Clinical trial NCT04762758: Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Charcot-Marie-Tooth Disease
Keywords: Charcot Marie Tooth Type 1
Peripheral Neuropathy
PXT3003
Lead sponsor: Pharnext S.C.A.
Sponsor class: OTHER
Collaborators: name: Worldwide Clinical Trials
First posted: 2021-02-21
Enrollment: 350
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 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.

Detailed description: This is an international, multi-center, randomized, double-blind, placebo-controlled, parallel-group, Phase III study of PXT3003 in subjects with CMT1A. The study will be conducted at approximately 52 sites worldwide.

This study consists of Double-blind Treatment and OLE Periods.

Double-blind Treatment Period:

Eligible subjects will be screened and randomized in a 1:1 ratio to receive either oral PXT3003 or matching placebo, 10 mL, twice daily (BID) for 15 months. In order to maximize the tolerability of (RS)-baclofen for all randomized subjects, treatment will start with a half-dose (5 mL), taken BID (morning and evening with food) during the first 2 weeks, and then will be increased to a full-dose (10 mL), taken BID (morning and evening with food) until completion of the Treatment Period at Month 15.

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. Telephone contacts will take place at weeks 2 or 3, Month 1 and Month 2, and then monthly between subsequent in-person visits. A genotyping test for the Peripheral Myelin Protein 22 (PMP22) gene duplication will take place at the Screening Visit if it is not already documented for the subject. All subjects completing the Double-blind Treatment Period of the study will be given an opportunity to enter the OLE Period at Month 15 (Visit 6). Subjects not consenting to enter the OLE Period will have their last study visit (ie, Safety Follow-up Visit, Visit 7), 30 days after their last dosing day.

The primary outcome measures modified Overall Neuropathy Limitations Score(mONLS) and the 10-Meter Walk Test (10mWT), along with the Columbia Suicide Severity Rating Scale (C-SSRS) will be evaluated at each post-randomization in-person visit. The other secondary outcome measures, exploratory outcome, and safety/tolerability assessments will be evaluated as per Schedule of Activities (SOA). 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.

Planned duration for sites to enroll subjects: approximately 12 months, Subject Screening Period: 35 days, Subject Treatment Period: up to 15 months, Safety Follow-up Period (for subjects not entering the OLE Period): 30 days

OLE Period:

A subject entering the OLE Period (whether the subject was randomized to oral PXT3003 or matching placebo in the Double-blind Treatment Period) will start taking a half-dose of PXT3003 (5 mL) BID (morning and evening with food) during the first 2 weeks, and then a full dose of PXT3003 (10 mL) BID (morning and evening with food) throughout the OLE Period. The visits and assessments during the OLE Period are described in the SOA.

For subjects entering the OLE Period, Screening Day will occur on the same day as Visit 6 (Month 15) of the Double-blind Treatment Period. The duration of the Treatment Period will be based on Sponsor discretion. Sponsor intends to keep the study open until the study drug PXT3003 is commercially available. Safety Follow-up Period: 30 days

Eligibility criteria: Double-blind Treatment Period

Inclusion Criteria:

1. 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.
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.

OLE Period

Inclusion Criteria:

1. Able to provide written informed consent/assent and comply with study procedures.
2. 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
   * IUD
   * IUS
   * Bilateral tubal occlusion
   * Vasectomized partner
   * Sexual abstinence or (c) of non-childbearing potential (ie, no menses for ≥12 consecutive months without any other underlying medical cause).
3. 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. Any clinically significant and/or uncontrolled medical condition that, in the opinion of the investigator, could be a confound factor, may increase subject's risk, or may preclude successful participation or completion of the study.
2. Concomitant treatments including but not limited to baclofen, naltrexone, sorbitol (pharmaceutical form) other than PXT3003 taken in the Double-blind Treatment Period of this study, opioids, potent CNS 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.
3. Diagnosis or history of substance use disorder by Diagnostic and Statistical Manual of Mental Disorders-5ᵗʰ Edition criteria within the past 12 months.
4. 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).
5. Currently active major depression, as determined by a BDI-II score ≥20.
6. Currently lactating, pregnant, or planning on becoming pregnant during the study.
7. ALT or AST levels greater than 2 × ULN relative to Baseline.
8. Estimated GFR of less than 50 mL/min.

Note: PXT3003 will be dispensed to all subjects before laboratory results are available, and if the laboratory results are out of range, ie, subject meeting the exclusion criteria, the subject will be called immediately to stop taking PXT3003. One retest within 4 weeks may be performed in consultation with the Medical Monitor if any of the above laboratory abnormalities are found. In case of eligibility determination after the retest, subjects will restart taking 2 weeks of half dose of PXT3003.

Primary outcomes:
measure: modified Overall Neuropathy Limitation Scale (mONLS)
timeFrame: From Baseline to Month 15
Secondary outcomes:
measure: 10-Meter Walk Test
timeFrame: From Baseline to Month 15
measure: Quantified Muscular Testing (QMT) (bilateral foot dorsiflexion dynamometry)
timeFrame: From Baseline to Month 15
measure: Patient Global Impression of Severity (PGI-S)
timeFrame: From Baseline to Month 15
measure: Patient Global Impression of Change (PGI-C)
timeFrame: From Baseline to Month 15
measure: CMTNS-V2
timeFrame: From Baseline to Month 15
measure: QMT (hand grip)
timeFrame: From Baseline to Month 15
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Los Angeles
country: United States
facility: UCLA Department of Psychiatry and Biobehavioral Sciences
state: California
city: Sacramento
country: United States
facility: UC Davis Health Department of Physical Medicine and Rehabilitation
state: California
city: New Britain
country: United States
facility: Hospital for Special Care
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida Clinical Research Center
state: Florida
city: Miami
country: United States
facility: University of Miami Leonard M. Miller School of Medicine
state: Florida
city: Orlando
country: United States
facility: Advent Health Medical Group Neurology Orlando
state: Florida
city: Fairway
country: United States
facility: University of Kansas Medical Center Research Institute
state: Kansas
city: Boston
country: United States
facility: Massachusetts General Hospital Neuromuscular Diagnostic Center
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota Health
state: Minnesota
city: Columbia
country: United States
facility: MU Health Care Neurology and Sleep Disorders Clinic
state: Missouri
city: Hackensack
country: United States
facility: Hackensack Meridian Health Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Colombia University Department of Neurology
state: New York
city: Chapel Hill
country: United States
facility: UNC Department of Neurology Peripheral Neuropathy Center
state: North Carolina
city: Charlotte
country: United States
facility: Atrium Health Neurosciences Institute
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: Springfield
country: United States
facility: Oregon Neurology
state: Oregon
city: Austin
country: United States
facility: National Neuromuscular Research Institute
state: Texas
city: Seattle
country: United States
facility: Neurology Clinic at University of Washington Medical Center
state: Washington
city: Spokane
country: United States
facility: Providence St. Luke's Rehabilitation Medical Center
state: Washington
city: Leuven
country: Belgium
facility: Universitaire Ziekenhuizen Leuven
city: Ottawa
country: Canada
facility: Ottawa Hospital Research Institute- Neuromuscular Research Centre
state: Ontario
city: Toronto
country: Canada
facility: UHN Toronto General Hospital Krembil Neuroscience Centre
state: Ontario
city: Chicoutimi
country: Canada
facility: CIUSS de Saguenay-Lac-Saint-Jean Centre d'etudes Cliniques
state: Quebec
city: Montréal
country: Canada
facility: Montreal Neurological Institute and Hospital-Clinical Research Unit
state: Quebec
city: Québec
country: Canada
facility: CHU de Quebec-Universite Laval- Hopital Enfant-Jesus
state: Quebec
city: Copenhagen
country: Denmark
facility: Rigshospitalet, University of Copenhagen Copenhagen Neuromuscular Center
city: Angers
country: France
facility: Centre de Reference des Maladies Neuromusculaires AOC Service de Neurologie, CHU d'Angers
city: Bordeaux
country: France
facility: Centre de reference des maladies neuromusculaires AOC Hopital Pellegrin CHU de Bordeaux
city: Lille
country: France
facility: CHU de Lille Hôpital Salengro
city: Marseille
country: France
facility: Service de Neurologie et Maladies Neuromusculaires, CHU de Marseille - Hopital La Timone
city: Paris
country: France
facility: Association lnstitut de Myologie Hopital Pitie-Salpetriere Service de Neuro-Myologie
city: Strasbourg
country: France
facility: Centre d'investigation Clinique CHU de Strasbourg Hopital de Hautepierre
city: Aachen
country: Germany
facility: University Hospital RWTH Aachen, Department of Neurology and Institute for Neuropathology
city: Göttingen
country: Germany
facility: University Medical Centre Goettingen, Dept. of Clinical Neurology
city: München
country: Germany
facility: Friedrich-Baur-Institut, Neurologische Klinik und Poliklinik Ludwig-Maximilians-Universität
city: Münster
country: Germany
facility: University Hospital Muenster UKM Department of Neurology
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen Crona Kliniken Neuromuskuläres Zentrum
city: Jerusalem
country: Israel
facility: Hadassah Ein Kerem University Medical Center Department of Neurology
city: Ramat Gan
country: Israel
facility: Sheba Medical Center
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Genova
country: Italy
facility: Azienda Ospedaliera Universitaria San Martino Universita Degli Studi di Genova Clinica Neurologica
city: Messina
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico "G. Martino" di Messina
city: Naples
country: Italy
facility: University of Naples Federico II
city: Rome
country: Italy
facility: Tor Vergata University of Rome
city: Verona
country: Italy
facility: University Hospital GB Rossi UOC Neurologia B, AOUI Verona Department of Neuroscience, Biomedicine and Movement Sciences
city: Madrid
country: Spain
facility: Hospital Universitario Clinico San Carlos
city: Santiago De Compostela
country: Spain
facility: Complejo Hospitalario Universitario de Santiago
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: Valencia
country: Spain
facility: Hospital Universitario y Politécnico La Fé
Study officials:
affiliation: CHU la Timone, Marseille , France
name: Sharam Attarian, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Miami Miller School of Medicine, USA
name: Mario Saporta, MD
role: PRINCIPAL_INVESTIGATOR
References: