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Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients (PLEO-CMT) (PLEO-CMT)

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ClinicalTrials.gov Identifier: NCT02579759
Recruitment Status : Completed
First Posted : October 20, 2015
Results First Posted : February 27, 2020
Last Update Posted : February 27, 2020
Sponsor:
Information provided by (Responsible Party):
Pharnext SA

Tracking Information
First Submitted Date  ICMJE September 28, 2015
First Posted Date  ICMJE October 20, 2015
Results First Submitted Date  ICMJE November 18, 2019
Results First Posted Date  ICMJE February 27, 2020
Last Update Posted Date February 27, 2020
Actual Study Start Date  ICMJE December 2015
Actual Primary Completion Date March 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 13, 2020)
Overall Neuropathy Limitation Scale (ONLS) Total Score [ Time Frame: From Baseline to Month 15 ]
The primary efficacy variable used in the main analysis is the mean of the available ONLS values at month 12 and month 15. The ONLS is a disability scale that was derived and improved from the Overall Disability Sum Score (ODSS) to measure limitations in the everyday activities of the upper limbs (rated on 5 points) and the lower limbs (rated on 7 points). The total score is a 12-point scale: 0 (no disability) to 12 (maximum disability). Lower values in the ONLS indicate a better clinical condition. Reported values are the values at Baseline (Base) and the average of the available values at Month 12 and Month 15 (Fin).
Original Primary Outcome Measures  ICMJE
 (submitted: October 16, 2015)
Disability measured by the change in the Overall Neuropathy Limitation Scale (ONLS) score [ Time Frame: 12 and 15 months of treatment ]
Analysis of Covariance on the summary mean of ONLS at 12 and 15 months adjusted for baseline ONLS values.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 13, 2020)
  • Mean of Ten Meter Walking Test (10MWT) [ Time Frame: From Baseline to Month 15 ]
    This outcome measure is the mean of the available 10MWT values at month 12 and month 15. The 10MWT is a simple to administer, standardized, reliable and valid evaluation of functional exercise capacity and gait that has been used to evaluate neurologic disorders and CMT patients. Lower Time to Walk 10 Meters values indicate a better clinical condition. Reported values are the values at Baseline (Base) and the average of the available values at Month 12 and Month 15 (Fin).
  • Mean of the CMTNS-v2 Sensory Score [ Time Frame: From Baseline to Month 15 ]
    This outcome measure is the mean of the available CMTNS-v2 Sensory Score values at month 12 and month 15. The CMTNS-v2 is a specific scale designed to assess severity of impairment in CMT disease. It is a 36-point scale based on nine items to quantify impairment (sensory symptoms, pin sensibility, vibration and arm and leg strength), activity limitations (motor symptoms arms and legs) and electrophysiological function (amplitudes of ulnar CMAP and SNAP). The CMTNS-v2 goes from 0 (no impairment) to 36 (maximum impairment) whom each sub-items goes from 0 to 4. The CMTNS-v2 Sensory score is summed of items 1+4+5 of CMTNS-v2 (Sensory symptoms, Pinprick sensibility and Vibration). It is a 12-point score: 0 (no impairment) to 12 (maximum impairment). Lower CMTNS-v2 Sensory Score values indicate a better clinical condition. Reported values are the values at Baseline (Base) and the average of the available values at Month 12 and Month 15 (Fin).
  • Mean of the CMTNS-v2 Examination Score (CMTES-v2) [ Time Frame: From Baseline to Month 15 ]
    This outcome measure is the mean of the available CMTNS-v2 Examination Score values at month 12 and month 15. The CMTNS-v2 is a specific scale designed to assess severity of impairment in CMT disease. It is a 36-point scale based on nine items to quantify impairment (sensory symptoms, pin sensibility, vibration and arm and leg strength), activity limitations (motor symptoms arms and legs) and electrophysiological function (amplitudes of ulnar CMAP and SNAP). The CMTNS-v2 goes from 0 (no impairment) to 36 (maximum impairment) whom each sub-items goes from 0 to 4. The CMTES-v2 is summed of item 1 to 7 of the CMTNS-v2 (limited to impairment items and excluding electrophysiological items). It is a 28-point score: 0 (no impairment) to 28 (maximum impairment). Lower CMTES-v2 values indicate a better clinical condition. Reported values are the values at Baseline (Base) and the average of the available values at Month 12 and Month 15 (Fin).
  • Mean of the Results at the Nine-Hole Peg Test (9-HPT) [ Time Frame: From Baseline to Month 15 ]
    This outcome measure is the mean of the available 9-HPT values at month 12 and month 15. The Nine-Hole Peg Test (9HPT) is a simple timed test of fine motor coordination of extremitied in the upper limbs. It measures the time needed by the patient to insert 9 pegs in nine holes and to remove them (normal required time 18 seconds). Lower 9HPT values indicate a better clinical condition. Reported values are the values at Baseline (Base) and the average of the available values at Month 12 and Month 15 (Fin).
  • Number of Subjects With at Least One TEAE [ Time Frame: The period between the patient signing the informed consent and 30 days after the end of study (i.e. completion/early discontinuation/last contact as recorded on the 'Study Completion on Early Termination' form up to 15 months) ]
    Safety selection was to include all randomized patients that have received at least one dose of study treatment. Safety and tolerability of PXT3003 were compared to placebo on the incidence of treatment-emergent adverse events (TEAEs); they were evaluated by type/nature, severity/intensity, seriousness, and relationship to study drug.
  • Incidence of AE Leading to Withdrawal of Study Drug [ Time Frame: The period between the patient signing the informed consent and 30 days after the end of study (i.e. completion/early discontinuation/last contact as recorded on the 'Study Completion on Early Termination' form up to 15 months) ]
    Safety and tolerability of PXT3003 were compared to placebo on the incidence of TEAEs leading to withdrawal of study drug.
  • Incidence of SAEs [ Time Frame: The period between the patient signing the informed consent and 30 days after the end of study (i.e. completion/early discontinuation/last contact as recorded on the 'Study Completion on Early Termination' form up to 15 months). ]
    Safety and tolerability of PXT3003 were compared to placebo on the incidence of serious adverse events (SAEs).
Original Secondary Outcome Measures  ICMJE
 (submitted: October 16, 2015)
  • Responder rate to PXT3003 therapy defined as a patients improving on ONLS at end of treatment [ Time Frame: 15 months of treatment ]
  • Arm and leg sub-items of ONLS [ Time Frame: 12 and 15 months of treatment ]
  • Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNS-v2), including its sub-items [ Time Frame: 12 and 15 months of treatment ]
  • Nine-hole Peg Test (9-HPT) performed on non-dominant hand [ Time Frame: 12 and 15 months of treatment ]
  • Quantified Muscular Testing (QMT) by Hand grip and Foot dorsiflexion dynamometry (mean of both sides) [ Time Frame: 12 and 15 months of treatment ]
  • Time to walk 10 meters [ Time Frame: 12 and 15 months of treatment ]
  • Compound Muscle Amplitude Potential (CMAP) in ulnar or median nerves (non-dominant side) [ Time Frame: 12 and 15 months of treatment ]
    mV
  • Sensory Nerve Potential Amplitude (SNAP) in radial nerve (non-dominant side) [ Time Frame: 12 and 15 months of treatment ]
    µV
  • Nerve Conduction Velocity (non-dominant side) [ Time Frame: 12 and 15 months of treatment ]
    m/sec
  • Quality of life measured by the EuroQol 5-Dimensional Health-related Quality of Life scale (EQ-5D-L) [ Time Frame: 12 and 15 months of treatment ]
  • visual analog scale on self-assessment of the individualized main impairment in daily activities defined at baseline with the patient [ Time Frame: 12 and 15 months of treatment ]
  • Safety and tolerability of PXT3003: assessment of some AE incidence and of the change in physical examination, vital signs, clinical laboratory variables, and ECGs. [ Time Frame: 15 months of treatment ]
    Incidence of Treatment Emergent Adverse Events (TEAE), of related TEAE with moderate or severe intensity, AE leading to withdrawal of study drug, and Serious Adverse Events,
Current Other Pre-specified Outcome Measures
 (submitted: February 13, 2020)
  • Mean of the CMTNS-v2 Sensory Symptoms [ Time Frame: From Baseline to Month 15 ]
    This outcome measure is the mean of the available CMTNS-v2 Sensory Symptoms values at month 12 and month 15. The CMTNS-v2 is a specific scale designed to assess severity of impairment in CMT disease. It is a 36-point scale based on nine items to quantify impairment (sensory symptoms, pin sensibility, vibration and arm and leg strength), activity limitations (motor symptoms arms and legs) and electrophysiological function (amplitudes of ulnar CMAP and SNAP). The CMTNS-v2 goes from 0 (no impairment) to 36 (maximum impairment) whom each sub-items goes from 0 to 4. The CMTNS-v2 Sensory Symptoms is the first item of the CMTNS-v2. It is a 4-point score: 0 (no impairment) to 4 (maximum impairment). Lower CMTNS-v2 Sensory Symptoms values indicate a better clinical condition. Reported values are the values at Baseline (Base) and the average of the available values at Month 12 and Month 15 (Fin).
  • Plasma Concentrations of Baclofen at Trough and at 90 Min After Drug Intake [ Time Frame: At Month 12 and Month 15 ]
    Plasma concentration of PXT3003 components were measured at trough (prior to dose) and 90 minutes after drug intake. The mean plasma values of the baseline correspond to half of the administered dose.
  • Plasma Concentrations of Naltrexone at Trough and at 90 Min After Drug Intake [ Time Frame: At Month 12 and month 15 ]
    Plasma concentration of PXT3003 components were measured at trough (prior to dose) and 90 minutes after drug intake. The mean plasma values of the baseline correspond to half of the administered dose.
  • Plasma Concentrations of 6β-naltrexol at Trough and at 90 Min After Drug Intake [ Time Frame: At Month 12 and Month 15 ]
    Plasma concentration of PXT3003 components were measured at trough (prior to dose) and peak (90 minutes post dose). The mean plasma values of the baseline correspond to half of the administered dose.
  • Number of Participants With ONLS Therapy Response 1 [ Time Frame: From Baseline to Month 15 ]
    ONLS Therapy Response 1 was defined as the number of participants (responders) with an improvement on final ONLS Total Score of at least one point. A higher response rate indicate a better clinical condition.
  • Number of Participants With ONLS Therapy Response 2 [ Time Frame: From Baseline to Month 15 ]
    ONLS Therapy Response 2 was defined as the number of participants with no deterioration (responders) on final ONLS Total Score. A higher response rate indicates a better clinical condition.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients (PLEO-CMT)
Official Title  ICMJE International, Multi-center, Randomized, Double-blind, Placebo-controlled Phase III Study Assessing in Parallel Groups the Efficacy and Safety of 2 Doses of PXT3003 in Patients With Charcot-Marie-Tooth Disease Type 1A Treated 15 Months
Brief Summary The purpose of this study is to determine whether PXT3003 is effective and safe in the treatment of Charcot-Marie-Tooth disease - Type 1 A (CMT1A). This double-blind study will assess in parallel groups 2 doses of PXT3003 compared to Placebo in CMT1A patients treated for 15 months.
Detailed Description PXT3003 is a fixed dose combination of (RS)-baclofen, naltrexone hydrochloride and D-sorbitol selected via a Systems Biology approach and developed by Pharnext, with the aim to limit the production of PMP22 and protect/improve axonal function in patients with CMT1A. On September 18th 2017, PXT3003 dose 2 was prematurely discontinued, due to an unexpected investigational medicinal product quality event (failed month 18 stability testing). This resulted in a large proportion of missing data that led us to reconsider the efficacy analysis that was initially planned in the protocol.The independent data safety monitoring committee did not identify any safety concern on September 5th 2017. All patients randomised to dose 2 were requested to undergo the end of study visit, and were offered to enter the extension study (CLN-PXT3003-03).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Charcot-Marie-Tooth Disease Type 1A
Intervention  ICMJE
  • Drug: PXT3003 dose 1
    Liquid oral solution, 5 ml twice a day, morning and evening with food
    Other Name: DOSE 1
  • Drug: PXT3003 dose 2
    Liquid oral solution, 5 ml twice a day, morning and evening with food
    Other Name: DOSE 2
  • Drug: placebo
    Liquid oral solution, 5 ml twice a day, morning and evening with food
Study Arms  ICMJE
  • Active Comparator: PXT3003 dose 1
    Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months
    Intervention: Drug: PXT3003 dose 1
  • Active Comparator: PXT3003 dose 2
    Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months
    Intervention: Drug: PXT3003 dose 2
  • Placebo Comparator: placebo
    Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months
    Intervention: Drug: placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 4, 2017)
323
Original Estimated Enrollment  ICMJE
 (submitted: October 16, 2015)
300
Actual Study Completion Date  ICMJE August 2018
Actual Primary Completion Date March 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male or female, aged from 16 to 65 years;
  • Patient with a proven genetic diagnosis of CMT1A;
  • Mild-to-moderate severity assessed by Charcot-Marie-Tooth Neuropathy Score (version 2) with a score >2 and ≤18;
  • Muscle weakness in at least foot dorsiflexion;
  • Motor nerve conduction of the ulnar nerve of at least 15 m/sec;
  • Providing signed written informed consent to participate in the study and willing and able to comply with all study procedures and scheduled visits.

Exclusion Criteria:

  • Any other associated cause of peripheral neuropathy such as diabetes;
  • Patient with another significant neurological disease or a concomitant major systemic disease;
  • Clinically significant history of unstable medical illness since the last 30 days (unstable angina, cancer…) that may jeopardize the participation in the study;
  • Significant hematologic disease, hepatitis or liver failure, renal failure;
  • Limb surgery within six months before randomization or planned before trial completion;
  • Clinically significant abnormalities on the pre-study laboratory evaluation, physical evaluation, electrocardiogram (ECG);
  • Elevated ASAT/ALAT (> 3 x ULN) and elevated serum creatinine levels (> 1.25 x ULN);
  • History of recent alcohol or drug abuse or non-adherence with treatment or other experimental protocols;
  • Patient using unauthorized concomitant treatments including but not limited to baclofen, naltrexone, sorbitol (pharmaceutical form), opioids, levothyroxin and potentially neurotoxic drugs such as amiodarone, chloroquine, cancer drugs susceptible to induce a peripheral neuropathy. Patient who can/agrees to stop these medications 4 weeks before randomization and during the whole study duration can be included;
  • Female of childbearing potential (apart of patient using adequate contraceptive measures), pregnant or breast feeding;
  • Known hypersensitivity to any of the individual components of PXT3003;
  • Porphyria as it is a contra indication to baclofen, and it may also induce neuropathy;
  • Suspected inability to complete the study follow-up (foreign workers, transient visitors, tourists or any others for whom follow-up evaluation is not assured);
  • Limited mental capacity or psychiatric disease rendering the subject unable to provide written informed consent or comply with evaluation procedures;
  • Patient who has participated in another trial of investigational drug(s) within the past 30 days;
  • If a patient from the same family, living in the same household, has already been included in this study, it will not be possible to include another patient from the same family to avoid mixing of therapeutic units; therefore there would be a risk of inversion of the blind treatments which could jeopardize the interpretation of study results.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 16 Years to 65 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Canada,   France,   Germany,   Netherlands,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02579759
Other Study ID Numbers  ICMJE CLN-PXT3003-02
2015-002378-19 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Pharnext SA
Study Sponsor  ICMJE Pharnext SA
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Shahram Attarian, MD CHU La Timone, Marseille, France
Principal Investigator: Peter Young, MD University Hospital Munster, Germany
Principal Investigator: Teresa Sevilla, MD Hospital Universitari i Politécnic La Fe, Valencia, Spain
Principal Investigator: Marianne De Visser, MD Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Principal Investigator: Philip Van Damme, MD UZ Leuven, Belgium
Principal Investigator: Mark Roberts, MD Salford Royal NHS Foundation Trust, Manchester, UK
Principal Investigator: Florian Thomas, MD Saint-Louis University, Saint-Louis, USA
Principal Investigator: Jack Puymirat, MD University Hospital of Quebec
PRS Account Pharnext SA
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP