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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

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Charcot-Marie-Tooth Disease Type 1A
Interventions Drug: PXT3003 dose 1
Drug: PXT3003 dose 2
Drug: placebo
Enrollment 323
Recruitment Details  
Pre-assignment Details  
Arm/Group Title PXT3003 Dose 1 PXT3003 Dose 2 Placebo
Hide Arm/Group Description

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

PXT3003 dose 1: 3 mg baclofen, 0.35 mg naltrexone and 105 mg sorbitol (twice a day, morning and evening with food).

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

PXT3003 dose 2: 6 mg baclofen, 0.70 mg naltrexone and 210 sorbitol (twice a day, morning and evening with food).

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

PXT3003 matching placebo had the same presentation, the same aspect and taste in order to be undistinguishable (twice a day, morning and evening with food).

Period Title: Overall Study
Started 109 113 101
Completed [1] 85 49 80
Not Completed 24 64 21
Reason Not Completed
Protocol Violation             2             0             0
Other (Sponsor stopped Dose 2)             0             1             0
BfArM hold             13             12             12
Sponsor stopped Dose 2             0             41             0
Non compliance             0             1             0
Pregnancy             0             1             0
Inclusion/exclusion criteria             0             0             1
Adverse Event             4             3             1
Withdrawal by Subject             3             3             5
Lost to Follow-up             2             2             2
[1]
Completed at 12 months
Arm/Group Title PXT3003 Dose 1 PXT3003 Dose 2 Placebo Total
Hide Arm/Group Description

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

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

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

Total of all reporting groups
Overall Number of Baseline Participants 109 113 101 323
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 109 participants 113 participants 101 participants 323 participants
<=18 years
5
   4.6%
8
   7.1%
2
   2.0%
15
   4.6%
Between 18 and 65 years
103
  94.5%
104
  92.0%
97
  96.0%
304
  94.1%
>=65 years
1
   0.9%
1
   0.9%
2
   2.0%
4
   1.2%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 109 participants 113 participants 101 participants 323 participants
41.0  (12.3) 39.6  (13.9) 42.1  (13.2) 40.9  (13.2)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 109 participants 113 participants 101 participants 323 participants
Female
60
  55.0%
68
  60.2%
62
  61.4%
190
  58.8%
Male
49
  45.0%
45
  39.8%
39
  38.6%
133
  41.2%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 109 participants 113 participants 101 participants 323 participants
Hispanic or Latino
0
   0.0%
2
   1.8%
1
   1.0%
3
   0.9%
Not Hispanic or Latino
108
  99.1%
111
  98.2%
100
  99.0%
319
  98.8%
Unknown or Not Reported
1
   0.9%
0
   0.0%
0
   0.0%
1
   0.3%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 109 participants 113 participants 101 participants 323 participants
Canada 5 4 5 14
Netherlands 2 3 3 8
Belgium 4 6 5 15
United States 21 24 18 63
United Kingdom 2 0 1 3
France 31 31 29 91
Germany 22 23 22 67
Spain 22 22 18 62
1.Primary Outcome
Title Overall Neuropathy Limitation Scale (ONLS) Total Score
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
mFAS selection
Arm/Group Title PXT3003 Dose 1 PXT3003 Dose 2 Placebo
Hide Arm/Group Description:

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

PXT3003 dose 1: 3 mg baclofen, 0.35 mg naltrexone and 105 mg sorbitol (twice a day, morning and evening with food).

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

PXT3003 dose 2: 6 mg baclofen, 0.70 mg naltrexone and 210 sorbitol (twice a day, morning and evening with food).

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

PXT3003 matching placebo had the same presentation, the same aspect and taste in order to be undistinguishable (twice a day, morning and evening with food).

Overall Number of Participants Analyzed 93 55 87
Mean (Standard Deviation)
Unit of Measure: Scores on the ONLS
Base 3.33  (1.05) 3.05  (1.13) 3.23  (1.19)
Fin 3.25  (1.00) 2.82  (1.28) 3.36  (1.16)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection PXT3003 Dose 2, Placebo
Comments

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 missingness
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.008
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.37
Confidence Interval (2-Sided) 97.5%
-0.68 to -0.06
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.14
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection PXT3003 Dose 1, Placebo
Comments

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 missingness
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.287
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.13
Confidence Interval (2-Sided) 97.5%
-0.39 to 0.14
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.12
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection PXT3003 Dose 2, Placebo
Comments

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 imputation
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.013
Comments [Not Specified]
Method Longitudinal mixed model
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.31
Confidence Interval (2-Sided) 97.5%
-0.59 to -0.03
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.13
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection PXT3003 Dose 1, Placebo
Comments

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 imputation
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.05
Comments [Not Specified]
Method Longitudinal mixed model
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.19
Confidence Interval (2-Sided) 97.5%
-0.42 to 0.03
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.1
Estimation Comments [Not Specified]
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection PXT3003 Dose 1, PXT3003 Dose 2, Placebo
Comments

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 missingness
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.013
Comments [Not Specified]
Method Regression, Linear
Comments [Not Specified]
Method of Estimation Estimation Parameter Slope
Estimated Value -0.17
Confidence Interval (2-Sided) 95%
-0.31 to -0.04
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.07
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Mean of Ten Meter Walking Test (10MWT)
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
mFAS selection
Arm/Group Title PXT3003 Dose 1 PXT3003 Dose 2 Placebo
Hide Arm/Group Description:

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

PXT3003 dose 1: 3 mg baclofen, 0.35 mg naltrexone and 105 mg sorbitol (twice a day, morning and evening with food).

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

PXT3003 dose 2: 6 mg baclofen, 0.70 mg naltrexone and 210 sorbitol (twice a day, morning and evening with food).

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

Overall Number of Participants Analyzed 93 55 87
Mean (Standard Deviation)
Unit of Measure: Seconds (s)
Base 6.93  (1.77) 7.14  (1.77) 7.28  (1.91)
Fin 6.47  (1.59) 6.52  (1.39) 6.91  (1.82)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection PXT3003 Dose 2, Placebo
Comments

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 missingness
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.016
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.47
Confidence Interval (2-Sided) 97.5%
-0.91 to -0.03
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.19
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection PXT3003 Dose 1, Placebo
Comments

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 missingness
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.084
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.28
Confidence Interval (2-Sided) 97.5%
-0.65 to 0.08
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.16
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection PXT3003 Dose 1, PXT3003 Dose 2, Placebo
Comments

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 missingness
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.015
Comments [Not Specified]
Method Regression, Linear
Comments [Not Specified]
Method of Estimation Estimation Parameter Slope
Estimated Value -0.22
Confidence Interval (2-Sided) 95%
-0.41 to -0.04
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.09
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Mean of the CMTNS-v2 Sensory Score
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
mFAS selection
Arm/Group Title PXT3003 Dose 1 PXT3003 Dose 2 Placebo
Hide Arm/Group Description:

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

PXT3003 dose 1: 3 mg baclofen, 0.35 mg naltrexone and 105 mg sorbitol (twice a day, morning and evening with food).

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

PXT3003 dose 2: 6 mg baclofen, 0.70 mg naltrexone and 210 sorbitol (twice a day, morning and evening with food).

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

PXT3003 matching placebo had the same presentation, the same aspect and taste in order to be undistinguishable (twice a day, morning and evening with food).

Overall Number of Participants Analyzed 93 55 87
Mean (Standard Deviation)
Unit of Measure: Scores on the CMTNS-v2 Sensory Score
Base 5.00  (2.28) 4.47  (2.21) 4.97  (2.04)
Fin 4.55  (1.96) 4.23  (2.38) 4.68  (2.14)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection PXT3003 Dose 2, Placebo
Comments

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 missingness
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.162
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.39
Confidence Interval (2-Sided) 97.5%
-1.01 to 0.23
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.28
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection PXT3003 Dose 1, Placebo
Comments

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 missingness
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.556
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.14
Confidence Interval (2-Sided) 97.5%
-0.66 to 0.39
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.23
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection PXT3003 Dose 1, PXT3003 Dose 2, Placebo
Comments

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 missingness
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.204
Comments [Not Specified]
Method Regression, Linear
Comments [Not Specified]
Method of Estimation Estimation Parameter Slope
Estimated Value -0.17
Confidence Interval (2-Sided) 95%
-0.43 to 0.09
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.13
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Mean of the CMTNS-v2 Examination Score (CMTES-v2)
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
mFAS selection
Arm/Group Title PXT3003 Dose 1 PXT3003 Dose 2 Placebo
Hide Arm/Group Description:

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

PXT3003 dose 1: 3 mg baclofen, 0.35 mg naltrexone and 105 mg sorbitol (twice a day, morning and evening with food).

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

PXT3003 dose 2: 6 mg baclofen, 0.70 mg naltrexone and 210 sorbitol (twice a day, morning and evening with food).

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

PXT3003 matching placebo had the same presentation, the same aspect and taste in order to be undistinguishable (twice a day, morning and evening with food).

Overall Number of Participants Analyzed 93 55 87
Mean (Standard Deviation)
Unit of Measure: Scores on the CMTES-v2
Base 9.49  (2.80) 8.78  (2.73) 9.51  (2.79)
Fin 9.01  (2.62) 8.24  (3.13) 9.02  (3.05)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection PXT3003 Dose 2, Placebo
Comments

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 missingness
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.232
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.43
Confidence Interval (2-Sided) 97.5%
-1.25 to 0.38
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.36
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection PXT3003 Dose 1, Placebo
Comments

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 missingness
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.868
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.05
Confidence Interval (2-Sided) 97.5%
-0.74 to 0.64
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.31
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection PXT3003 Dose 1, PXT3003 Dose 2, Placebo
Comments

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 missingness
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.322
Comments [Not Specified]
Method Regression, Linear
Comments [Not Specified]
Method of Estimation Estimation Parameter Slope
Estimated Value -0.18
Confidence Interval (2-Sided) 95%
-0.53 to 0.17
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.18
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Mean of the Results at the Nine-Hole Peg Test (9-HPT)
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
mFAS selection
Arm/Group Title PXT3003 Dose 1 PXT3003 Dose 2 Placebo
Hide Arm/Group Description:

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

PXT3003 dose 1: 3 mg baclofen, 0.35 mg naltrexone and 105 mg sorbitol (twice a day, morning and evening with food).

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

PXT3003 dose 2: 6 mg baclofen, 0.70 mg naltrexone and 210 sorbitol (twice a day, morning and evening with food).

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

PXT3003 matching placebo had the same presentation, the same aspect and taste in order to be undistinguishable (twice a day, morning and evening with food).

Overall Number of Participants Analyzed 93 55 87
Mean (Standard Deviation)
Unit of Measure: Seconds (s)
Base 25.62  (5.60) 27.33  (11.15) 25.18  (4.41)
Fin 23.85  (4.52) 25.67  (8.29) 24.41  (4.01)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection PXT3003 Dose 2, Placebo
Comments

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 missingness
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.377
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.4
Confidence Interval (2-Sided) 97.5%
-1.43 to 0.62
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.46
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection PXT3003 Dose 1, Placebo
Comments

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 missingness
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.334
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.36
Confidence Interval (2-Sided) 97.5%
-1.21 to 0.48
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.38
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection PXT3003 Dose 1, PXT3003 Dose 2, Placebo
Comments

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 missingness
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.373
Comments [Not Specified]
Method Regression, Linear
Comments [Not Specified]
Method of Estimation Estimation Parameter Slope
Estimated Value -0.19
Confidence Interval (2-Sided) 95%
-0.62 to 0.23
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.22
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Number of Subjects With at Least One TEAE
Hide Description

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)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS selection
Arm/Group Title PXT3003 Dose 1 PXT3003 Dose 2 Placebo
Hide Arm/Group Description:

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

PXT3003 dose 1: 3 mg baclofen, 0.35 mg naltrexone and 105 mg sorbitol (twice a day, morning and evening with food).

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

PXT3003 dose 2: 6 mg baclofen, 0.70 mg naltrexone and 210 sorbitol (twice a day, morning and evening with food).

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

PXT3003 matching placebo had the same presentation, the same aspect and taste in order to be undistinguishable (twice a day, morning and evening with food).

Overall Number of Participants Analyzed 109 113 101
Measure Type: Number
Unit of Measure: participants
Any TEAE 89 87 83
Any related TEAE 39 38 34
Any moderately severe or severe related TEAE 8 5 10
7.Secondary Outcome
Title Incidence of AE Leading to Withdrawal of Study Drug
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS selection
Arm/Group Title PXT3003 Dose 1 PXT3003 Dose 2 Placebo
Hide Arm/Group Description:

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

PXT3003 dose 1: 3 mg baclofen, 0.35 mg naltrexone and 105 mg sorbitol (twice a day, morning and evening with food).

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

PXT3003 dose 2: 6 mg baclofen, 0.70 mg naltrexone and 210 sorbitol (twice a day, morning and evening with food).

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

PXT3003 matching placebo had the same presentation, the same aspect and taste in order to be undistinguishable (twice a day, morning and evening with food).

Overall Number of Participants Analyzed 109 113 101
Measure Type: Number
Unit of Measure: participants
Any TEAE leading to drug withdrawal 6 6 6
Any related TEAE leading to drug withdrawal 3 2 2
8.Secondary Outcome
Title Incidence of SAEs
Hide Description 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).
Hide Outcome Measure Data
Hide Analysis Population Description
FAS selection
Arm/Group Title PXT3003 Dose 1 PXT3003 Dose 2 Placebo
Hide Arm/Group Description:

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

PXT3003 dose 1: 3 mg baclofen, 0.35 mg naltrexone and 105 mg sorbitol (twice a day, morning and evening with food).

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

PXT3003 dose 2: 6 mg baclofen, 0.70 mg naltrexone and 210 sorbitol (twice a day, morning and evening with food).

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

PXT3003 matching placebo had the same presentation, the same aspect and taste in order to be undistinguishable (twice a day, morning and evening with food).

Overall Number of Participants Analyzed 109 113 101
Measure Type: Number
Unit of Measure: participants
Any serious TEAE 10 3 5
Any related serious TEAE 0 0 0
Any serious TEAE leading to drug withdrawal 1 0 0
9.Other Pre-specified Outcome
Title Mean of the CMTNS-v2 Sensory Symptoms
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
mFAS selection
Arm/Group Title PXT3003 Dose 1 PXT3003 Dose 2 Placebo
Hide Arm/Group Description:

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

PXT3003 dose 1: 3 mg baclofen, 0.35 mg naltrexone and 105 mg sorbitol (twice a day, morning and evening with food).

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

PXT3003 dose 2: 6 mg baclofen, 0.70 mg naltrexone and 210 sorbitol (twice a day, morning and evening with food).

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

PXT3003 matching placebo had the same presentation, the same aspect and taste in order to be undistinguishable (twice a day, morning and evening with food).

Overall Number of Participants Analyzed 93 55 87
Mean (Standard Deviation)
Unit of Measure: Scores on the CMTNS-v2 Sensory Symptoms
Base 1.26  (0.95) 0.96  (0.98) 1.09  (0.90)
Fin 1.18  (0.81) 0.93  (0.96) 1.21  (0.94)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection PXT3003 Dose 2, Placebo
Comments

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 missingness
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.023
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.29
Confidence Interval (2-Sided) 97.5%
-0.58 to 0
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.13
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection PXT3003 Dose 1, Placebo
Comments

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 missingness
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.162
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.15
Confidence Interval (2-Sided) 97.5%
-0.4 to 0.09
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.11
Estimation Comments [Not Specified]
10.Other Pre-specified Outcome
Title Plasma Concentrations of Baclofen at Trough and at 90 Min After Drug Intake
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
PP selection LLOQ = 30 pg/mL The placebo arm has not been described for this endpoint.
Arm/Group Title PXT3003 Dose 1 PXT3003 Dose 2
Hide Arm/Group Description:

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

PXT3003 dose 1: 3 mg baclofen, 0.35 mg naltrexone and 105 mg sorbitol (twice a day, morning and evening with food).

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

PXT3003 dose 2: 6 mg baclofen, 0.70 mg naltrexone and 210 sorbitol (twice a day, morning and evening with food).

Overall Number of Participants Analyzed 68 38
Mean (Standard Deviation)
Unit of Measure: pg/mL
At trough, at Month 12 13739.3  (20313.6) 11651.9  (6151.1)
At trough, at Month 15 9009.7  (10910.3) 8686.6  (9172.8)
At 90 min after drug intake, at Month 12 52201.6  (21494.6) 90238.7  (29972.8)
At 90 min after drug intake, at Month 15 47021.1  (19834.5) 105825.4  (38756.7)
11.Other Pre-specified Outcome
Title Plasma Concentrations of Naltrexone at Trough and at 90 Min After Drug Intake
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
PP selection LLOQ = 30 pg/mL The placebo arm has not been described for this endpoint.
Arm/Group Title PXT3003 Dose 1 PXT3003 Dose 2
Hide Arm/Group Description:

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

PXT3003 dose 1: 3 mg baclofen, 0.35 mg naltrexone and 105 mg sorbitol (twice a day, morning and evening with food).

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

PXT3003 dose 2: 6 mg baclofen, 0.70 mg naltrexone and 210 sorbitol (twice a day, morning and evening with food).

Overall Number of Participants Analyzed 68 38
Mean (Standard Deviation)
Unit of Measure: pg/mL
At trough, at Month 12 33.0  (15.8) 42.0  (66.0)
At trough, at Month 15 31.8  (14.0) 30.0  (0.0)
At 90 min after drug intake, at Month 12 63.0  (47.4) 107.5  (88.6)
At 90 min after drug intake, at Month 15 55.0  (39.3) 130.9  (81.4)
12.Other Pre-specified Outcome
Title Plasma Concentrations of 6β-naltrexol at Trough and at 90 Min After Drug Intake
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
PP selection LLOQ = 50 pg/mL The placebo arm has not been described for this endpoint.
Arm/Group Title PXT3003 Dose 1 PXT3003 Dose 2
Hide Arm/Group Description:

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

PXT3003 dose 1: 3 mg baclofen, 0.35 mg naltrexone and 105 mg sorbitol (twice a day, morning and evening with food).

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

PXT3003 dose 2: 6 mg baclofen, 0.70 mg naltrexone and 210 sorbitol (twice a day, morning and evening with food).

Overall Number of Participants Analyzed 68 38
Mean (Standard Deviation)
Unit of Measure: pg/mL
At trough, at Month 12 290.1  (177.4) 526.4  (245.6)
At trough, at Month 15 260.4  (121.8) 352.3  (319.0)
At 90 min after drug intake, at Month 12 632.5  (230.1) 1257.1  (454.3)
At 90 min after drug intake, at Month 15 586.4  (205.4) 1450.9  (438.0)
13.Other Pre-specified Outcome
Title Number of Participants With ONLS Therapy Response 1
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Completers selection
Arm/Group Title PXT3003 Dose 1 PXT3003 Dose 2 Placebo
Hide Arm/Group Description:

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

PXT3003 dose 1: 3 mg baclofen, 0.35 mg naltrexone and 105 mg sorbitol (twice a day, morning and evening with food).

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

PXT3003 dose 2: 6 mg baclofen, 0.70 mg naltrexone and 210 sorbitol (twice a day, morning and evening with food).

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

Overall Number of Participants Analyzed 85 49 80
Measure Type: Number
Unit of Measure: Number of Participants
16 14 14
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection PXT3003 Dose 2, Placebo
Comments 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.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.097
Comments [Not Specified]
Method General Linear Mixed Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.09
Confidence Interval (2-Sided) 97.5%
0.77 to 5.68
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection PXT3003 Dose 1, Placebo
Comments 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.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.865
Comments [Not Specified]
Method General Linear Mixed Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.07
Confidence Interval (2-Sided) 97.5%
0.42 to 2.7
Estimation Comments [Not Specified]
14.Other Pre-specified Outcome
Title Number of Participants With ONLS Therapy Response 2
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
Completers selection
Arm/Group Title PXT3003 Dose 1 PXT3003 Dose 2 Placebo
Hide Arm/Group Description:

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

PXT3003 dose 1: 3 mg baclofen, 0.35 mg naltrexone and 105 mg sorbitol (twice a day, morning and evening with food).

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

PXT3003 dose 2: 6 mg baclofen, 0.70 mg naltrexone and 210 sorbitol (twice a day, morning and evening with food).

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

PXT3003 matching placebo had the same presentation, the same aspect and taste in order to be undistinguishable (twice a day, morning and evening with food).

Overall Number of Participants Analyzed 85 89 80
Measure Type: Number
Unit of Measure: Number of Participants
66 42 58
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection PXT3003 Dose 2, Placebo
Comments 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.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.026
Comments [Not Specified]
Method General Linear Mixed Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 3.39
Confidence Interval (2-Sided) 97.5%
0.99 to 11.62
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection PXT3003 Dose 1, Placebo
Comments 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.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.569
Comments [Not Specified]
Method General Linear Mixed Model
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.26
Confidence Interval (2-Sided) 97.5%
0.5 to 3.16
Estimation Comments [Not Specified]
Time Frame 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)
Adverse Event Reporting Description

This definition was extended due to the discontinuation of Dose 2 and study on hold in Germany. The period of AE reporting was extended to 1 month after the end of study, without informed consent signed for study CLN-PXT3003-03 during this period.

Only Treatment-Emergent Adverse Events (TEAE) have been reported for non-serious advers events.

 
Arm/Group Title PXT3003 Dose 1 PXT3003 Dose 2 Placebo
Hide Arm/Group Description

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

PXT3003 dose 1: 3 mg baclofen, 0.35 mg naltrexone and 105 mg sorbitol (twice a day, morning and evening with food).

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

PXT3003 dose 2: 6 mg baclofen, 0.70 mg naltrexone and 210 sorbitol (twice a day, morning and evening with food).

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

PXT3003 matching placebo had the same presentation, the same aspect and taste in order to be undistinguishable (twice a day, morning and evening with food).

All-Cause Mortality
PXT3003 Dose 1 PXT3003 Dose 2 Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/109 (0.00%)      0/113 (0.00%)      0/101 (0.00%)    
Hide Serious Adverse Events
PXT3003 Dose 1 PXT3003 Dose 2 Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   10/109 (9.17%)      3/113 (2.65%)      5/101 (4.95%)    
Cardiac disorders       
Palpitations  1  1/109 (0.92%)  0/113 (0.00%)  0/101 (0.00%) 
Congenital, familial and genetic disorders       
Congenital foot malformation  1  0/109 (0.00%)  0/113 (0.00%)  1/101 (0.99%) 
Patent ductus arteriosus  1  0/109 (0.00%)  1/113 (0.88%)  0/101 (0.00%) 
Gastrointestinal disorders       
Proctitis  1  0/109 (0.00%)  1/113 (0.88%)  0/101 (0.00%) 
Hepatobiliary disorders       
Cholecystitis  1  1/109 (0.92%)  0/113 (0.00%)  0/101 (0.00%) 
Infections and infestations       
Appendicitis  1  1/109 (0.92%)  0/113 (0.00%)  0/101 (0.00%) 
Enteritis infectious  1  0/109 (0.00%)  1/113 (0.88%)  0/101 (0.00%) 
Injury, poisoning and procedural complications       
Clavicle fracture  1  0/109 (0.00%)  0/113 (0.00%)  1/101 (0.99%) 
Femoral neck fracture  1  1/109 (0.92%)  0/113 (0.00%)  0/101 (0.00%) 
Hand fracture  1  0/109 (0.00%)  0/113 (0.00%)  1/101 (0.99%) 
Injury  1  1/109 (0.92%)  0/113 (0.00%)  0/101 (0.00%) 
Median nerve injury  1  1/109 (0.92%)  0/113 (0.00%)  0/101 (0.00%) 
Patella fracture  1  1/109 (0.92%)  0/113 (0.00%)  0/101 (0.00%) 
Rib fracture  1  0/109 (0.00%)  0/113 (0.00%)  1/101 (0.99%) 
Musculoskeletal and connective tissue disorders       
Chest wall haematoma  1  0/109 (0.00%)  0/113 (0.00%)  1/101 (0.99%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Basal cell carcinoma  1  1/109 (0.92%)  0/113 (0.00%)  0/101 (0.00%) 
Thyroid adenoma  1  1/109 (0.92%)  0/113 (0.00%)  0/101 (0.00%) 
Uterine leiomyoma  1  1/109 (0.92%)  0/113 (0.00%)  0/101 (0.00%) 
Nervous system disorders       
Seizure  1  1/109 (0.92%)  0/113 (0.00%)  0/101 (0.00%) 
Psychiatric disorders       
Suicide attempt  1  0/109 (0.00%)  0/113 (0.00%)  1/101 (0.99%) 
Renal and urinary disorders       
Hydronephrosis  1  0/109 (0.00%)  1/113 (0.88%)  0/101 (0.00%) 
Ureterolithiasis  1  0/109 (0.00%)  1/113 (0.88%)  0/101 (0.00%) 
Reproductive system and breast disorders       
Endometriosis  1  1/109 (0.92%)  0/113 (0.00%)  0/101 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Sleep apnoea syndrome  1  1/109 (0.92%)  0/113 (0.00%)  1/101 (0.99%) 
Surgical and medical procedures       
Arthrolysis  1  0/109 (0.00%)  0/113 (0.00%)  1/101 (0.99%) 
1
Term from vocabulary, MedDRA 21.0
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
PXT3003 Dose 1 PXT3003 Dose 2 Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   89/109 (81.65%)      87/113 (76.99%)      83/101 (82.18%)    
Cardiac disorders       
Palpitations  1  0/109 (0.00%)  0 1/113 (0.88%)  1 2/101 (1.98%)  3
Ear and labyrinth disorders       
Tinnitus  1  2/109 (1.83%)  2 1/113 (0.88%)  1 2/101 (1.98%)  2
Vertigo  1  3/109 (2.75%)  4 1/113 (0.88%)  1 2/101 (1.98%)  2
Gastrointestinal disorders       
Abdominal pain  1  2/109 (1.83%)  2 5/113 (4.42%)  5 3/101 (2.97%)  4
Abdominal pain upper  1  3/109 (2.75%)  3 4/113 (3.54%)  5 3/101 (2.97%)  3
Constipation  1  4/109 (3.67%)  4 2/113 (1.77%)  2 2/101 (1.98%)  2
Diarrhoea  1  7/109 (6.42%)  9 7/113 (6.19%)  8 7/101 (6.93%)  8
Dry mouth  1  3/109 (2.75%)  3 3/113 (2.65%)  3 4/101 (3.96%)  4
Dyspepsia  1  1/109 (0.92%)  1 2/113 (1.77%)  2 3/101 (2.97%)  4
Nausea  1  12/109 (11.01%)  17 7/113 (6.19%)  7 6/101 (5.94%)  6
Toothache  1  4/109 (3.67%)  4 0/113 (0.00%)  0 1/101 (0.99%)  1
Vomiting  1  2/109 (1.83%)  2 5/113 (4.42%)  5 1/101 (0.99%)  1
General disorders       
Asthenia  1 [1]  3/109 (2.75%)  3 2/113 (1.77%)  2 7/101 (6.93%)  9
Fatigue  1 [1]  11/109 (10.09%)  15 2/113 (1.77%)  2 6/101 (5.94%)  6
Influenza like illness  1 [1]  3/109 (2.75%)  5 6/113 (5.31%)  9 0/101 (0.00%)  0
Peripheral swelling  1 [1]  1/109 (0.92%)  1 0/113 (0.00%)  0 2/101 (1.98%)  2
Infections and infestations       
Bronchitis  1  2/109 (1.83%)  3 1/113 (0.88%)  1 6/101 (5.94%)  6
Cystitis  1  2/109 (1.83%)  3 0/113 (0.00%)  0 2/101 (1.98%)  2
Gastroenteritis  1  3/109 (2.75%)  4 3/113 (2.65%)  3 5/101 (4.95%)  5
Influenza  1  3/109 (2.75%)  3 6/113 (5.31%)  6 3/101 (2.97%)  3
Nasopharyngitis  1  24/109 (22.02%)  31 18/113 (15.93%)  26 15/101 (14.85%)  24
Pharyngitis  1  2/109 (1.83%)  2 0/113 (0.00%)  0 2/101 (1.98%)  2
Respiratory tract infection  1  1/109 (0.92%)  1 0/113 (0.00%)  0 2/101 (1.98%)  2
Rhinitis  1  3/109 (2.75%)  3 3/113 (2.65%)  4 4/101 (3.96%)  5
Sinusitis  1  7/109 (6.42%)  8 6/113 (5.31%)  6 1/101 (0.99%)  1
Tracheitis  1  0/109 (0.00%)  0 0/113 (0.00%)  0 2/101 (1.98%)  2
Upper respiratory tract infection  1  2/109 (1.83%)  2 1/113 (0.88%)  1 2/101 (1.98%)  2
Urinary tract infection  1  1/109 (0.92%)  1 3/113 (2.65%)  5 2/101 (1.98%)  2
Injury, poisoning and procedural complications       
Contusion  1  1/109 (0.92%)  1 1/113 (0.88%)  1 3/101 (2.97%)  4
Fall  1  9/109 (8.26%)  15 3/113 (2.65%)  3 7/101 (6.93%)  9
Laceration  1  3/109 (2.75%)  3 0/113 (0.00%)  0 0/101 (0.00%)  0
Ligament sprain  1  8/109 (7.34%)  9 2/113 (1.77%)  2 9/101 (8.91%)  12
Limb injury  1  1/109 (0.92%)  1 1/113 (0.88%)  1 2/101 (1.98%)  2
Investigations       
Weight increased  1  1/109 (0.92%)  1 0/113 (0.00%)  0 5/101 (4.95%)  6
Metabolism and nutrition disorders       
Decreased appetite  1  0/109 (0.00%)  0 3/113 (2.65%)  3 1/101 (0.99%)  1
Vitamin D deficiency  1  0/109 (0.00%)  0 1/113 (0.88%)  1 3/101 (2.97%)  3
Musculoskeletal and connective tissue disorders       
Arthralgia  1  13/109 (11.93%)  19 3/113 (2.65%)  3 8/101 (7.92%)  8
Back pain  1  10/109 (9.17%)  12 5/113 (4.42%)  5 3/101 (2.97%)  3
Bone callus excessive  1  0/109 (0.00%)  0 0/113 (0.00%)  0 2/101 (1.98%)  2
Joint swelling  1  1/109 (0.92%)  1 0/113 (0.00%)  0 4/101 (3.96%)  4
Muscle spasms  1  5/109 (4.59%)  7 8/113 (7.08%)  9 6/101 (5.94%)  6
Musculoskeletal pain  1  1/109 (0.92%)  1 4/113 (3.54%)  4 1/101 (0.99%)  1
Myalgia  1  3/109 (2.75%)  3 1/113 (0.88%)  1 2/101 (1.98%)  2
Neck pain  1  3/109 (2.75%)  4 3/113 (2.65%)  3 3/101 (2.97%)  3
Osteoarthritis  1  3/109 (2.75%)  3 2/113 (1.77%)  2 0/101 (0.00%)  0
Pain in extremity  1  10/109 (9.17%)  13 5/113 (4.42%)  6 9/101 (8.91%)  13
Rotator cuff syndrome  1  0/109 (0.00%)  0 0/113 (0.00%)  0 3/101 (2.97%)  4
Tendonitis  1  2/109 (1.83%)  2 3/113 (2.65%)  3 4/101 (3.96%)  4
Nervous system disorders       
Dizziness  1  9/109 (8.26%)  10 5/113 (4.42%)  5 2/101 (1.98%)  3
Headache  1  17/109 (15.60%)  22 13/113 (11.50%)  20 11/101 (10.89%)  14
Hypoaesthesia  1  1/109 (0.92%)  1 3/113 (2.65%)  3 2/101 (1.98%)  2
Migraine  1  1/109 (0.92%)  2 3/113 (2.65%)  3 2/101 (1.98%)  3
Paraesthesia  1  2/109 (1.83%)  2 3/113 (2.65%)  5 0/101 (0.00%)  0
Sciatica  1  1/109 (0.92%)  1 2/113 (1.77%)  2 2/101 (1.98%)  3
Somnolence  1  5/109 (4.59%)  5 2/113 (1.77%)  2 1/101 (0.99%)  1
Tremor  1  0/109 (0.00%)  0 3/113 (2.65%)  3 1/101 (0.99%)  1
Psychiatric disorders       
Anxiety  1  3/109 (2.75%)  3 2/113 (1.77%)  3 2/101 (1.98%)  2
Depression  1  1/109 (0.92%)  1 0/113 (0.00%)  0 5/101 (4.95%)  5
Insomnia  1  1/109 (0.92%)  4 1/113 (0.88%)  1 3/101 (2.97%)  3
Sleep disorder  1  1/109 (0.92%)  1 2/113 (1.77%)  2 2/101 (1.98%)  2
Respiratory, thoracic and mediastinal disorders       
Nasal congestion  1  0/109 (0.00%)  0 0/113 (0.00%)  0 2/101 (1.98%)  2
Oropharyngeal pain  1  3/109 (2.75%)  6 2/113 (1.77%)  2 5/101 (4.95%)  8
Skin and subcutaneous tissue disorders       
Rash  1  1/109 (0.92%)  1 2/113 (1.77%)  2 2/101 (1.98%)  2
Vascular disorders       
Hypotension  1  1/109 (0.92%)  1 1/113 (0.88%)  1 2/101 (1.98%)  2
1
Term from vocabulary, MedDRA 21.0
Indicates events were collected by systematic assessment
[1]
and administation site conditions
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.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Susanne Dorn
Organization: Pharnext
Phone: +33 (0)1 41 09 22 30
EMail: contact@pharnext.com
Publications of Results:
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
Layout table for additonal information
Responsible Party: Pharnext SA
ClinicalTrials.gov Identifier: NCT02579759    
Other Study ID Numbers: CLN-PXT3003-02
2015-002378-19 ( EudraCT Number )
First Submitted: September 28, 2015
First Posted: October 20, 2015
Results First Submitted: November 18, 2019
Results First Posted: February 27, 2020
Last Update Posted: February 27, 2020