Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients (PREMIER)
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|ClinicalTrials.gov Identifier: NCT04762758|
Recruitment Status : Active, not recruiting
First Posted : February 21, 2021
Last Update Posted : October 13, 2022
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:
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).
To evaluate the safety and tolerability of PXT3003 treatment in subjects with CMT1A.
To characterize the relationship between plasma biomarkers and response to PXT3003 treatment.
OLE Period Objective:
To evaluate the long-term safety and efficacy of PXT3003.
|Condition or disease||Intervention/treatment||Phase|
|Charcot-Marie-Tooth Disease||Drug: (RS)-baclofen, naltrexone hydrochloride and D-sorbitol Drug: Placebo||Phase 3|
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
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
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||350 participants|
|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.|
|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|
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
liquid oral solution
- 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.
- 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.
- 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.
- 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.
- 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".
- 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.
- 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.
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 ClinicalTrials.gov identifier (NCT number): NCT04762758
|Principal Investigator:||Sharam Attarian, MD||CHU la Timone, Marseille , France|
|Principal Investigator:||Mario Saporta, MD||University of Miami Miller School of Medicine, USA|