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

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	PXT3003 Dose 1	PXT3003 Dose 2	Placebo
Arm/Group Description	Liquid oral solution, 5 ml b.i.d. (...	Liquid oral solution, 5 ml b.i.d. (...	Liquid oral solution, 5 ml b.i.d. (...
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

Baseline Characteristics

Arm/Group Title		PXT3003 Dose 1	PXT3003 Dose 2	Placebo	Total
Arm/Group Description		Oral solution, 5 ml b.i.d. (taken m...	Oral solution, 5 ml b.i.d. (taken m...	Oral solution, 5 ml b.i.d. (taken m...	Total of all reporting groups
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
Baseline Analysis Population Description		[Not Specified]
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

Outcome Measures

1.Primary Outcome


Title	Overall Neuropathy Limitation Scale (ONLS) Total Score
Description	The primary efficacy variable used in the main analysis is the mean of...
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

Outcome Measure Data

Analysis Population Description

mFAS selection


Arm/Group Title	PXT3003 Dose 1	PXT3003 Dose 2	Placebo
Arm/Group Description:	Liquid oral solution, 5 ml b.i.d. (...	Liquid oral solution, 5 ml b.i.d. (...	Oral solution, 5 ml b.i.d. (taken m...
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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PXT3003 Dose 2, Placebo
	Comments	The main analysis was performed as follows: Analysis population: modified Full Analysis Set (mFAS) 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 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]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	PXT3003 Dose 1, Placebo
	Comments	The main analysis was performed as follows: Analysis population: modified Full Analysis Set (mFAS) 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 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]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	PXT3003 Dose 2, Placebo
	Comments	This analysis was performed as follows: Analysis population: modified Full Analysis Set (mFAS) 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 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]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	PXT3003 Dose 1, Placebo
	Comments	This analysis was performed as follows: Analysis population: modified Full Analysis Set (mFAS) 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 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]

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: Analysis population: modified Full Analysis Set (mFAS) 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 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)
Description	This outcome measure is the mean of the available 10MWT values at mont...
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

Outcome Measure Data

Analysis Population Description

mFAS selection


Arm/Group Title	PXT3003 Dose 1	PXT3003 Dose 2	Placebo
Arm/Group Description:	Liquid oral solution, 5 ml b.i.d. (...	Liquid oral solution, 5 ml b.i.d. (...	Oral solution, 5 ml b.i.d. (taken m...
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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PXT3003 Dose 2, Placebo
	Comments	The main analysis was performed as follows: Analysis population: modified Full Analysis Set (mFAS) 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 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]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	PXT3003 Dose 1, Placebo
	Comments	The main analysis was performed as follows: Analysis population: modified Full Analysis Set (mFAS) 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 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]

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: Analysis population: modified Full Analysis Set (mFAS) 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 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
Description	This outcome measure is the mean of the available CMTNS-v2 Sensory Sco...
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

Outcome Measure Data

Analysis Population Description

mFAS selection


Arm/Group Title	PXT3003 Dose 1	PXT3003 Dose 2	Placebo
Arm/Group Description:	Liquid oral solution, 5 ml b.i.d. (...	Liquid oral solution, 5 ml b.i.d. (...	Oral solution, 5 ml b.i.d. (taken m...
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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PXT3003 Dose 2, Placebo
	Comments	The main analysis was performed as follows: Analysis population: modified Full Analysis Set (mFAS) 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 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]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	PXT3003 Dose 1, Placebo
	Comments	The main analysis was performed as follows: Analysis population: modified Full Analysis Set (mFAS) 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 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]

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: Analysis population: modified Full Analysis Set (mFAS) 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 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)
Description	This outcome measure is the mean of the available CMTNS-v2 Examination...
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

Outcome Measure Data

Analysis Population Description

mFAS selection


Arm/Group Title	PXT3003 Dose 1	PXT3003 Dose 2	Placebo
Arm/Group Description:	Liquid oral solution, 5 ml b.i.d. (...	Liquid oral solution, 5 ml b.i.d. (...	Oral solution, 5 ml b.i.d. (taken m...
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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PXT3003 Dose 2, Placebo
	Comments	The main analysis was performed as follows: Analysis population: modified Full Analysis Set (mFAS) 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 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]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	PXT3003 Dose 1, Placebo
	Comments	The main analysis was performed as follows: Analysis population: modified Full Analysis Set (mFAS) 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 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]

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: Analysis population: modified Full Analysis Set (mFAS) 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 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)
Description	This outcome measure is the mean of the available 9-HPT values at mont...
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

Outcome Measure Data

Analysis Population Description

mFAS selection


Arm/Group Title	PXT3003 Dose 1	PXT3003 Dose 2	Placebo
Arm/Group Description:	Liquid oral solution, 5 ml b.i.d. (...	Liquid oral solution, 5 ml b.i.d. (...	Oral solution, 5 ml b.i.d. (taken m...
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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PXT3003 Dose 2, Placebo
	Comments	The main analysis was performed as follows: Analysis population: modified Full Analysis Set (mFAS) 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 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]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	PXT3003 Dose 1, Placebo
	Comments	The main analysis was performed as follows: Analysis population: modified Full Analysis Set (mFAS) 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 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]

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: Analysis population: modified Full Analysis Set (mFAS) 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 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
Description	Safety selection was to include all randomized patients that have rece...
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)

Outcome Measure Data

Analysis Population Description

FAS selection


Arm/Group Title	PXT3003 Dose 1	PXT3003 Dose 2	Placebo
Arm/Group Description:	Liquid oral solution, 5 ml b.i.d. (...	Liquid oral solution, 5 ml b.i.d. (...	Oral solution, 5 ml b.i.d. (taken m...
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
Description	Safety and tolerability of PXT3003 were compared to placebo on the inc...
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)

Outcome Measure Data

Analysis Population Description

FAS selection


Arm/Group Title	PXT3003 Dose 1	PXT3003 Dose 2	Placebo
Arm/Group Description:	Liquid oral solution, 5 ml b.i.d. (...	Liquid oral solution, 5 ml b.i.d. (...	Oral solution, 5 ml b.i.d. (taken m...
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
Description	Safety and tolerability of PXT3003 were compared to placebo on the inc...
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).

Outcome Measure Data

Analysis Population Description

FAS selection


Arm/Group Title	PXT3003 Dose 1	PXT3003 Dose 2	Placebo
Arm/Group Description:	Liquid oral solution, 5 ml b.i.d. (...	Liquid oral solution, 5 ml b.i.d. (...	Oral solution, 5 ml b.i.d. (taken m...
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
Description	This outcome measure is the mean of the available CMTNS-v2 Sensory Sym...
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

Outcome Measure Data

Analysis Population Description

mFAS selection


Arm/Group Title	PXT3003 Dose 1	PXT3003 Dose 2	Placebo
Arm/Group Description:	Liquid oral solution, 5 ml b.i.d. (...	Liquid oral solution, 5 ml b.i.d. (...	Oral solution, 5 ml b.i.d. (taken m...
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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PXT3003 Dose 2, Placebo
	Comments	The main analysis was performed as follows: Analysis population: modified Full Analysis Set (mFAS) 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 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]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	PXT3003 Dose 1, Placebo
	Comments	The main analysis was performed as follows: Analysis population: modified Full Analysis Set (mFAS) 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 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
Description	Plasma concentration of PXT3003 components were measured at trough (pr...
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

Outcome Measure Data

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
Arm/Group Description:	Liquid oral solution, 5 ml b.i.d. (...	Liquid oral solution, 5 ml b.i.d. (...
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
Description	Plasma concentration of PXT3003 components were measured at trough (pr...
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

Outcome Measure Data

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
Arm/Group Description:	Liquid oral solution, 5 ml b.i.d. (...	Liquid oral solution, 5 ml b.i.d. (...
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
Description	Plasma concentration of PXT3003 components were measured at trough (pr...
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

Outcome Measure Data

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
Arm/Group Description:	Liquid oral solution, 5 ml b.i.d. (...	Liquid oral solution, 5 ml b.i.d. (...
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
Description	ONLS Therapy Response 1 was defined as the number of participants (res...
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

Outcome Measure Data

Analysis Population Description

Completers selection


Arm/Group Title	PXT3003 Dose 1	PXT3003 Dose 2	Placebo
Arm/Group Description:	Liquid oral solution, 5 ml b.i.d. (...	Liquid oral solution, 5 ml b.i.d. (...	Oral solution, 5 ml b.i.d. (taken m...
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

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]

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
Description	ONLS Therapy Response 2 was defined as the number of participants with...
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

Outcome Measure Data

Analysis Population Description

Completers selection


Arm/Group Title	PXT3003 Dose 1	PXT3003 Dose 2	Placebo
Arm/Group Description:	Liquid oral solution, 5 ml b.i.d. (...	Liquid oral solution, 5 ml b.i.d. (...	Oral solution, 5 ml b.i.d. (taken m...
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

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]

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]

Adverse Events

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
Arm/Group Description	Oral solution, 5 ml b.i.d. (taken m...		Oral solution, 5 ml b.i.d. (taken m...		Oral solution, 5 ml b.i.d. (taken m...
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%)
Serious Adverse Events 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
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

Limitations and Caveats

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

More Information

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:

Attarian S, Vallat JM, Magy L, Funalot B, Gonnaud PM, Lacour A, Péréon Y, Dubourg O, Pouget J, Micallef J, Franques J, Lefebvre MN, Ghorab K, Al-Moussawi M, Tiffreau V, Preudhomme M, Magot A, Leclair-Visonneau L, Stojkovic T, Bossi L, Lehert P, Gilbert W, Bertrand V, Mandel J, Milet A, Hajj R, Boudiaf L, Scart-Grès C, Nabirotchkin S, Guedj M, Chumakov I, Cohen D. An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A. Orphanet J Rare Dis. 2014 Dec 18;9:199. doi: 10.1186/s13023-014-0199-0. Erratum in: Orphanet J Rare Dis. 2016;11(1):92.

Chumakov I, Milet A, Cholet N, Primas G, Boucard A, Pereira Y, Graudens E, Mandel J, Laffaire J, Foucquier J, Glibert F, Bertrand V, Nave KA, Sereda MW, Vial E, Guedj M, Hajj R, Nabirotchkin S, Cohen D. Polytherapy with a combination of three repurposed drugs (PXT3003) down-regulates Pmp22 over-expression and improves myelination, axonal and functional parameters in models of CMT1A neuropathy. Orphanet J Rare Dis. 2014 Dec 10;9:201. doi: 10.1186/s13023-014-0201-x.

Mandel J, Bertrand V, Lehert P, Attarian S, Magy L, Micallef J, Chumakov I, Scart-Grès C, Guedj M, Cohen D. A meta-analysis of randomized double-blind clinical trials in CMT1A to assess the change from baseline in CMTNS and ONLS scales after one year of treatment. Orphanet J Rare Dis. 2015 Jun 13;10:74. doi: 10.1186/s13023-015-0293-y.

Prukop T, Stenzel J, Wernick S, Kungl T, Mroczek M, Adam J, Ewers D, Nabirotchkin S, Nave KA, Hajj R, Cohen D, Sereda MW. Early short-term PXT3003 combinational therapy delays disease onset in a transgenic rat model of Charcot-Marie-Tooth disease 1A (CMT1A). PLoS One. 2019 Jan 16;14(1):e0209752. doi: 10.1371/journal.pone.0209752. eCollection 2019.

Hajj R, Prukop T, Wernick S, Ewers D, Brureau A, Cholet N, Laffaire J, Nave KA, Cohen D, Sereda M. Baclofen, Naltrexone and Sorbitol all contribute to the efficacy of PXT3003 in CMT1A Rats. EMJ Neurol, 2019;7[1]:47-49

Attarian S, Vallat JM, Magy L, Funalot B, Gonnaud PM, Lacour A, Péréon Y, Dubourg O, Pouget J, Micallef J, Franques J, Lefebvre MN, Ghorab K, Al-Moussawi M, Tiffreau V, Preudhomme M, Magot A, Leclair-Visonneau L, Stojkovic T, Bossi L, Lehert P, Gilbert W, Bertrand V, Mandel J, Milet A, Hajj R, Boudiaf L, Scart-Grès C, Nabirotchkin S, Guedj M, Chumakov I, Cohen D. Erratum to: An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A. Orphanet J Rare Dis. 2016 Jul 7;11(1):92.

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

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