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)

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 drug(s) (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 medication(s) (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:
o Oral
o Intravaginal
o Transdermal
* Progestogen-only hormonal contraception associated with inhibition of
ovulation:
o Oral
o Injectable
o Implantable
* Intrauterine device
* Intrauterine hormone-releasing system
* 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)
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.

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 carpal 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 1 year 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 (see Appendix 2 from the protocol: List of Prohibited
Treatments).
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.