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CompletedNCT02579759PLEO-CMTUpdated Feb 27, 2020Results posted

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

A Phase 3 interventional study of PXT3003 dose 1 and PXT3003 dose 2 in Charcot-Marie-Tooth Disease Type 1A, sponsored by Pharnext S.C.A.. Completed at 30 sites in 8 countries. Open to participants aged 16 Years to 65 Years. Per ClinicalTrials.gov, last updated 2020-02-27.

Sponsored by Pharnext S.C.A. · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
323
Allocation
Randomized
Ages
16 Years to 65 Years
Sex
All
01

Study 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.

Read the 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).

02

Conditions studied

  • Charcot-Marie-Tooth Disease Type 1A

Keywords

  • PXT3003
03

Who can participate

Ages eligible
16 Years to 65 Years
Sexes eligible
All
Accepts healthy volunteers
No

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

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.
04

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Triple (Participant, Investigator, Outcomes assessor)
Enrollment
323 participants (actual)

Study arms

  • Active comparator
    PXT3003 dose 1

    Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months

    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

    Drug: PXT3003 dose 2

  • Placebo comparator
    placebo

    Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months

    Drug: placebo

Interventions

  • DrugPXT3003 dose 1

    Liquid oral solution, 5 ml twice a day, morning and evening with food

    Also known as: DOSE 1

  • DrugPXT3003 dose 2

    Liquid oral solution, 5 ml twice a day, morning and evening with food

    Also known as: DOSE 2

  • Drugplacebo

    Liquid oral solution, 5 ml twice a day, morning and evening with food

05

What researchers measure

Primary outcomes

  1. Overall Neuropathy Limitation Scale (ONLS) Total Score

    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).

    Time frame: From Baseline to Month 15

Secondary outcomes

  1. Mean of Ten Meter Walking Test (10MWT)

    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).

    Time frame: From Baseline to Month 15

  2. Mean of the CMTNS-v2 Sensory Score

    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).

    Time frame: From Baseline to Month 15

  3. Mean of the CMTNS-v2 Examination Score (CMTES-v2)

    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).

    Time frame: From Baseline to Month 15

  4. Mean of the Results at the Nine-Hole Peg Test (9-HPT)

    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).

    Time frame: From Baseline to Month 15

  5. Number of Subjects With at Least One TEAE

    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.

    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)

  6. Incidence of AE Leading to Withdrawal of Study Drug

    Safety and tolerability of PXT3003 were compared to placebo on the incidence of TEAEs 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)

  7. Incidence of SAEs

    Safety and tolerability of PXT3003 were compared to placebo on the incidence of serious adverse events (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).

Other outcomes

  1. Mean of the CMTNS-v2 Sensory Symptoms

    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).

    Time frame: From Baseline to Month 15

  2. Plasma Concentrations of Baclofen at Trough and at 90 Min After Drug Intake

    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.

    Time frame: At Month 12 and Month 15

  3. Plasma Concentrations of Naltrexone at Trough and at 90 Min After Drug Intake

    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.

    Time frame: At Month 12 and month 15

  4. Plasma Concentrations of 6β-naltrexol at Trough and at 90 Min After Drug Intake

    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.

    Time frame: At Month 12 and Month 15

  5. Number of Participants With ONLS Therapy Response 1

    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.

    Time frame: From Baseline to Month 15

  6. Number of Participants With ONLS Therapy Response 2

    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.

    Time frame: From Baseline to Month 15

06

Results

Posted Feb 27, 2020
Limitations and caveats
Two events occured during the trial due to crytals in Dose 2 formulation: hold of all subjects enrolled in Germany (Jun-17) and discontinuation of Dose 2 arm by the sponsor worldwide due to discovery of crystals in the ICH stability batch in Sep-17.

Participant flow

Participant flow — Overall Study
MilestonePXT3003 Dose 1PXT3003 Dose 2Placebo
Started109113101
Completed854980
Not completed246421
Withdrew: Protocol violation200
Withdrew: Other (sponsor stopped dose 2)010
Withdrew: Bfarm hold131212
Withdrew: Sponsor stopped dose 20410
Withdrew: Non compliance010
Withdrew: Pregnancy010
Withdrew: Inclusion/exclusion criteria001
Withdrew: Adverse event431
Withdrew: Withdrawal by subject335
Withdrew: Lost to follow-up222

Outcome measures

PrimaryOverall Neuropathy Limitation Scale (ONLS) Total Score

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).

Time frame:
From Baseline to Month 15
Reported as:
Mean · Scores on the ONLS
Overall Neuropathy Limitation Scale (ONLS) Total Score
Scores on the ONLSPXT3003 Dose 1PXT3003 Dose 2Placebo
Base3.33 ± 1.053.05 ± 1.133.23 ± 1.19
Fin3.25 ± 1.002.82 ± 1.283.36 ± 1.16
Statistical analysis
  • PXT3003 Dose 2 vs Placebo · ANCOVA · p = 0.008 · Mean difference (final values): -0.37 · 97.5% CI -0.68 to -0.06
  • PXT3003 Dose 1 vs Placebo · ANCOVA · p = 0.287 · Mean difference (final values): -0.13 · 97.5% CI -0.39 to 0.14
  • PXT3003 Dose 2 vs Placebo · Longitudinal mixed model · p = 0.013 · Mean difference (final values): -0.31 · 97.5% CI -0.59 to -0.03
  • PXT3003 Dose 1 vs Placebo · Longitudinal mixed model · p = 0.05 · Mean difference (final values): -0.19 · 97.5% CI -0.42 to 0.03
  • PXT3003 Dose 1 vs PXT3003 Dose 2 vs Placebo · Regression, Linear · p = 0.013 · Slope: -0.17 · 95% CI -0.31 to -0.04
SecondaryMean of Ten Meter Walking Test (10MWT)

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).

Time frame:
From Baseline to Month 15
Reported as:
Mean · Seconds (s)
Mean of Ten Meter Walking Test (10MWT)
Seconds (s)PXT3003 Dose 1PXT3003 Dose 2Placebo
Base6.93 ± 1.777.14 ± 1.777.28 ± 1.91
Fin6.47 ± 1.596.52 ± 1.396.91 ± 1.82
Statistical analysis
  • PXT3003 Dose 2 vs Placebo · ANCOVA · p = 0.016 · Mean difference (final values): -0.47 · 97.5% CI -0.91 to -0.03
  • PXT3003 Dose 1 vs Placebo · ANCOVA · p = 0.084 · Mean difference (final values): -0.28 · 97.5% CI -0.65 to 0.08
  • PXT3003 Dose 1 vs PXT3003 Dose 2 vs Placebo · Regression, Linear · p = 0.015 · Slope: -0.22 · 95% CI -0.41 to -0.04
SecondaryMean of the CMTNS-v2 Sensory Score

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).

Time frame:
From Baseline to Month 15
Reported as:
Mean · Scores on the CMTNS-v2 Sensory Score
Mean of the CMTNS-v2 Sensory Score
Scores on the CMTNS-v2 Sensory ScorePXT3003 Dose 1PXT3003 Dose 2Placebo
Base5.00 ± 2.284.47 ± 2.214.97 ± 2.04
Fin4.55 ± 1.964.23 ± 2.384.68 ± 2.14
Statistical analysis
  • PXT3003 Dose 2 vs Placebo · ANCOVA · p = 0.162 · Mean difference (final values): -0.39 · 97.5% CI -1.01 to 0.23
  • PXT3003 Dose 1 vs Placebo · ANCOVA · p = 0.556 · Mean difference (final values): -0.14 · 97.5% CI -0.66 to 0.39
  • PXT3003 Dose 1 vs PXT3003 Dose 2 vs Placebo · Regression, Linear · p = 0.204 · Slope: -0.17 · 95% CI -0.43 to 0.09
SecondaryMean of the CMTNS-v2 Examination Score (CMTES-v2)

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).

Time frame:
From Baseline to Month 15
Reported as:
Mean · Scores on the CMTES-v2
Mean of the CMTNS-v2 Examination Score (CMTES-v2)
Scores on the CMTES-v2PXT3003 Dose 1PXT3003 Dose 2Placebo
Base9.49 ± 2.808.78 ± 2.739.51 ± 2.79
Fin9.01 ± 2.628.24 ± 3.139.02 ± 3.05
Statistical analysis
  • PXT3003 Dose 2 vs Placebo · ANCOVA · p = 0.232 · Mean difference (final values): -0.43 · 97.5% CI -1.25 to 0.38
  • PXT3003 Dose 1 vs Placebo · ANCOVA · p = 0.868 · Mean difference (final values): -0.05 · 97.5% CI -0.74 to 0.64
  • PXT3003 Dose 1 vs PXT3003 Dose 2 vs Placebo · Regression, Linear · p = 0.322 · Slope: -0.18 · 95% CI -0.53 to 0.17
SecondaryMean of the Results at the Nine-Hole Peg Test (9-HPT)

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).

Time frame:
From Baseline to Month 15
Reported as:
Mean · Seconds (s)
Mean of the Results at the Nine-Hole Peg Test (9-HPT)
Seconds (s)PXT3003 Dose 1PXT3003 Dose 2Placebo
Base25.62 ± 5.6027.33 ± 11.1525.18 ± 4.41
Fin23.85 ± 4.5225.67 ± 8.2924.41 ± 4.01
Statistical analysis
  • PXT3003 Dose 2 vs Placebo · ANCOVA · p = 0.377 · Mean difference (final values): -0.4 · 97.5% CI -1.43 to 0.62
  • PXT3003 Dose 1 vs Placebo · ANCOVA · p = 0.334 · Mean difference (final values): -0.36 · 97.5% CI -1.21 to 0.48
  • PXT3003 Dose 1 vs PXT3003 Dose 2 vs Placebo · Regression, Linear · p = 0.373 · Slope: -0.19 · 95% CI -0.62 to 0.23
SecondaryNumber of Subjects With at Least One TEAE

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.

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)
Reported as:
Number · participants
Number of Subjects With at Least One TEAE
participantsPXT3003 Dose 1PXT3003 Dose 2Placebo
Any TEAE898783
Any related TEAE393834
Any moderately severe or severe related TEAE8510
SecondaryIncidence of AE Leading to Withdrawal of Study Drug

Safety and tolerability of PXT3003 were compared to placebo on the incidence of TEAEs 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)
Reported as:
Number · participants
Incidence of AE Leading to Withdrawal of Study Drug
participantsPXT3003 Dose 1PXT3003 Dose 2Placebo
Any TEAE leading to drug withdrawal666
Any related TEAE leading to drug withdrawal322
SecondaryIncidence of SAEs

Safety and tolerability of PXT3003 were compared to placebo on the incidence of serious adverse events (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).
Reported as:
Number · participants
Incidence of SAEs
participantsPXT3003 Dose 1PXT3003 Dose 2Placebo
Any serious TEAE1035
Any related serious TEAE000
Any serious TEAE leading to drug withdrawal100
Other pre-specifiedMean of the CMTNS-v2 Sensory Symptoms

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).

Time frame:
From Baseline to Month 15
Reported as:
Mean · Scores on the CMTNS-v2 Sensory Symptoms
Mean of the CMTNS-v2 Sensory Symptoms
Scores on the CMTNS-v2 Sensory SymptomsPXT3003 Dose 1PXT3003 Dose 2Placebo
Base1.26 ± 0.950.96 ± 0.981.09 ± 0.90
Fin1.18 ± 0.810.93 ± 0.961.21 ± 0.94
Statistical analysis
  • PXT3003 Dose 2 vs Placebo · ANCOVA · p = 0.023 · Mean difference (final values): -0.29 · 97.5% CI -0.58 to 0
  • PXT3003 Dose 1 vs Placebo · ANCOVA · p = 0.162 · Mean difference (final values): -0.15 · 97.5% CI -0.4 to 0.09
Other pre-specifiedPlasma Concentrations of Baclofen at Trough and at 90 Min After Drug Intake

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.

Time frame:
At Month 12 and Month 15
Reported as:
Mean · pg/mL
Plasma Concentrations of Baclofen at Trough and at 90 Min After Drug Intake
pg/mLPXT3003 Dose 1PXT3003 Dose 2
At trough, at Month 1213739.3 ± 20313.611651.9 ± 6151.1
At trough, at Month 159009.7 ± 10910.38686.6 ± 9172.8
At 90 min after drug intake, at Month 1252201.6 ± 21494.690238.7 ± 29972.8
At 90 min after drug intake, at Month 1547021.1 ± 19834.5105825.4 ± 38756.7
Other pre-specifiedPlasma Concentrations of Naltrexone at Trough and at 90 Min After Drug Intake

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.

Time frame:
At Month 12 and month 15
Reported as:
Mean · pg/mL
Plasma Concentrations of Naltrexone at Trough and at 90 Min After Drug Intake
pg/mLPXT3003 Dose 1PXT3003 Dose 2
At trough, at Month 1233.0 ± 15.842.0 ± 66.0
At trough, at Month 1531.8 ± 14.030.0 ± 0.0
At 90 min after drug intake, at Month 1263.0 ± 47.4107.5 ± 88.6
At 90 min after drug intake, at Month 1555.0 ± 39.3130.9 ± 81.4
Other pre-specifiedPlasma Concentrations of 6β-naltrexol at Trough and at 90 Min After Drug Intake

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.

Time frame:
At Month 12 and Month 15
Reported as:
Mean · pg/mL
Plasma Concentrations of 6β-naltrexol at Trough and at 90 Min After Drug Intake
pg/mLPXT3003 Dose 1PXT3003 Dose 2
At trough, at Month 12290.1 ± 177.4526.4 ± 245.6
At trough, at Month 15260.4 ± 121.8352.3 ± 319.0
At 90 min after drug intake, at Month 12632.5 ± 230.11257.1 ± 454.3
At 90 min after drug intake, at Month 15586.4 ± 205.41450.9 ± 438.0
Other pre-specifiedNumber of Participants With ONLS Therapy Response 1

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.

Time frame:
From Baseline to Month 15
Reported as:
Number · Number of Participants
Number of Participants With ONLS Therapy Response 1
Number of ParticipantsPXT3003 Dose 1PXT3003 Dose 2Placebo
Number of Participants With ONLS Therapy Response 1161414
Statistical analysis
  • PXT3003 Dose 2 vs Placebo · General Linear Mixed Model · p = 0.097 · Odds ratio (or): 2.09 · 97.5% CI 0.77 to 5.68
  • PXT3003 Dose 1 vs Placebo · General Linear Mixed Model · p = 0.865 · Odds ratio (or): 1.07 · 97.5% CI 0.42 to 2.7
Other pre-specifiedNumber of Participants With ONLS Therapy Response 2

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.

Time frame:
From Baseline to Month 15
Reported as:
Number · Number of Participants
Number of Participants With ONLS Therapy Response 2
Number of ParticipantsPXT3003 Dose 1PXT3003 Dose 2Placebo
Number of Participants With ONLS Therapy Response 2664258
Statistical analysis
  • PXT3003 Dose 2 vs Placebo · General Linear Mixed Model · p = 0.026 · Odds ratio (or): 3.39 · 97.5% CI 0.99 to 11.62
  • PXT3003 Dose 1 vs Placebo · General Linear Mixed Model · p = 0.569 · Odds ratio (or): 1.26 · 97.5% CI 0.5 to 3.16

Adverse events

Collected over The AE reporting period therefore started with the subject signing the informed consent form and ended 30 days after the end of study (corresponding to the date of "Date of completion/early discontinuation/last contact" recorded in the termination module up to 15 months). Non-serious events are listed at a 2% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
PXT3003 Dose 10/109 (0%)10/109 (9.2%)89/109 (81.7%)
PXT3003 Dose 20/113 (0%)3/113 (2.7%)87/113 (77%)
Placebo0/101 (0%)5/101 (5%)83/101 (82.2%)
Most frequent serious events
Showing 10 of 25
Most frequent serious events
EventPXT3003 Dose 1PXT3003 Dose 2Placebo
ArthrolysisSurgical and medical procedures0/1090/1131/101
Suicide attemptPsychiatric disorders0/1090/1131/101
Clavicle fractureInjury, poisoning and procedural complications0/1090/1131/101
Hand fractureInjury, poisoning and procedural complications0/1090/1131/101
Rib fractureInjury, poisoning and procedural complications0/1090/1131/101
Congenital foot malformationCongenital, familial and genetic disorders0/1090/1131/101
Sleep apnoea syndromeRespiratory, thoracic and mediastinal disorders1/1090/1131/101
Chest wall haematomaMusculoskeletal and connective tissue disorders0/1090/1131/101
Basal cell carcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)1/1090/1130/101
Thyroid adenomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)1/1090/1130/101
Most frequent other events
Showing 10 of 64
Most frequent other events
EventPXT3003 Dose 1PXT3003 Dose 2Placebo
NasopharyngitisInfections and infestations24/10918/11315/101
HeadacheNervous system disorders17/10913/11311/101
ArthralgiaMusculoskeletal and connective tissue disorders13/1093/1138/101
NauseaGastrointestinal disorders12/1097/1136/101
FatigueGeneral disorders11/1092/1136/101
Back painMusculoskeletal and connective tissue disorders10/1095/1133/101
Pain in extremityMusculoskeletal and connective tissue disorders10/1095/1139/101
Ligament sprainInjury, poisoning and procedural complications8/1092/1139/101
FallInjury, poisoning and procedural complications9/1093/1137/101
DizzinessNervous system disorders9/1095/1132/101

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)PXT3003 Dose 1PXT3003 Dose 2PlaceboTotal
<=18 years58215
Between 18 and 65 years10310497304
>=65 years1124
Age, Continuous
Age, Continuous(years)PXT3003 Dose 1PXT3003 Dose 2PlaceboTotal
Mean41.0 ± 12.339.6 ± 13.942.1 ± 13.240.9 ± 13.2
Sex: Female, Male
Sex: Female, Male(Participants)PXT3003 Dose 1PXT3003 Dose 2PlaceboTotal
Female606862190
Male494539133
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)PXT3003 Dose 1PXT3003 Dose 2PlaceboTotal
Hispanic or Latino0213
Not Hispanic or Latino108111100319
Unknown or Not Reported1001
Region of Enrollment
Region of Enrollment(participants)PXT3003 Dose 1PXT3003 Dose 2PlaceboTotal
Canada54514
Netherlands2338
Belgium46515
United States21241863
United Kingdom2013
France31312991
Germany22232267
Spain22221862
07

Study locations

30 sites
  • Department of Neurology, Cedars-Sinai Medical Center
    Los Angeles, California 90048, United States
  • Hospital for Special Care, New Britain
    New Britain, Connecticut 06053, United States
  • Department of Neurology, McKnight Brain Institute
    Gainesville, Florida 32610, United States
  • University of Kansas Medical Center
    Kansas City, Kansas 66160, United States
  • Brigham and Women's Hospital
    Boston, Massachusetts 02115, United States
  • University of Michigan Health System
    Ann Arbor, Michigan 48109-5322, United States
  • Department of Neurology, University of Minnesota
    Minneapolis, Minnesota 55455, United States
  • Department of Neurology and Psichiatry, Saint Louis University
    Saint Louis, Missouri 63104-1027, United States
  • Peripheral Neuropathy Center, Neurological Institue Building, Columbia University Medical Center
    New York, New York 10032, United States
  • Ohio State University
    Columbus, Ohio 43210, United States
  • Saint Luke's Rehabilitation Institute
    Spokane, Washington 99202-1330, United States
  • Departement of Neurology, UZ Leuven
    Leuven, Belgium
  • University Hospital of Quebec
    Quebec, G1J 1Z4, Canada
  • Centre de Référence des Maladies Neuromusculaires, Hôpital Swynghedauwl, CHU de Lille
    Lille, France
  • Centre de Référence des Neuropathies Périphériques Rares, Hôpital Dupuytren, CHU Limoges
    Limoges, France
  • Service de Neurologie et du Sommeil, CHU Lyon Sud
    Lyon, France
  • Centre de Référence des Maladies Neuromusculaires, Pôle des Neurosciences Clinique, CHU la Timone
    Marseille, France
  • Centre de Référence des Maladies Neuromusculaires; Hôtel Dieu, CHU de Nantes
    Nantes, France
  • Service de Neurologie, Hôpital Kremlin Bicêtre
    Paris, France
  • Department of Neurology and Institute for Neuropathology, University Hospital RWTH Aachen
    Aachen, Germany
  • Department of Clinical Neurophysiology, University Medical Center Göttingen
    Göttingen, Germany
  • Department of Neurology, Ludwig-Maximillian University, Munich
    Munich, Germany
  • Department for Sleep Medicine and Neuromuscular, University Hospital Münster
    Münster, Germany
  • Departement of Neurology, Academic Medical Center
    Amsterdam, Netherlands
  • Department of neurology, Hospital Univesitario de Bellvitge
    Barcelona, Spain
  • Servicio de Neurologia, Hospital Universitario La Paz
    Madrid, Spain
  • Centro de Diagnostico y Tratamiento, Hospital Universitario Virgen del Rocio
    Sevilla, Spain
  • Servicio de Neurologia, Hospital Univesitari i Politécnic La Fe
    Valencia, Spain
  • Department of Neurology, Salford Royal NHS Foundation Trust
    Salford, Manchester M6 8HD, United Kingdom
  • Ninewells Hospital and Medical School
    Dundee, Scotland DD1 9SY, United Kingdom
08

References and documents

Publications

  • Attarian S, Vallat JM, Magy L, Funalot B, Gonnaud PM, Lacour A, Pereon Y, Dubourg O, Pouget J, Micallef J, Franques J, Lefebvre MN, Ghorab K, Al-Moussawi M, Tiffreau V, Preudhomme M, Magot A, Leclair-Visonneau L, Stojkovic T, Bossi L, Lehert P, Gilbert W, Bertrand V, Mandel J, Milet A, Hajj R, Boudiaf L, Scart-Gres C, Nabirotchkin S, Guedj M, Chumakov I, Cohen D. An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A. Orphanet J Rare Dis. 2014 Dec 18;9:199. doi: 10.1186/s13023-014-0199-0. Erratum In: Orphanet J Rare Dis. 2016 Jul 7;11(1):92. doi: 10.1186/s13023-016-0463-6. PubMed 25519680 ↗
  • Chumakov I, Milet A, Cholet N, Primas G, Boucard A, Pereira Y, Graudens E, Mandel J, Laffaire J, Foucquier J, Glibert F, Bertrand V, Nave KA, Sereda MW, Vial E, Guedj M, Hajj R, Nabirotchkin S, Cohen D. Polytherapy with a combination of three repurposed drugs (PXT3003) down-regulates Pmp22 over-expression and improves myelination, axonal and functional parameters in models of CMT1A neuropathy. Orphanet J Rare Dis. 2014 Dec 10;9:201. doi: 10.1186/s13023-014-0201-x. PubMed 25491744 ↗
  • Mandel J, Bertrand V, Lehert P, Attarian S, Magy L, Micallef J, Chumakov I, Scart-Gres C, Guedj M, Cohen D. A meta-analysis of randomized double-blind clinical trials in CMT1A to assess the change from baseline in CMTNS and ONLS scales after one year of treatment. Orphanet J Rare Dis. 2015 Jun 13;10:74. doi: 10.1186/s13023-015-0293-y. PubMed 26070802 ↗
  • Prukop T, Stenzel J, Wernick S, Kungl T, Mroczek M, Adam J, Ewers D, Nabirotchkin S, Nave KA, Hajj R, Cohen D, Sereda MW. Early short-term PXT3003 combinational therapy delays disease onset in a transgenic rat model of Charcot-Marie-Tooth disease 1A (CMT1A). PLoS One. 2019 Jan 16;14(1):e0209752. doi: 10.1371/journal.pone.0209752. eCollection 2019. PubMed 30650121 ↗
  • Hajj R, Prukop T, Wernick S, Ewers D, Brureau A, Cholet N, Laffaire J, Nave KA, Cohen D, Sereda M. Baclofen, Naltrexone and Sorbitol all contribute to the efficacy of PXT3003 in CMT1A Rats. EMJ Neurol, 2019;7[1]:47-49
  • Attarian S, Vallat JM, Magy L, Funalot B, Gonnaud PM, Lacour A, Pereon Y, Dubourg O, Pouget J, Micallef J, Franques J, Lefebvre MN, Ghorab K, Al-Moussawi M, Tiffreau V, Preudhomme M, Magot A, Leclair-Visonneau L, Stojkovic T, Bossi L, Lehert P, Gilbert W, Bertrand V, Mandel J, Milet A, Hajj R, Boudiaf L, Scart-Gres C, Nabirotchkin S, Guedj M, Chumakov I, Cohen D. Erratum to: An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A. Orphanet J Rare Dis. 2016 Jul 7;11(1):92. doi: 10.1186/s13023-016-0463-6. No abstract available. PubMed 27387831 ↗

Study documents

  • Protocol and statistical analysis plan · Dec 5, 2017

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

09

Registry details

Key details

Study ID
NCT02579759
Lead sponsor
Pharnext S.C.A.
Responsible party
Sponsor
First posted
Oct 20, 2015
Start date
Dec 2015
Primary completion
Mar 2018
Completion
Aug 2018
Results posted
Feb 27, 2020
Last update
Feb 27, 2020

Study contacts

Shahram Attarian, MD
principal investigator · CHU La Timone, Marseille, France
Peter Young, MD
principal investigator · University Hospital Munster, Germany
Teresa Sevilla, MD
principal investigator · Hospital Universitari i Politécnic La Fe, Valencia, Spain
Marianne De Visser, MD
principal investigator · Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Philip Van Damme, MD
principal investigator · UZ Leuven, Belgium
Mark Roberts, MD
principal investigator · Salford Royal NHS Foundation Trust, Manchester, UK
Florian Thomas, MD
principal investigator · Saint-Louis University, Saint-Louis, USA
Jack Puymirat, MD
principal investigator · University Hospital of Quebec

Oversight

Data monitoring committee
Yes
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