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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT04762758
Recruitment Status : Active, not recruiting
First Posted : February 21, 2021
Last Update Posted : May 5, 2022
Worldwide Clinical Trials
Information provided by (Responsible Party):
Pharnext SA

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
Charcot-Marie-Tooth Disease 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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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 : March 30, 2021
Estimated Primary Completion Date : October 31, 2023
Estimated Study Completion Date : March 31, 2024

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 Name: PXT3003

Placebo Comparator: Placebo
Liquid oral solution, 10 mL twice a day, morning and evening with food
Drug: Placebo
liquid oral solution

Primary Outcome Measures :
  1. modified Overall Neuropathy Limitation Scale (mONLS) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   16 Years to 65 Years   (Child, Adult, Older Adult)
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)
  9. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04762758

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Sponsors and Collaborators
Pharnext SA
Worldwide Clinical Trials
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Principal Investigator: Sharam Attarian, MD CHU la Timone, Marseille , France
Principal Investigator: Mario Saporta, MD University of Miami Miller School of Medicine, USA
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Responsible Party: Pharnext SA Identifier: NCT04762758    
Other Study ID Numbers: CLN-PXT3003-06
2020-004805-30 ( EudraCT Number )
First Posted: February 21, 2021    Key Record Dates
Last Update Posted: May 5, 2022
Last Verified: May 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Pharnext SA:
Charcot Marie Tooth Type 1
Peripheral Neuropathy
Additional relevant MeSH terms:
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Tooth Diseases
Charcot-Marie-Tooth Disease
Nerve Compression Syndromes
Hereditary Sensory and Motor Neuropathy
Stomatognathic Diseases
Nervous System Malformations
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Congenital Abnormalities
Genetic Diseases, Inborn
Alcohol Deterrents
Narcotic Antagonists
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents
Muscle Relaxants, Central
Neuromuscular Agents
GABA-B Receptor Agonists
GABA Agonists
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action