Charcot-Marie-Tooth Disease Type 1A
Conditions
Keywords
PXT3003
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).
Interventions
DRUGPXT3003 dose 1
Liquid oral solution, 5 ml twice a day, morning and evening with food
DRUGPXT3003 dose 2
Liquid oral solution, 5 ml twice a day, morning and evening with food
DRUGplacebo
Liquid oral solution, 5 ml twice a day, morning and evening with food
Sponsors
Pharnext S.C.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
16 Years to 65 Years
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
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Neuropathy Limitation Scale (ONLS) Total Score | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean of the CMTNS-v2 Sensory Score | 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 Ten Meter Walking Test (10MWT) | 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 Examination Score (CMTES-v2) | 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) | 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 | 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 | 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 | 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). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Plasma Concentrations of Naltrexone at Trough and at 90 Min After Drug Intake | 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 | 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 | 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 | 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. |
| Plasma Concentrations of Baclofen at Trough and at 90 Min After Drug Intake | 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. |
| Mean of the CMTNS-v2 Sensory Symptoms | 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). |
Countries
Belgium, Canada, France, Germany, Netherlands, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PXT3003 Dose 1 Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months
PXT3003 dose 1: Liquid oral solution, 5 ml twice a day, morning and evening with food | 109 |
| PXT3003 Dose 2 Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months
PXT3003 dose 2: Liquid oral solution, 5 ml twice a day, morning and evening with food | 113 |
| Placebo Oral solution, 5 ml b.i.d. (taken morning and evening with food) during 15 months
placebo: Liquid oral solution, 5 ml twice a day, morning and evening with food | 101 |
| Total | 323 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 3 | 1 |
| Overall Study | BfArM hold | 13 | 12 | 12 |
| Overall Study | Inclusion/exclusion criteria | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 2 | 2 |
| Overall Study | Non compliance | 0 | 1 | 0 |
| Overall Study | Other (Sponsor stopped Dose 2) | 0 | 1 | 0 |
| Overall Study | Pregnancy | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 2 | 0 | 0 |
| Overall Study | Sponsor stopped Dose 2 | 0 | 41 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 3 | 5 |
Baseline characteristics
| Characteristic | PXT3003 Dose 1 | PXT3003 Dose 2 | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 5 Participants | 8 Participants | 2 Participants | 15 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 103 Participants | 104 Participants | 97 Participants | 304 Participants |
| Age, Continuous | 41.0 years STANDARD_DEVIATION 12.3 | 39.6 years STANDARD_DEVIATION 13.9 | 42.1 years STANDARD_DEVIATION 13.2 | 40.9 years STANDARD_DEVIATION 13.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 108 Participants | 111 Participants | 100 Participants | 319 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Belgium | 4 participants | 6 participants | 5 participants | 15 participants |
| Region of Enrollment Canada | 5 participants | 4 participants | 5 participants | 14 participants |
| Region of Enrollment France | 31 participants | 31 participants | 29 participants | 91 participants |
| Region of Enrollment Germany | 22 participants | 23 participants | 22 participants | 67 participants |
| Region of Enrollment Netherlands | 2 participants | 3 participants | 3 participants | 8 participants |
| Region of Enrollment Spain | 22 participants | 22 participants | 18 participants | 62 participants |
| Region of Enrollment United Kingdom | 2 participants | 0 participants | 1 participants | 3 participants |
| Region of Enrollment United States | 21 participants | 24 participants | 18 participants | 63 participants |
| Sex: Female, Male Female | 60 Participants | 68 Participants | 62 Participants | 190 Participants |
| Sex: Female, Male Male | 49 Participants | 45 Participants | 39 Participants | 133 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 109 | 0 / 113 | 0 / 101 |
| other Total, other adverse events | 89 / 109 | 87 / 113 | 83 / 101 |
| serious Total, serious adverse events | 10 / 109 | 3 / 113 | 5 / 101 |
Outcome results
Primary
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
Population: mFAS selection
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PXT3003 Dose 1 | Overall Neuropathy Limitation Scale (ONLS) Total Score | Base | 3.33 Scores on the ONLS | Standard Deviation 1.05 |
| PXT3003 Dose 1 | Overall Neuropathy Limitation Scale (ONLS) Total Score | Fin | 3.25 Scores on the ONLS | Standard Deviation 1 |
| PXT3003 Dose 2 | Overall Neuropathy Limitation Scale (ONLS) Total Score | Base | 3.05 Scores on the ONLS | Standard Deviation 1.13 |
| PXT3003 Dose 2 | Overall Neuropathy Limitation Scale (ONLS) Total Score | Fin | 2.82 Scores on the ONLS | Standard Deviation 1.28 |
| Placebo | Overall Neuropathy Limitation Scale (ONLS) Total Score | Base | 3.23 Scores on the ONLS | Standard Deviation 1.19 |
| Placebo | Overall Neuropathy Limitation Scale (ONLS) Total Score | Fin | 3.36 Scores on the ONLS | Standard Deviation 1.16 |
Comparison: The main analysis was performed as follows:~1. Analysis population: modified Full Analysis Set (mFAS)~2. Statistical model: ANCOVA where the mean at 12 and 15 months of each treatment group was compared against the placebo group, adjusting for the baseline value and assuming centre as a random effect~3. Missing value imputation: multiple imputation taking into account the reason of missingnessp-value: 0.00897.5% CI: [-0.68, -0.06]ANCOVA
Comparison: The main analysis was performed as follows:~1. Analysis population: modified Full Analysis Set (mFAS)~2. Statistical model: ANCOVA where the mean at 12 and 15 months of each treatment group was compared against the placebo group, adjusting for the baseline value and assuming centre as a random effect~3. Missing value imputation: multiple imputation taking into account the reason of missingnessp-value: 0.28797.5% CI: [-0.39, 0.14]ANCOVA
Comparison: This analysis was performed as follows:~1. Analysis population: modified Full Analysis Set (mFAS)~2. Statistical model: Longitudinal model where the effect of each treatment over time (baseline, 6, 12 and 15 months) was estimated through a mixed model with repeated measures (MMRM) assuming time from baseline (Time) and Time-by-Treatment full interaction as fixed effects and patient as random effect and considering Time as continuous linear effect~3. Missing value imputation: No imputationp-value: 0.01397.5% CI: [-0.59, -0.03]Longitudinal mixed model
Comparison: This analysis was performed as follows:~1. Analysis population: modified Full Analysis Set (mFAS)~2. Statistical model: Longitudinal model where the effect of each treatment over time (baseline, 6, 12 and 15 months) was estimated through a mixed model with repeated measures (MMRM) assuming time from baseline (Time) and Time-by-Treatment full interaction as fixed effects and patient as random effect and considering Time as continuous linear effect~3. Missing value imputation: No imputationp-value: 0.0597.5% CI: [-0.42, 0.03]Longitudinal mixed model
Comparison: Dose effect:~Dose is defined as a numerical variable proportional to quantity of PXT3003 administered (0 for Placebo, 1 for Dose 1, 2 for Dose 2).~The analysis was performed as follows:~1. Analysis population: modified Full Analysis Set (mFAS)~2. Statistical model: ANCOVA assessing the dose-effect at the mean of 12 and 15 months, adjusting for baseline value and assuming centre as random effect~3. Missing value imputation: multiple imputation taking into account the reason of missingnessp-value: 0.01395% CI: [-0.31, -0.04]Regression, Linear
Secondary
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)
Population: FAS selection
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PXT3003 Dose 1 | Incidence of AE Leading to Withdrawal of Study Drug | Any TEAE leading to drug withdrawal | 6 participants |
| PXT3003 Dose 1 | Incidence of AE Leading to Withdrawal of Study Drug | Any related TEAE leading to drug withdrawal | 3 participants |
| PXT3003 Dose 2 | Incidence of AE Leading to Withdrawal of Study Drug | Any TEAE leading to drug withdrawal | 6 participants |
| PXT3003 Dose 2 | Incidence of AE Leading to Withdrawal of Study Drug | Any related TEAE leading to drug withdrawal | 2 participants |
| Placebo | Incidence of AE Leading to Withdrawal of Study Drug | Any TEAE leading to drug withdrawal | 6 participants |
| Placebo | Incidence of AE Leading to Withdrawal of Study Drug | Any related TEAE leading to drug withdrawal | 2 participants |
Secondary
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).
Population: FAS selection
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PXT3003 Dose 1 | Incidence of SAEs | Any serious TEAE leading to drug withdrawal | 1 participants |
| PXT3003 Dose 1 | Incidence of SAEs | Any serious TEAE | 10 participants |
| PXT3003 Dose 1 | Incidence of SAEs | Any related serious TEAE | 0 participants |
| PXT3003 Dose 2 | Incidence of SAEs | Any related serious TEAE | 0 participants |
| PXT3003 Dose 2 | Incidence of SAEs | Any serious TEAE leading to drug withdrawal | 0 participants |
| PXT3003 Dose 2 | Incidence of SAEs | Any serious TEAE | 3 participants |
| Placebo | Incidence of SAEs | Any serious TEAE | 5 participants |
| Placebo | Incidence of SAEs | Any serious TEAE leading to drug withdrawal | 0 participants |
| Placebo | Incidence of SAEs | Any related serious TEAE | 0 participants |
Secondary
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
Population: mFAS selection
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PXT3003 Dose 1 | Mean of Ten Meter Walking Test (10MWT) | Base | 6.93 Seconds (s) | Standard Deviation 1.77 |
| PXT3003 Dose 1 | Mean of Ten Meter Walking Test (10MWT) | Fin | 6.47 Seconds (s) | Standard Deviation 1.59 |
| PXT3003 Dose 2 | Mean of Ten Meter Walking Test (10MWT) | Base | 7.14 Seconds (s) | Standard Deviation 1.77 |
| PXT3003 Dose 2 | Mean of Ten Meter Walking Test (10MWT) | Fin | 6.52 Seconds (s) | Standard Deviation 1.39 |
| Placebo | Mean of Ten Meter Walking Test (10MWT) | Base | 7.28 Seconds (s) | Standard Deviation 1.91 |
| Placebo | Mean of Ten Meter Walking Test (10MWT) | Fin | 6.91 Seconds (s) | Standard Deviation 1.82 |
Comparison: The main analysis was performed as follows:~1. Analysis population: modified Full Analysis Set (mFAS)~2. Statistical model: ANCOVA where the mean at 12 and 15 months of each treatment group was compared against the placebo group, adjusting for the baseline value and assuming centre as a random effect~3. Missing value imputation: multiple imputation taking into account the reason of missingnessp-value: 0.01697.5% CI: [-0.91, -0.03]ANCOVA
Comparison: The main analysis was performed as follows:~1. Analysis population: modified Full Analysis Set (mFAS)~2. Statistical model: ANCOVA where the mean at 12 and 15 months of each treatment group was compared against the placebo group, adjusting for the baseline value and assuming centre as a random effect~3. Missing value imputation: multiple imputation taking into account the reason of missingnessp-value: 0.08497.5% CI: [-0.65, 0.08]ANCOVA
Comparison: Dose effect:~Dose is defined as a numerical variable proportional to quantity of PXT3003 administered (0 for Placebo, 1 for Dose 1, 2 for Dose 2).~The analysis was performed as follows:~1. Analysis population: modified Full Analysis Set (mFAS)~2. Statistical model: ANCOVA assessing the dose-effect at the mean of 12 and 15 months, adjusting for baseline value and assuming centre as random effect~3. Missing value imputation: multiple imputation taking into account the reason of missingnessp-value: 0.01595% CI: [-0.41, -0.04]Regression, Linear
Secondary
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
Population: mFAS selection
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PXT3003 Dose 1 | Mean of the CMTNS-v2 Examination Score (CMTES-v2) | Base | 9.49 Scores on the CMTES-v2 | Standard Deviation 2.8 |
| PXT3003 Dose 1 | Mean of the CMTNS-v2 Examination Score (CMTES-v2) | Fin | 9.01 Scores on the CMTES-v2 | Standard Deviation 2.62 |
| PXT3003 Dose 2 | Mean of the CMTNS-v2 Examination Score (CMTES-v2) | Base | 8.78 Scores on the CMTES-v2 | Standard Deviation 2.73 |
| PXT3003 Dose 2 | Mean of the CMTNS-v2 Examination Score (CMTES-v2) | Fin | 8.24 Scores on the CMTES-v2 | Standard Deviation 3.13 |
| Placebo | Mean of the CMTNS-v2 Examination Score (CMTES-v2) | Base | 9.51 Scores on the CMTES-v2 | Standard Deviation 2.79 |
| Placebo | Mean of the CMTNS-v2 Examination Score (CMTES-v2) | Fin | 9.02 Scores on the CMTES-v2 | Standard Deviation 3.05 |
Comparison: The main analysis was performed as follows:~1. Analysis population: modified Full Analysis Set (mFAS)~2. Statistical model: ANCOVA where the mean at 12 and 15 months of each treatment group was compared against the placebo group, adjusting for the baseline value and assuming centre as a random effect~3. Missing value imputation: multiple imputation taking into account the reason of missingnessp-value: 0.23297.5% CI: [-1.25, 0.38]ANCOVA
Comparison: The main analysis was performed as follows:~1. Analysis population: modified Full Analysis Set (mFAS)~2. Statistical model: ANCOVA where the mean at 12 and 15 months of each treatment group was compared against the placebo group, adjusting for the baseline value and assuming centre as a random effect~3. Missing value imputation: multiple imputation taking into account the reason of missingnessp-value: 0.86897.5% CI: [-0.74, 0.64]ANCOVA
Comparison: Dose is defined as a numerical variable proportional to quantity of PXT3003 administered (0 for Placebo, 1 for Dose 1, 2 for Dose 2).~The analysis was performed as follows:~1. Analysis population: modified Full Analysis Set (mFAS)~2. Statistical model: ANCOVA assessing the dose-effect at the mean of 12 and 15 months, adjusting for baseline value and assuming centre as random effect~3. Missing value imputation: multiple imputation taking into account the reason of missingnessp-value: 0.32295% CI: [-0.53, 0.17]Regression, Linear
Secondary
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
Population: mFAS selection
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PXT3003 Dose 1 | Mean of the CMTNS-v2 Sensory Score | Base | 5.00 Scores on the CMTNS-v2 Sensory Score | Standard Deviation 2.28 |
| PXT3003 Dose 1 | Mean of the CMTNS-v2 Sensory Score | Fin | 4.55 Scores on the CMTNS-v2 Sensory Score | Standard Deviation 1.96 |
| PXT3003 Dose 2 | Mean of the CMTNS-v2 Sensory Score | Base | 4.47 Scores on the CMTNS-v2 Sensory Score | Standard Deviation 2.21 |
| PXT3003 Dose 2 | Mean of the CMTNS-v2 Sensory Score | Fin | 4.23 Scores on the CMTNS-v2 Sensory Score | Standard Deviation 2.38 |
| Placebo | Mean of the CMTNS-v2 Sensory Score | Base | 4.97 Scores on the CMTNS-v2 Sensory Score | Standard Deviation 2.04 |
| Placebo | Mean of the CMTNS-v2 Sensory Score | Fin | 4.68 Scores on the CMTNS-v2 Sensory Score | Standard Deviation 2.14 |
Comparison: The main analysis was performed as follows:~1. Analysis population: modified Full Analysis Set (mFAS)~2. Statistical model: ANCOVA where the mean at 12 and 15 months of each treatment group was compared against the placebo group, adjusting for the baseline value and assuming centre as a random effect~3. Missing value imputation: multiple imputation taking into account the reason of missingnessp-value: 0.16297.5% CI: [-1.01, 0.23]ANCOVA
Comparison: The main analysis was performed as follows:~1. Analysis population: modified Full Analysis Set (mFAS)~2. Statistical model: ANCOVA where the mean at 12 and 15 months of each treatment group was compared against the placebo group, adjusting for the baseline value and assuming centre as a random effect~3. Missing value imputation: multiple imputation taking into account the reason of missingnessp-value: 0.55697.5% CI: [-0.66, 0.39]ANCOVA
Comparison: Dose is defined as a numerical variable proportional to quantity of PXT3003 administered (0 for Placebo, 1 for Dose 1, 2 for Dose 2).~The analysis was performed as follows:~1. Analysis population: modified Full Analysis Set (mFAS)~2. Statistical model: ANCOVA assessing the dose-effect at the mean of 12 and 15 months, adjusting for baseline value and assuming centre as random effect~3. Missing value imputation: multiple imputation taking into account the reason of missingnessp-value: 0.20495% CI: [-0.43, 0.09]Regression, Linear
Secondary
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
Population: mFAS selection
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PXT3003 Dose 1 | Mean of the Results at the Nine-Hole Peg Test (9-HPT) | Base | 25.62 Seconds (s) | Standard Deviation 5.6 |
| PXT3003 Dose 1 | Mean of the Results at the Nine-Hole Peg Test (9-HPT) | Fin | 23.85 Seconds (s) | Standard Deviation 4.52 |
| PXT3003 Dose 2 | Mean of the Results at the Nine-Hole Peg Test (9-HPT) | Base | 27.33 Seconds (s) | Standard Deviation 11.15 |
| PXT3003 Dose 2 | Mean of the Results at the Nine-Hole Peg Test (9-HPT) | Fin | 25.67 Seconds (s) | Standard Deviation 8.29 |
| Placebo | Mean of the Results at the Nine-Hole Peg Test (9-HPT) | Base | 25.18 Seconds (s) | Standard Deviation 4.41 |
| Placebo | Mean of the Results at the Nine-Hole Peg Test (9-HPT) | Fin | 24.41 Seconds (s) | Standard Deviation 4.01 |
Comparison: The main analysis was performed as follows:~1. Analysis population: modified Full Analysis Set (mFAS)~2. Statistical model: ANCOVA where the mean at 12 and 15 months of each treatment group was compared against the placebo group, adjusting for the baseline value and assuming centre as a random effect~3. Missing value imputation: multiple imputation taking into account the reason of missingnessp-value: 0.37797.5% CI: [-1.43, 0.62]ANCOVA
Comparison: The main analysis was performed as follows:~1. Analysis population: modified Full Analysis Set (mFAS)~2. Statistical model: ANCOVA where the mean at 12 and 15 months of each treatment group was compared against the placebo group, adjusting for the baseline value and assuming centre as a random effect~3. Missing value imputation: multiple imputation taking into account the reason of missingnessp-value: 0.33497.5% CI: [-1.21, 0.48]ANCOVA
Comparison: Dose is defined as a numerical variable proportional to quantity of PXT3003 administered (0 for Placebo, 1 for Dose 1, 2 for Dose 2).~The analysis was performed as follows:~1. Analysis population: modified Full Analysis Set (mFAS)~2. Statistical model: ANCOVA assessing the dose-effect at the mean of 12 and 15 months, adjusting for baseline value and assuming centre as random effect~3. Missing value imputation: multiple imputation taking into account the reason of missingnessp-value: 0.37395% CI: [-0.62, 0.23]Regression, Linear
Secondary
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)
Population: FAS selection
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PXT3003 Dose 1 | Number of Subjects With at Least One TEAE | Any related TEAE | 39 participants |
| PXT3003 Dose 1 | Number of Subjects With at Least One TEAE | Any TEAE | 89 participants |
| PXT3003 Dose 1 | Number of Subjects With at Least One TEAE | Any moderately severe or severe related TEAE | 8 participants |
| PXT3003 Dose 2 | Number of Subjects With at Least One TEAE | Any related TEAE | 38 participants |
| PXT3003 Dose 2 | Number of Subjects With at Least One TEAE | Any TEAE | 87 participants |
| PXT3003 Dose 2 | Number of Subjects With at Least One TEAE | Any moderately severe or severe related TEAE | 5 participants |
| Placebo | Number of Subjects With at Least One TEAE | Any TEAE | 83 participants |
| Placebo | Number of Subjects With at Least One TEAE | Any moderately severe or severe related TEAE | 10 participants |
| Placebo | Number of Subjects With at Least One TEAE | Any related TEAE | 34 participants |
Other Pre-specified
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
Population: mFAS selection
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PXT3003 Dose 1 | Mean of the CMTNS-v2 Sensory Symptoms | Base | 1.26 Scores on the CMTNS-v2 Sensory Symptoms | Standard Deviation 0.95 |
| PXT3003 Dose 1 | Mean of the CMTNS-v2 Sensory Symptoms | Fin | 1.18 Scores on the CMTNS-v2 Sensory Symptoms | Standard Deviation 0.81 |
| PXT3003 Dose 2 | Mean of the CMTNS-v2 Sensory Symptoms | Base | 0.96 Scores on the CMTNS-v2 Sensory Symptoms | Standard Deviation 0.98 |
| PXT3003 Dose 2 | Mean of the CMTNS-v2 Sensory Symptoms | Fin | 0.93 Scores on the CMTNS-v2 Sensory Symptoms | Standard Deviation 0.96 |
| Placebo | Mean of the CMTNS-v2 Sensory Symptoms | Base | 1.09 Scores on the CMTNS-v2 Sensory Symptoms | Standard Deviation 0.9 |
| Placebo | Mean of the CMTNS-v2 Sensory Symptoms | Fin | 1.21 Scores on the CMTNS-v2 Sensory Symptoms | Standard Deviation 0.94 |
Comparison: The main analysis was performed as follows:~1. Analysis population: modified Full Analysis Set (mFAS)~2. Statistical model: ANCOVA where the mean at 12 and 15 months of each treatment group was compared against the placebo group, adjusting for the baseline value and assuming centre as a random effect~3. Missing value imputation: multiple imputation taking into account the reason of missingnessp-value: 0.02397.5% CI: [-0.58, 0]ANCOVA
Comparison: The main analysis was performed as follows:~1. Analysis population: modified Full Analysis Set (mFAS)~2. Statistical model: ANCOVA where the mean at 12 and 15 months of each treatment group was compared against the placebo group, adjusting for the baseline value and assuming centre as a random effect~3. Missing value imputation: multiple imputation taking into account the reason of missingnessp-value: 0.16297.5% CI: [-0.4, 0.09]ANCOVA
Other Pre-specified
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
Population: Completers selection
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PXT3003 Dose 1 | Number of Participants With ONLS Therapy Response 1 | 16 Number of Participants |
| PXT3003 Dose 2 | Number of Participants With ONLS Therapy Response 1 | 14 Number of Participants |
| Placebo | Number of Participants With ONLS Therapy Response 1 | 14 Number of Participants |
Comparison: The proportion of responders (on Completers selection only) at the end of treatment was assessed through a Generalized Linear Mixed Model (GLMM) featuring logistic regression including treatment as a fixed effect, adjusting for the baseline value and center as a random effect.p-value: 0.09797.5% CI: [0.77, 5.68]General Linear Mixed Model
Comparison: The proportion of responders (on Completers selection only) at the end of treatment was assessed through a Generalized Linear Mixed Model (GLMM) featuring logistic regression including treatment as a fixed effect, adjusting for the baseline value and center as a random effect.p-value: 0.86597.5% CI: [0.42, 2.7]General Linear Mixed Model
Other Pre-specified
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
Population: Completers selection
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PXT3003 Dose 1 | Number of Participants With ONLS Therapy Response 2 | 66 Number of Participants |
| PXT3003 Dose 2 | Number of Participants With ONLS Therapy Response 2 | 42 Number of Participants |
| Placebo | Number of Participants With ONLS Therapy Response 2 | 58 Number of Participants |
Comparison: The proportion of responders (on Completers selection only) at the end of treatment was assessed through a Generalized Linear Mixed Model (GLMM) featuring logistic regression including treatment as a fixed effect, adjusting for the baseline value and center as a random effect.p-value: 0.02697.5% CI: [0.99, 11.62]General Linear Mixed Model
Comparison: The proportion of responders (on Completers selection only) at the end of treatment was assessed through a Generalized Linear Mixed Model (GLMM) featuring logistic regression including treatment as a fixed effect, adjusting for the baseline value and center as a random effect.p-value: 0.56997.5% CI: [0.5, 3.16]General Linear Mixed Model
Other Pre-specified
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
Population: PP selection LLOQ = 50 pg/mL The placebo arm has not been described for this endpoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PXT3003 Dose 1 | Plasma Concentrations of 6β-naltrexol at Trough and at 90 Min After Drug Intake | At trough, at Month 12 | 290.1 pg/mL | Standard Deviation 177.4 |
| PXT3003 Dose 1 | Plasma Concentrations of 6β-naltrexol at Trough and at 90 Min After Drug Intake | At trough, at Month 15 | 260.4 pg/mL | Standard Deviation 121.8 |
| PXT3003 Dose 1 | Plasma Concentrations of 6β-naltrexol at Trough and at 90 Min After Drug Intake | At 90 min after drug intake, at Month 12 | 632.5 pg/mL | Standard Deviation 230.1 |
| PXT3003 Dose 1 | Plasma Concentrations of 6β-naltrexol at Trough and at 90 Min After Drug Intake | At 90 min after drug intake, at Month 15 | 586.4 pg/mL | Standard Deviation 205.4 |
| PXT3003 Dose 2 | Plasma Concentrations of 6β-naltrexol at Trough and at 90 Min After Drug Intake | At 90 min after drug intake, at Month 15 | 1450.9 pg/mL | Standard Deviation 438 |
| PXT3003 Dose 2 | Plasma Concentrations of 6β-naltrexol at Trough and at 90 Min After Drug Intake | At trough, at Month 12 | 526.4 pg/mL | Standard Deviation 245.6 |
| PXT3003 Dose 2 | Plasma Concentrations of 6β-naltrexol at Trough and at 90 Min After Drug Intake | At 90 min after drug intake, at Month 12 | 1257.1 pg/mL | Standard Deviation 454.3 |
| PXT3003 Dose 2 | Plasma Concentrations of 6β-naltrexol at Trough and at 90 Min After Drug Intake | At trough, at Month 15 | 352.3 pg/mL | Standard Deviation 319 |
Other Pre-specified
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
Population: PP selection LLOQ = 30 pg/mL The placebo arm has not been described for this endpoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PXT3003 Dose 1 | Plasma Concentrations of Baclofen at Trough and at 90 Min After Drug Intake | At trough, at Month 12 | 13739.3 pg/mL | Standard Deviation 20313.6 |
| PXT3003 Dose 1 | Plasma Concentrations of Baclofen at Trough and at 90 Min After Drug Intake | At trough, at Month 15 | 9009.7 pg/mL | Standard Deviation 10910.3 |
| PXT3003 Dose 1 | Plasma Concentrations of Baclofen at Trough and at 90 Min After Drug Intake | At 90 min after drug intake, at Month 12 | 52201.6 pg/mL | Standard Deviation 21494.6 |
| PXT3003 Dose 1 | Plasma Concentrations of Baclofen at Trough and at 90 Min After Drug Intake | At 90 min after drug intake, at Month 15 | 47021.1 pg/mL | Standard Deviation 19834.5 |
| PXT3003 Dose 2 | Plasma Concentrations of Baclofen at Trough and at 90 Min After Drug Intake | At 90 min after drug intake, at Month 15 | 105825.4 pg/mL | Standard Deviation 38756.7 |
| PXT3003 Dose 2 | Plasma Concentrations of Baclofen at Trough and at 90 Min After Drug Intake | At trough, at Month 12 | 11651.9 pg/mL | Standard Deviation 6151.1 |
| PXT3003 Dose 2 | Plasma Concentrations of Baclofen at Trough and at 90 Min After Drug Intake | At 90 min after drug intake, at Month 12 | 90238.7 pg/mL | Standard Deviation 29972.8 |
| PXT3003 Dose 2 | Plasma Concentrations of Baclofen at Trough and at 90 Min After Drug Intake | At trough, at Month 15 | 8686.6 pg/mL | Standard Deviation 9172.8 |
Other Pre-specified
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
Population: PP selection LLOQ = 30 pg/mL The placebo arm has not been described for this endpoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PXT3003 Dose 1 | Plasma Concentrations of Naltrexone at Trough and at 90 Min After Drug Intake | At trough, at Month 12 | 33.0 pg/mL | Standard Deviation 15.8 |
| PXT3003 Dose 1 | Plasma Concentrations of Naltrexone at Trough and at 90 Min After Drug Intake | At trough, at Month 15 | 31.8 pg/mL | Standard Deviation 14 |
| PXT3003 Dose 1 | Plasma Concentrations of Naltrexone at Trough and at 90 Min After Drug Intake | At 90 min after drug intake, at Month 12 | 63.0 pg/mL | Standard Deviation 47.4 |
| PXT3003 Dose 1 | Plasma Concentrations of Naltrexone at Trough and at 90 Min After Drug Intake | At 90 min after drug intake, at Month 15 | 55.0 pg/mL | Standard Deviation 39.3 |
| PXT3003 Dose 2 | Plasma Concentrations of Naltrexone at Trough and at 90 Min After Drug Intake | At 90 min after drug intake, at Month 15 | 130.9 pg/mL | Standard Deviation 81.4 |
| PXT3003 Dose 2 | Plasma Concentrations of Naltrexone at Trough and at 90 Min After Drug Intake | At trough, at Month 12 | 42.0 pg/mL | Standard Deviation 66 |
| PXT3003 Dose 2 | Plasma Concentrations of Naltrexone at Trough and at 90 Min After Drug Intake | At 90 min after drug intake, at Month 12 | 107.5 pg/mL | Standard Deviation 88.6 |
| PXT3003 Dose 2 | Plasma Concentrations of Naltrexone at Trough and at 90 Min After Drug Intake | At trough, at Month 15 | 30.0 pg/mL | Standard Deviation 0 |