E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Charcot Marie Tooth Type 1A |
|
E.1.1.1 | Medical condition in easily understood language |
Hereditary Motor and Sensory Neuropathy |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008414 |
E.1.2 | Term | Charcot-Marie-Tooth disease |
E.1.2 | System Organ Class | 100000004850 |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of treatment with PXT3003 (a fixed-dose combination of (RS)-baclofen, naltrexone hydrochloride, and D-sorbitol) compared to placebo in subjects with CMT1A |
|
E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of PXT3003 treatment in subjects with CMT1A |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 In the event of a negative genetic test result, the subject will be withdrawn from the study 2) Able to provide written informed consent/assent and comply with study procedures 3) Mild-to-moderate severity assessed by CMTNS-v2 score 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 15m/s 6) If taking prescribed psychoactive drug(s) (eg, antidepressants, stimulants, tranquilizers, anti-epileptics), 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), 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 • IUD • IUS • Intrauterine device (IUD) • Intrauterine hormone-releasing system (IUS) • Bilateral tubal occlusion • Vasectomized partner • Sexual abstinence; or (c) Of non-childbearing potential (i.e., postmenopausal for at least 1 year) 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.
For subjects consenting to enter the OLE Period, the following Inclusion criteria will be confirmed/reassessed on Screening Day (SV6) of the OLE Period: 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: o Oral o Intravaginal o Transdermal • Progestogen-only hormonal contraception associated with inhibition of ovulation: o Oral o Injectable o 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. |
|
E.4 | Principal 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.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 that reduces the mobility of the ankle 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 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 and/or any of its excipients 10) Concomitant treatments including but not limited to baclofen, naltrexone, sorbitol (pharmaceutical form), opioids, 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 11) History of porphyria 12) Diagnosis or history of substance use disorder by DSM-V 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 (e.g. any suicide attempts within the past 12 months or any current suicide intent, including a plan, as assessed by the Columbia Suicide Severity Rating Scale (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 BDI-II score ≥ 20 16) Currently lactating, pregnant, or planning on becoming pregnant during the study 17) ALT or AST levels greater than 2 times the ULN 18) Significant renal impairment as determined by GFR 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 investigator. For subjects consenting to enter the OLE Period, the following criteria will be confirmed/reassessed on SV6 of the OLE Period 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, 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 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.1 8.Estimated GFR of less than 50 mL/min.1 1.Note: If the laboratory values are not normal (out of range), the subjects will be contacted, and therapy will be stopped. 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. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The change in the modified Overall Neuropathy Limitation Scale (mONLS) between baseline and the Month 15 visit. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
The change from baseline to month 15 in the following outcome measures in hierarchical order: 1) 10-Meter Walk Test (10mWT) 2) CMTNS-V2 3) Patient Global Impression of Severity (PGI-S) 4) Patient Global Impression of Change (PGI-C)* 5) Quantified Muscular Testing (hand grip) 5) Quantified Muscular Testing (bilateral foot dorsiflexion dynamometry) * Because the PGI-C is already a change assessment, the change from Baseline is not needed for this endpoint. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
Israel |
United States |
Belgium |
Denmark |
France |
Germany |
Italy |
Spain |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
For Double-blind Treatment Period - LVLS - completion of the Month 15 Visit by the last subject For OLE Period – The duration of OLE Period will be based on Sponsor discretion, ie, Sponsor intends to keep the study open until the study drug PXT3003 is commercially available. Hence, the duration to attain EOS will be based on Sponsor discretion |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 22 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 23 |