Principal Investigator
Enrollment Status
Clinical Trial ID
Clinical Trial 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.
Phase
Phase 3
Funding Agency/Sponsor
Other
Disease
Other
Enrollment Eligibility
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genetic test result, the subject will be withdrawn from the study.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.