutimi Quebec Canada G7H 5H6
    25 Montreal Neurological Institute and Hospital-Clinical Research Unit Montréal Quebec Canada H3A 2B4
    26 CHU de Quebec-Universite Laval- Hopital Enfant-Jesus Québec Quebec Canada G1J 1Z4
    27 Rigshospitalet, University of Copenhagen Copenhagen Neuromuscular Center Copenhagen Denmark DK-1200
    28 Centre de Reference des Maladies Neuromusculaires AOC Service de Neurologie, CHU d'Angers Angers France 49933
    29 Centre de reference des maladies neuromusculaires AOC Hopital Pellegrin CHU de Bordeaux Bordeaux France 33076
    30 CHU de Lille Hôpital Salengro Lille France 59037
    31 Service de Neurologie et Maladies Neuromusculaires, CHU de Marseille - Hopital La Timone Marseille France 13385
    32 Association lnstitut de Myologie Hopital Pitie-Salpetriere Service de Neuro-Myologie Paris France 75013
    33 Centre d'investigation Clinique CHU de Strasbourg Hopital de Hautepierre Strasbourg France 67098
    34 University Hospital RWTH Aachen, Department of Neurology and Institute for Neuropathology Aachen Germany D-52074
    35 University Medical Centre Goettingen, Dept. of Clinical Neurology Göttingen Germany D-37075
    36 Friedrich-Baur-Institut, Neurologische Klinik und Poliklinik Ludwig-Maximilians-Universität München Germany D-80336
    37 University Hospital Muenster UKM Department of Neurology Münster Germany 48149
    38 Universitätsklinikum Tübingen Crona Kliniken Neuromuskuläres Zentrum Tübingen Germany 72076
    39 Hadassah Ein Kerem University Medical Center Department of Neurology Jerusalem Israel 91120
    40 Sheba Medical Center Ramat Gan Israel 52662
    41 Tel Aviv Sourasky Medical Center Tel Aviv Israel 6423906
    42 Azienda Ospedaliera Universitaria San Martino Universita Degli Studi di Genova Clinica Neurologica Genova Italy 16132
    43 Azienda Ospedaliera Universitaria Policlinico "G. Martino" di Messina Messina Italy 98125
    44 University of Naples Federico II Naples Italy 80131
    45 Tor Vergata University of Rome Rome Italy 00133
    46 University Hospital GB Rossi UOC Neurologia B, AOUI Verona Department of Neuroscience, Biomedicine and Movement Sciences Verona Italy 37134
    47 Hospital Universitario Clinico San Carlos Madrid Spain 28040
    48 Complejo Hospitalario Universitario de Santiago Santiago De Compostela Spain 15706
    49 Hospital Universitario Virgen del Rocío Sevilla Spain 41013
    50 Hospital Universitario y Politécnico La Fé Valencia Spain 46026

    Sponsors and Collaborators

    • Pharnext SA
    • Worldwide Clinical Trials

    Investigators

    • Principal Investigator: Sharam Attarian, MD, CHU la Timone, Marseille , France
    • Principal Investigator: Mario Saporta, MD, University of Miami Miller School of Medicine, USA

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Pharnext SA
    ClinicalTrials.gov Identifier:
    NCT04762758
    Other Study ID Numbers:
    • CLN-PXT3003-06
    • 2020-004805-30
    First Posted:
    Feb 21, 2021
    Last Update Posted:
    May 5, 2022
    Last Verified:
    May 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Pharnext SA
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of May 5, 2022