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Clinical Trial Results:
International, multi-center, randomized, double-blind, placebo-controlled phase III study assessing in parallel groups the efficacy and safety of 2 doses of PXT3003 in patients with Charcot-Marie-Tooth Disease type 1A treated for 15 months

Summary
EudraCT number	2015-002378-19
Trial protocol	FR DE ES BE GB NL
Global end of trial date	22 Mar 2018

Results information
Results version number	v1(current)
This version publication date	04 Oct 2019
First version publication date	04 Oct 2019
Other versions
Summary report(s)	CLN-PXT3003-02_Synopsis_CSR_190708

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

CLN-PXT3003-02

ISRCTN number

US NCT number

NCT02579759

WHO universal trial number (UTN)

Other trial identifiers

US IND: 122505

Sponsor organisation name

PHARNEXT

Sponsor organisation address

Immeuble Vivaldi, 11-13 rue René Jacques, Issy Les Moulineaux, France, 92130

Public contact

Susanne Dorn, PHARNEXT, +33 (0)1 41 09 22 30, contact@pharnext.com

Scientific contact

Susanne Dorn, PHARNEXT, +33 (0)1 41 09 22 30, contact@pharnext.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-002164-PIP01-17

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

22 Mar 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

22 Mar 2018

Global end of trial reached?

Yes

Global end of trial date

22 Mar 2018

Was the trial ended prematurely?

Main objective of the trial

To assess the efficacy of 2 doses of PXT3003 compared to Placebo on the disability measured by the Overall Neuropathy Limitation Scale (ONLS) score in CMT1A patients treated for 15 months.

Protection of trial subjects

This study was conducted with the principles of the Declaration of Helsinki, the ICH and GCP guidelines, the study protocol, the European directives on clinical trials (Directive 2001/20/EC) and the applicable local country laws and regulations. Patients have been informed through the informed consent process of the possible or potential risks of each procedure. In case of children 16 to 18 year-old age, both parent’s and children’s consents were collected.

Background therapy

PXT3003 was administered on top of standard of care (SOC) consisting of supportive therapies such as pain killers (except neurotoxic drugs or opiates), physiotherapy, occupational therapy, and orthopedic devices that were authorized during the entire study.

Evidence for comparator

As there is no approved specific treatment in CMT1A, there is no active comparator to introduce; placebo was then used as control. PXT3003 or placebo were given on top of standard cares.

Actual start date of recruitment

11 Dec 2015

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy, Ethical reason, Scientific research

Long term follow-up duration

9 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 63

Country: Number of subjects enrolled

Netherlands: 8

Country: Number of subjects enrolled

Spain: 62

Country: Number of subjects enrolled

United Kingdom: 3

Country: Number of subjects enrolled

Belgium: 15

Country: Number of subjects enrolled

France: 91

Country: Number of subjects enrolled

Germany: 67

Country: Number of subjects enrolled

Canada: 14

Worldwide total number of subjects

323

EEA total number of subjects

246

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

314

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Approximately 100 subjects in each arm (Dose 2, Dose 1 and Placebo) were planned. Patients were randomized at a 1:1:1 ratio into the 3 parallel groups. First patients first visit occurred on 11-Dec-15 in FR, 21-Mar-16 in BE, 08-Apr-16 in DE, 01-Jun-16 in US, 28-Jun-16 in ES, 23-Aug-16 in NL, 29-Sep-16 in UK and 10-Nov-16 in CA

Screening details

437 patients were screened for inclusion, between 11 December 2015 and 2 December 2016. Of those, 323 patients (73.9%) were randomized, 113 to the Dose 2 group, 109 to the Dose 1 group, and 101 to the Placebo group.

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Blinding implementation details

The treatment codes remained blinded until the time of the final statistical analysis following database lock. Dose 2 arm was unblinded at the time of the discontinuation on September 18th 2017 by sponsor decision. Study treatments were numbered according to a material randomization list, separate from the subject randomization list.

Are arms mutually exclusive

Yes

PXT3003 Dose 2

Arm description

Patients were randomized to the PXT3003 Dose 2 arm with a 1:1:1 ratio.

Arm type

Experimental

Investigational medicinal product name

PXT3003

Investigational medicinal product code

PXT3003 Dose 2

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

5mL administered twice daily, i.e. 10mL per day PXT3003 Dose 2 corresponded to 6 mg baclofen, 0.70 mg naltrexone and 210 mg sorbitol given twice daily.

PXT3003 Dose 1

Arm description

Patients were randomized to the PXT3003 Dose 1 arm with a 1:1:1 ratio.

Arm type

Experimental

Investigational medicinal product name

PXT3003

Investigational medicinal product code

PXT3003 Dose 1

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

5mL administered twice daily, i.e. 10mL per day PXT3003 Dose 1 corresponded to 3 mg baclofen, 0.35 mg naltrexone and 105 mg sorbitol given twice daily.

Placebo

Arm description

Patients were randomized to the Placebo arm with a 1:1:1 ratio.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Placebo

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

5mL administered twice daily, i.e. 10mL per day

Number of subjects in period 1	PXT3003 Dose 2	PXT3003 Dose 1	Placebo
Started	113	109	101
Completed	49	85	80
Not completed	64	24	21
Inclusion/exclusion criteria	-	-	1
Consent withdrawn by subject	3	3	5
Adverse event, non-fatal	3	4	1
Other	1	-	-
Pregnancy	1	-	-
BfArM hold	12	13	12
Non-compliance	1	-	-
Sponsor stopped Dose 2	41	-	-
Lost to follow-up	2	2	2
Protocol deviation	-	2	-

Baseline characteristics

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Reporting group title

PXT3003 Dose 2

Reporting group description

Patients were randomized to the PXT3003 Dose 2 arm with a 1:1:1 ratio.

Reporting group title

PXT3003 Dose 1

Reporting group description

Patients were randomized to the PXT3003 Dose 1 arm with a 1:1:1 ratio.

Reporting group title

Placebo

Reporting group description

Patients were randomized to the Placebo arm with a 1:1:1 ratio.

Reporting group values	PXT3003 Dose 2	PXT3003 Dose 1	Placebo	Total
Number of subjects	113	109	101	323
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	4	4	1	9
Adults (18-64 years)	109	105	100	314
From 65-84 years	0	0	0	0
85 years and over	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	39.6 ± 13.9	41.0 ± 12.3	42.1 ± 13.2	-
Gender categorical
Units: Subjects
Female	68	60	62	190
Male	45	49	39	133

End points

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Reporting group title

PXT3003 Dose 2

Reporting group description

Patients were randomized to the PXT3003 Dose 2 arm with a 1:1:1 ratio.

Reporting group title

PXT3003 Dose 1

Reporting group description

Patients were randomized to the PXT3003 Dose 1 arm with a 1:1:1 ratio.

Reporting group title

Placebo

Reporting group description

Patients were randomized to the Placebo arm with a 1:1:1 ratio.

Primary: Mean of the ONLS total score at Month 12 and Month 15

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End point title

Mean of the ONLS total score at Month 12 and Month 15

End point description

The primary efficacy variable is the mean of the ONLS score at month 12 and month 15 or the ONLS value at month 12 alone if no month 15 value was available. The ONLS is a disability scale that was derived and improved from the Overall Disability Sum Score 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 goes from 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).

End point type

Primary

End point timeframe

From Baseline to Month 15

End point values	PXT3003 Dose 2	PXT3003 Dose 1	Placebo
Number of subjects analysed	55 ^[1]	93 ^[2]	87 ^[3]
Units: ONLS total score
arithmetic mean (standard deviation)
Base	3.05 ± 1.13	3.33 ± 1.05	3.23 ± 1.19
Fin	2.82 ± 1.28	3.25 ± 1.00	3.36 ± 1.16

Notes
[1] - mFAS selection
[2] - mFAS selection
[3] - mFAS selection

Main analysis for PXT3003 Dose 2

Statistical analysis description

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 reason of missingness

Comparison groups

PXT3003 Dose 2 v Placebo

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.008

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.37

Confidence interval

level

97.5%

sides

2-sided

lower limit

-0.68

upper limit

-0.06

Variability estimate

Standard error of the mean

Dispersion value

0.14

Main analysis for PXT3003 Dose 1

Statistical analysis description

Comparison groups

PXT3003 Dose 1 v Placebo

Number of subjects included in analysis

180

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.287

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.13

Confidence interval

level

97.5%

sides

2-sided

lower limit

-0.39

upper limit

0.14

Variability estimate

Standard error of the mean

Dispersion value

0.12

Longitudinal model (mFAS) - PXT3003 Dose 2

Statistical analysis description

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

Comparison groups

PXT3003 Dose 2 v Placebo

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.013

Method

Longitudinal mixed model

Parameter type

Mean difference (final values)

Point estimate

-0.31

Confidence interval

level

97.5%

sides

2-sided

lower limit

-0.59

upper limit

-0.03

Variability estimate

Standard error of the mean

Dispersion value

0.13

Longitudinal model (mFAS) - PXT3003 Dose 1

Statistical analysis description

Comparison groups

PXT3003 Dose 1 v Placebo

Number of subjects included in analysis

180

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.05

Method

Longitudinal mixed model

Parameter type

Mean difference (net)

Point estimate

-0.19

Confidence interval

level

97.5%

sides

2-sided

lower limit

-0.42

upper limit

0.03

Variability estimate

Standard error of the mean

Dispersion value

0.1

Relationship of Drug Dose to Response (mFAS)

Statistical analysis description

Dose is defined as a numerical variable proportional to quantity of PXT3003 administered (0 for Placebo, 1 for Dose 1 and 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

Comparison groups

PXT3003 Dose 2 v PXT3003 Dose 1 v Placebo

Number of subjects included in analysis

235

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.013

Method

Regression, Linear

Parameter type

Slope

Point estimate

-0.17

Confidence interval

level

95%

sides

2-sided

lower limit

-0.31

upper limit

-0.04

Variability estimate

Standard error of the mean

Dispersion value

0.07

Secondary: Mean change of the Ten Meter Walking Test (10MWT) score

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End point title

Mean change of the Ten Meter Walking Test (10MWT) score

End point description

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)

End point type

Secondary

End point timeframe

From Baseline to Month 15

End point values	PXT3003 Dose 2	PXT3003 Dose 1	Placebo
Number of subjects analysed	55 ^[4]	93 ^[5]	87 ^[6]
Units: Seconds (s)
arithmetic mean (standard deviation)
Base	7.14 ± 1.77	6.93 ± 1.77	7.28 ± 1.91
Fin	6.52 ± 1.39	6.47 ± 1.59	6.91 ± 1.82

Notes
[4] - mFAS selection
[5] - mFAS selection
[6] - mFAS selection

Main analysis for PXT3003 Dose 2

Statistical analysis description

Comparison groups

Placebo v PXT3003 Dose 2

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.016

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.47

Confidence interval

level

97.5%

sides

2-sided

lower limit

-0.91

upper limit

-0.03

Variability estimate

Standard error of the mean

Dispersion value

0.19

Main analysis for PXT3003 Dose 1

Statistical analysis description

Comparison groups

Placebo v PXT3003 Dose 1

Number of subjects included in analysis

180

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.084

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.28

Confidence interval

level

97.5%

sides

2-sided

lower limit

-0.65

upper limit

0.08

Variability estimate

Standard error of the mean

Dispersion value

0.16

Relationship of Drug Dose to Response (mFAS)

Statistical analysis description

Dose is defined as a numerical variable proportional to quantity of PXT3003 administered (0 for Placebo, 1 for Dose 1 and 2 for Dose 2). And 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

Comparison groups

PXT3003 Dose 2 v PXT3003 Dose 1 v Placebo

Number of subjects included in analysis

235

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.015

Method

Regression, Linear

Parameter type

Slope

Point estimate

-0.22

Confidence interval

level

95%

sides

2-sided

lower limit

-0.41

upper limit

-0.04

Variability estimate

Standard error of the mean

Dispersion value

0.09

Secondary: Mean change of the CMTNS-v2 Sensory Score

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End point title

Mean change of the CMTNS-v2 Sensory Score

End point description

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 Sensory Score is calculated as the sum of items 1+4+5 of CMTNS-v2 (Sensory symptoms, Pinprick sensibility and Vibration). 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)

End point type

Secondary

End point timeframe

From Baseline to Month 15

End point values	PXT3003 Dose 2	PXT3003 Dose 1	Placebo
Number of subjects analysed	55 ^[7]	93 ^[8]	87 ^[9]
Units: CMTNS-2 score
arithmetic mean (standard deviation)
Base	4.47 ± 2.21	5.00 ± 2.28	4.97 ± 2.04
Fin	4.23 ± 2.38	4.55 ± 1.96	4.68 ± 2.14

Notes
[7] - mFAS selection
[8] - mFAS selection
[9] - mFAS selection

Main analysis for PXT3003 Dose 2

Statistical analysis description

Comparison groups

PXT3003 Dose 2 v Placebo

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.162

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.39

Confidence interval

level

97.5%

sides

2-sided

lower limit

-1.01

upper limit

0.23

Variability estimate

Standard error of the mean

Dispersion value

0.28

Main analysis for PXT3003 Dose 1

Statistical analysis description

Comparison groups

PXT3003 Dose 1 v Placebo

Number of subjects included in analysis

180

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.556

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.14

Confidence interval

level

97.5%

sides

2-sided

lower limit

-0.66

upper limit

0.39

Variability estimate

Standard error of the mean

Dispersion value

0.23

Relationship of Drug Dose to Response (mFAS)

Statistical analysis description

Comparison groups

PXT3003 Dose 2 v PXT3003 Dose 1 v Placebo

Number of subjects included in analysis

235

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.204

Method

Regression, Linear

Parameter type

Slope

Point estimate

-0.17

Confidence interval

level

95%

sides

2-sided

lower limit

-0.43

upper limit

0.09

Variability estimate

Standard error of the mean

Dispersion value

0.13

Secondary: Mean change of the CMTNS-v2 Examination Score

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End point title

Mean change of the CMTNS-v2 Examination Score

End point description

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 Examination Score is limited to impairment items and excluding electrophysiological items (sum score of item 1 to 7). Lower CMTNS-v2 Examination 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)

End point type

Secondary

End point timeframe

From Baseline to Month 15

End point values	PXT3003 Dose 2	PXT3003 Dose 1	Placebo
Number of subjects analysed	55 ^[10]	93 ^[11]	87 ^[12]
Units: CMTNS score
arithmetic mean (standard deviation)
Base	8.78 ± 2.73	9.49 ± 2.80	9.51 ± 2.79
Fin	8.24 ± 3.13	9.01 ± 2.62	9.02 ± 3.05

Notes
[10] - mFAS selection
[11] - mFAS selection
[12] - mFAS selection

Main analysis for PXT3003 Dose 2

Statistical analysis description

Comparison groups

PXT3003 Dose 2 v Placebo

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.232

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.43

Confidence interval

level

97.5%

sides

2-sided

lower limit

-1.25

upper limit

0.38

Variability estimate

Standard error of the mean

Dispersion value

0.36

Main analysis for PXT3003 Dose 1

Statistical analysis description

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) Imputation of missing values: multiple imputation taking into account reason of missingness

Comparison groups

Placebo v PXT3003 Dose 1

Number of subjects included in analysis

180

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.868

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.05

Confidence interval

level

97.5%

sides

2-sided

lower limit

-0.74

upper limit

0.64

Variability estimate

Standard error of the mean

Dispersion value

0.31

Relationship of Drug Dose to Response (mFAS)

Statistical analysis description

Comparison groups

PXT3003 Dose 1 v Placebo v PXT3003 Dose 2

Number of subjects included in analysis

235

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.322

Method

Regression, Linear

Parameter type

Slope

Point estimate

-0.18

Confidence interval

level

95%

sides

2-sided

lower limit

-0.53

upper limit

0.17

Variability estimate

Standard error of the mean

Dispersion value

0.18

Secondary: Mean change of the results at the Nine-Hole Peg Test

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End point title

Mean change of the results at the Nine-Hole Peg Test

End point description

The Nine-Hole Peg Test (9HPT) is a simple timed test of fine motor coordination of extremities 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 Nine-Hole Peg Test (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)

End point type

Secondary

End point timeframe

From Baseline to Month 15

End point values	PXT3003 Dose 2	PXT3003 Dose 1	Placebo
Number of subjects analysed	55 ^[13]	93 ^[14]	87 ^[15]
Units: seconds (s)
arithmetic mean (standard deviation)
Base	27.33 ± 11.15	25.62 ± 5.60	25.18 ± 4.41
Fin	25.67 ± 8.29	23.85 ± 4.52	24.41 ± 4.01

Notes
[13] - mFAS selection
[14] - mFAS selection
[15] - mFAS selection

Main analysis for PXT3003 Dose 2

Statistical analysis description

Comparison groups

PXT3003 Dose 2 v Placebo

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.377

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.4

Confidence interval

level

97.5%

sides

2-sided

lower limit

-1.43

upper limit

0.62

Variability estimate

Standard error of the mean

Dispersion value

0.46

Main analysis for PXT3003 Dose 1

Statistical analysis description

Comparison groups

Placebo v PXT3003 Dose 1

Number of subjects included in analysis

180

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.334

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.36

Confidence interval

level

97.5%

sides

2-sided

lower limit

-1.21

upper limit

0.48

Variability estimate

Standard error of the mean

Dispersion value

0.38

Relationship of Drug Dose to Response (mFAS)

Statistical analysis description

Comparison groups

PXT3003 Dose 2 v PXT3003 Dose 1 v Placebo

Number of subjects included in analysis

235

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.373

Method

Regression, Linear

Parameter type

Slope

Point estimate

-0.19

Confidence interval

level

95%

sides

2-sided

lower limit

-0.62

upper limit

0.23

Variability estimate

Standard error of the mean

Dispersion value

0.22

Secondary: Incidence of all TEAEs

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End point title

Incidence of all TEAEs

End point 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.

End point type

Secondary

End point timeframe

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)

End point values	PXT3003 Dose 2	PXT3003 Dose 1	Placebo
Number of subjects analysed	113	109	101
Units: number of TEAEs
number (not applicable)
Any TEAE	87	89	83
Any related TEAE	38	39	34
Any moderately severe or severe related TEAE	5	8	10

No statistical analyses for this end point

Secondary: Incidence of AE leading to withdrawal of study drug

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End point title

Incidence of AE leading to withdrawal of study drug

End point description

Safety and tolerability of PXT3003 were compared to placebo on the incidence of TEAEs leading to withdrawal of study drug.

End point type

Secondary

End point timeframe

End point values	PXT3003 Dose 2	PXT3003 Dose 1	Placebo
Number of subjects analysed	113	109	101
Units: number of TEAEs
number (not applicable)
Any TEAE leading to drug withdrawal	6	6	6
Any related TEAE leading to drug withdrawal	2	3	2

No statistical analyses for this end point

Secondary: Incidence of SAEs

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End point title

Incidence of SAEs

End point description

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

End point type

Secondary

End point timeframe

End point values	PXT3003 Dose 2	PXT3003 Dose 1	Placebo
Number of subjects analysed	113	109	101
Units: number of TEAE
number (not applicable)
Any serious TEAE	3	10	5
Any related serious TEAE	0	0	0
Any serious TEAE leading to drug withdrawal	0	1	0

No statistical analyses for this end point

Other pre-specified: Plasma concentrations of baclofen at trough and at peak

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End point title

Plasma concentrations of baclofen at trough and at peak ^[16]

End point 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 base correspond to half of the administered dose.

End point type

Other pre-specified

End point timeframe

At 12 months, and 15 months.

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: For Placebo the values correspond to LLOQ: 30 pg/mL

End point values	PXT3003 Dose 2	PXT3003 Dose 1
Number of subjects analysed	38 ^[17]	68 ^[18]
Units: pg/mL
arithmetic mean (standard deviation)
At trough, at Month 12	11651.9 ± 6151.1	13739.3 ± 20313.6
At trough, at Month 15	8686.6 ± 9172.8	9009.7 ± 10910.3
At peak, at Month 12	90238.7 ± 29972.8	52201.6 ± 21494.6
At peak, at Month 15	105825.4 ± 38756.7	47021.1 ± 19834.5

Notes
[17] - PP selection LLOQ = 30 pg/mL
[18] - PP selection LLOQ = 30 pg/mL

No statistical analyses for this end point

Other pre-specified: Plasma concentrations of naltrexone at trough and at peak

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End point title

Plasma concentrations of naltrexone at trough and at peak ^[19]

End point 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 base correspond to half of the administered dose.

End point type

Other pre-specified

End point timeframe

At Month 12 and at Month 15

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: For Placebo the values correspond to LLOQ: 30 pg/mL

End point values	PXT3003 Dose 2	PXT3003 Dose 1
Number of subjects analysed	38 ^[20]	68 ^[21]
Units: pg/mL
arithmetic mean (standard deviation)
At trough, at Month 12	42.0 ± 66.0	33.0 ± 15.8
At trough, at Month 15	30.0 ± 0.0	31.8 ± 14.0
At peak, at Month 12	107.5 ± 88.6	63.0 ± 47.4
At peak, at Month 15	130.9 ± 81.4	55.0 ± 39.3

Notes
[20] - PP selection LLOQ = 30 pg/mL
[21] - PP selection LLOQ = 30 pg/mL

No statistical analyses for this end point

Other pre-specified: Plasma concentrations of 6β-naltrexol at trough and at peak

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End point title

Plasma concentrations of 6β-naltrexol at trough and at peak ^[22]

End point 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 base correspond to half of the administered dose.

End point type

Other pre-specified

End point timeframe

At Month 12 and at Month 15

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: For Placebo the values correspond to LLOQ: 50 pg/mL

End point values	PXT3003 Dose 2	PXT3003 Dose 1
Number of subjects analysed	38 ^[23]	68 ^[24]
Units: pg/mL
arithmetic mean (standard deviation)
At trough, at Month 12	526.4 ± 245.6	290.1 ± 177.4
At trough, at Month 15	352.3 ± 319.0	260.4 ± 121.8
At peak, at Month 12	1257.1 ± 454.3	632.5 ± 230.1
At peak, at Month 15	1450.9 ± 438.0	586.4 ± 205.4

Notes
[23] - PP selection LLOQ = 50 pg/mL
[24] - PP selection LLOQ = 50 pg/mL

No statistical analyses for this end point

Other pre-specified: Mean change CMTNS-v2 Sensory Symptoms

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End point title

Mean change CMTNS-v2 Sensory Symptoms

End point description

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 Sensory symptoms is the first item of the CMTNS-v2. Lower values in the CMTNS-v2 Sensory Symptoms 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)

End point type

Other pre-specified

End point timeframe

From Baseline to Month 15

End point values	PXT3003 Dose 2	PXT3003 Dose 1	Placebo
Number of subjects analysed	55 ^[25]	93 ^[26]	87 ^[27]
Units: CMTNS score
arithmetic mean (standard deviation)
Base	0.96 ± 0.98	1.26 ± 0.95	1.09 ± 0.90
Fin	0.93 ± 0.96	1.18 ± 0.81	1.21 ± 0.94

Notes
[25] - mFAS selection
[26] - mFAS selection
[27] - mFAS selection

Main analysis for PXT3003 Dose 2

Statistical analysis description

Comparison groups

PXT3003 Dose 2 v Placebo

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.023

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.29

Confidence interval

level

97.5%

sides

2-sided

lower limit

-0.58

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.13

Main analysis for PXT3003 Dose 1

Statistical analysis description

Comparison groups

PXT3003 Dose 1 v Placebo

Number of subjects included in analysis

180

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.162

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.15

Confidence interval

level

97.5%

sides

2-sided

lower limit

-0.4

upper limit

0.09

Variability estimate

Standard error of the mean

Dispersion value

0.11

Other pre-specified: ONLS Therapy Response 1

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End point title

ONLS Therapy Response 1

End point description

ONLS Therapy Response 1 was defined as improvement on final ONLS Total Score of at least one point. A higher response rate indicates a better clinical condition. Reported values are the average of the available values at Month 12 and Month 15 (Fin).

End point type

Other pre-specified

End point timeframe

From Baseline to Month 15

End point values	PXT3003 Dose 2	PXT3003 Dose 1	Placebo
Number of subjects analysed	49 ^[28]	85 ^[29]	80 ^[30]
Units: Responders
number (not applicable)	14	16	14

Notes
[28] - Completers selection
[29] - Completers selection
[30] - Completers selection

Responder Analysis - PXT3003 Dose 2 (Completers)

Statistical analysis description

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.

Comparison groups

PXT3003 Dose 2 v Placebo

Number of subjects included in analysis

129

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.097

Method

General Linear Mixed Model

Parameter type

Odds ratio (OR)

Point estimate

2.09

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.77

upper limit

5.68

Responder Analysis - PXT3003 Dose 1 (Completers)

Statistical analysis description

Comparison groups

Placebo v PXT3003 Dose 1

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.865

Method

General Linear Mixed Model

Parameter type

Odds ratio (OR)

Point estimate

1.07

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.42

upper limit

2.7

Other pre-specified: ONLS Therapy Response 2

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End point title

ONLS Therapy Response 2

End point description

ONLS Therapy Response 2 was defined as no deterioration on final ONLS Total Score. A higher response rate indicates a better clinical condition. Reported values are the average of the available values at Month 12 and Month 15 (Fin).

End point type

Other pre-specified

End point timeframe

From Baseline to Month 15

End point values	PXT3003 Dose 2	PXT3003 Dose 1	Placebo
Number of subjects analysed	49 ^[31]	85 ^[32]	80 ^[33]
Units: Responders
number (not applicable)	42	66	58

Notes
[31] - Completers selection
[32] - Completers selection
[33] - Completers selection

Responder Analysis - PXT3003 Dose 2 (Completers)

Statistical analysis description

Comparison groups

PXT3003 Dose 2 v Placebo

Number of subjects included in analysis

129

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.026

Method

General Linear Mixed Model

Parameter type

Odds ratio (OR)

Point estimate

3.39

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.99

upper limit

11.62

Responder Analysis - PXT3003 Dose 1 (Completers)

Statistical analysis description

Comparison groups

PXT3003 Dose 1 v Placebo

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.569

Method

General Linear Mixed Model

Parameter type

Odds ratio (OR)

Point estimate

1.26

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.5

upper limit

3.16

Adverse events

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Timeframe for reporting adverse events

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)

Adverse event reporting additional 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 adverse events.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

PXT3003 Dose 2

Reporting group description

The subjects have been randomized to the PXT3003 Dose 2 arm with a 1:1:1 ratio. PXT3003 Dose 2 corresponds to 6 mg baclofen, 0.70 mg naltrexone and 210 mg sorbitol given twice daily.

Reporting group title

PXT3003 Dose 1

Reporting group description

The subjects have been randomized to the PXT3003 Dose 1 arm with a 1:1:1 ratio. PXT3003 Dose 1 corresponds to 3 mg baclofen, 0.35 mg naltrexone and 105 mg sorbitol given twice daily.

Reporting group title

Placebo

Reporting group description

The subjects have been randomized to the Placebo arm with a 1:1:1 ratio.

Serious adverse events	PXT3003 Dose 2	PXT3003 Dose 1	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 113 (2.65%)	10 / 109 (9.17%)	5 / 101 (4.95%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	0 / 113 (0.00%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thyroid adenoma
subjects affected / exposed	0 / 113 (0.00%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Uterine leiomyoma
subjects affected / exposed	0 / 113 (0.00%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Arthrolysis
subjects affected / exposed	0 / 113 (0.00%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Endometriosis
subjects affected / exposed	0 / 113 (0.00%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Sleep apnoea syndrome
subjects affected / exposed	0 / 113 (0.00%)	1 / 109 (0.92%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Suicide attempt
subjects affected / exposed	0 / 113 (0.00%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Clavicle fracture
subjects affected / exposed	0 / 113 (0.00%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 113 (0.00%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hand fracture
subjects affected / exposed	0 / 113 (0.00%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury
subjects affected / exposed	0 / 113 (0.00%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Median nerve injury
subjects affected / exposed	0 / 113 (0.00%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Patella fracture
subjects affected / exposed	0 / 113 (0.00%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 113 (0.00%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Congenital foot malformation
subjects affected / exposed	0 / 113 (0.00%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Patent ductus arteriosus
subjects affected / exposed	1 / 113 (0.88%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 113 (0.00%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Seizure
subjects affected / exposed	0 / 113 (0.00%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Proctitis
subjects affected / exposed	1 / 113 (0.88%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 113 (0.00%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Hydronephrosis
subjects affected / exposed	1 / 113 (0.88%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	1 / 113 (0.88%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Chest wall haematoma
subjects affected / exposed	0 / 113 (0.00%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 113 (0.00%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enteritis infectious
subjects affected / exposed	1 / 113 (0.88%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 2%

Non-serious adverse events	PXT3003 Dose 2	PXT3003 Dose 1	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	87 / 113 (76.99%)	89 / 109 (81.65%)	83 / 101 (82.18%)
Vascular disorders
Hypotension
subjects affected / exposed	1 / 113 (0.88%)	1 / 109 (0.92%)	2 / 101 (1.98%)
occurrences all number	1	1	2
General disorders and administration site conditions
Asthenia
subjects affected / exposed	2 / 113 (1.77%)	3 / 109 (2.75%)	7 / 101 (6.93%)
occurrences all number	2	3	9
Fatigue
subjects affected / exposed	2 / 113 (1.77%)	11 / 109 (10.09%)	6 / 101 (5.94%)
occurrences all number	2	15	6
Influenza like illness
subjects affected / exposed	6 / 113 (5.31%)	3 / 109 (2.75%)	0 / 101 (0.00%)
occurrences all number	9	5	0
Peripheral swelling
subjects affected / exposed	0 / 113 (0.00%)	1 / 109 (0.92%)	2 / 101 (1.98%)
occurrences all number	0	1	2
Respiratory, thoracic and mediastinal disorders
Nasal congestion
subjects affected / exposed	0 / 113 (0.00%)	0 / 109 (0.00%)	2 / 101 (1.98%)
occurrences all number	0	0	2
Oropharyngeal pain
subjects affected / exposed	2 / 113 (1.77%)	3 / 109 (2.75%)	5 / 101 (4.95%)
occurrences all number	2	6	8
Psychiatric disorders
Anxiety
subjects affected / exposed	2 / 113 (1.77%)	3 / 109 (2.75%)	2 / 101 (1.98%)
occurrences all number	3	3	2
Depression
subjects affected / exposed	0 / 113 (0.00%)	1 / 109 (0.92%)	5 / 101 (4.95%)
occurrences all number	0	1	5
Insomnia
subjects affected / exposed	1 / 113 (0.88%)	1 / 109 (0.92%)	3 / 101 (2.97%)
occurrences all number	1	4	3
Sleep disorder
subjects affected / exposed	2 / 113 (1.77%)	1 / 109 (0.92%)	2 / 101 (1.98%)
occurrences all number	2	1	2
Investigations
Weight increased
subjects affected / exposed	0 / 113 (0.00%)	1 / 109 (0.92%)	5 / 101 (4.95%)
occurrences all number	0	1	6
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 113 (0.88%)	1 / 109 (0.92%)	3 / 101 (2.97%)
occurrences all number	1	1	4
Fall
subjects affected / exposed	3 / 113 (2.65%)	9 / 109 (8.26%)	7 / 101 (6.93%)
occurrences all number	3	15	9
Laceration
subjects affected / exposed	0 / 113 (0.00%)	3 / 109 (2.75%)	0 / 101 (0.00%)
occurrences all number	0	3	0
Ligament sprain
subjects affected / exposed	2 / 113 (1.77%)	8 / 109 (7.34%)	9 / 101 (8.91%)
occurrences all number	2	9	12
Limb injury
subjects affected / exposed	1 / 113 (0.88%)	1 / 109 (0.92%)	2 / 101 (1.98%)
occurrences all number	1	1	2
Cardiac disorders
Palpitations
subjects affected / exposed	1 / 113 (0.88%)	0 / 109 (0.00%)	2 / 101 (1.98%)
occurrences all number	1	0	3
Nervous system disorders
Dizziness
subjects affected / exposed	5 / 113 (4.42%)	9 / 109 (8.26%)	2 / 101 (1.98%)
occurrences all number	5	10	3
Headache
subjects affected / exposed	13 / 113 (11.50%)	17 / 109 (15.60%)	11 / 101 (10.89%)
occurrences all number	20	22	14
Hypoaesthesia
subjects affected / exposed	3 / 113 (2.65%)	1 / 109 (0.92%)	2 / 101 (1.98%)
occurrences all number	3	1	2
Migraine
subjects affected / exposed	3 / 113 (2.65%)	1 / 109 (0.92%)	2 / 101 (1.98%)
occurrences all number	3	2	3
Paraesthesia
subjects affected / exposed	3 / 113 (2.65%)	2 / 109 (1.83%)	0 / 101 (0.00%)
occurrences all number	5	2	0
Sciatica
subjects affected / exposed	2 / 113 (1.77%)	1 / 109 (0.92%)	2 / 101 (1.98%)
occurrences all number	2	1	3
Somnolence
subjects affected / exposed	2 / 113 (1.77%)	5 / 109 (4.59%)	1 / 101 (0.99%)
occurrences all number	2	5	1
Tremor
subjects affected / exposed	3 / 113 (2.65%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences all number	3	0	1
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	1 / 113 (0.88%)	2 / 109 (1.83%)	2 / 101 (1.98%)
occurrences all number	1	2	2
Vertigo
subjects affected / exposed	1 / 113 (0.88%)	3 / 109 (2.75%)	2 / 101 (1.98%)
occurrences all number	1	4	2
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	5 / 113 (4.42%)	2 / 109 (1.83%)	3 / 101 (2.97%)
occurrences all number	5	2	4
Abdominal pain upper
subjects affected / exposed	4 / 113 (3.54%)	3 / 109 (2.75%)	3 / 101 (2.97%)
occurrences all number	5	3	3
Constipation
subjects affected / exposed	2 / 113 (1.77%)	4 / 109 (3.67%)	2 / 101 (1.98%)
occurrences all number	2	4	2
Diarrhoea
subjects affected / exposed	7 / 113 (6.19%)	7 / 109 (6.42%)	7 / 101 (6.93%)
occurrences all number	8	9	8
Dry mouth
subjects affected / exposed	3 / 113 (2.65%)	3 / 109 (2.75%)	4 / 101 (3.96%)
occurrences all number	3	3	4
Dyspepsia
subjects affected / exposed	2 / 113 (1.77%)	1 / 109 (0.92%)	3 / 101 (2.97%)
occurrences all number	2	1	4
Nausea
subjects affected / exposed	7 / 113 (6.19%)	12 / 109 (11.01%)	6 / 101 (5.94%)
occurrences all number	7	17	6
Toothache
subjects affected / exposed	0 / 113 (0.00%)	4 / 109 (3.67%)	1 / 101 (0.99%)
occurrences all number	0	4	1
Vomiting
subjects affected / exposed	5 / 113 (4.42%)	2 / 109 (1.83%)	1 / 101 (0.99%)
occurrences all number	5	2	1
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	2 / 113 (1.77%)	1 / 109 (0.92%)	2 / 101 (1.98%)
occurrences all number	2	1	2
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	3 / 113 (2.65%)	13 / 109 (11.93%)	8 / 101 (7.92%)
occurrences all number	3	19	8
Back pain
subjects affected / exposed	5 / 113 (4.42%)	10 / 109 (9.17%)	3 / 101 (2.97%)
occurrences all number	5	12	3
Bone callus excessive
subjects affected / exposed	0 / 113 (0.00%)	0 / 109 (0.00%)	2 / 101 (1.98%)
occurrences all number	0	0	2
Joint swelling
subjects affected / exposed	0 / 113 (0.00%)	1 / 109 (0.92%)	4 / 101 (3.96%)
occurrences all number	0	1	4
Muscle spasms
subjects affected / exposed	8 / 113 (7.08%)	5 / 109 (4.59%)	6 / 101 (5.94%)
occurrences all number	9	7	6
Musculoskeletal pain
subjects affected / exposed	4 / 113 (3.54%)	1 / 109 (0.92%)	1 / 101 (0.99%)
occurrences all number	4	1	1
Myalgia
subjects affected / exposed	1 / 113 (0.88%)	3 / 109 (2.75%)	2 / 101 (1.98%)
occurrences all number	1	3	2
Neck pain
subjects affected / exposed	3 / 113 (2.65%)	3 / 109 (2.75%)	3 / 101 (2.97%)
occurrences all number	3	4	3
Osteoarthritis
subjects affected / exposed	2 / 113 (1.77%)	3 / 109 (2.75%)	0 / 101 (0.00%)
occurrences all number	2	3	0
Pain in extremity
subjects affected / exposed	5 / 113 (4.42%)	10 / 109 (9.17%)	9 / 101 (8.91%)
occurrences all number	6	13	13
Rotator cuff syndrome
subjects affected / exposed	0 / 113 (0.00%)	0 / 109 (0.00%)	3 / 101 (2.97%)
occurrences all number	0	0	4
Tendonitis
subjects affected / exposed	3 / 113 (2.65%)	2 / 109 (1.83%)	4 / 101 (3.96%)
occurrences all number	3	2	4
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 113 (0.88%)	2 / 109 (1.83%)	6 / 101 (5.94%)
occurrences all number	1	3	6
Cystitis
subjects affected / exposed	0 / 113 (0.00%)	2 / 109 (1.83%)	2 / 101 (1.98%)
occurrences all number	0	3	2
Gastroenteritis
subjects affected / exposed	3 / 113 (2.65%)	3 / 109 (2.75%)	5 / 101 (4.95%)
occurrences all number	3	4	5
Influenza
subjects affected / exposed	6 / 113 (5.31%)	3 / 109 (2.75%)	3 / 101 (2.97%)
occurrences all number	6	3	3
Nasopharyngitis
subjects affected / exposed	18 / 113 (15.93%)	24 / 109 (22.02%)	15 / 101 (14.85%)
occurrences all number	26	31	24
Pharyngitis
subjects affected / exposed	0 / 113 (0.00%)	2 / 109 (1.83%)	2 / 101 (1.98%)
occurrences all number	0	2	2
Respiratory tract infection
subjects affected / exposed	0 / 113 (0.00%)	1 / 109 (0.92%)	2 / 101 (1.98%)
occurrences all number	0	1	2
Rhinitis
subjects affected / exposed	3 / 113 (2.65%)	3 / 109 (2.75%)	4 / 101 (3.96%)
occurrences all number	4	3	5
Sinusitis
subjects affected / exposed	6 / 113 (5.31%)	7 / 109 (6.42%)	1 / 101 (0.99%)
occurrences all number	6	8	1
Tracheitis
subjects affected / exposed	0 / 113 (0.00%)	0 / 109 (0.00%)	2 / 101 (1.98%)
occurrences all number	0	0	2
Upper respiratory tract infection
subjects affected / exposed	1 / 113 (0.88%)	2 / 109 (1.83%)	2 / 101 (1.98%)
occurrences all number	1	2	2
Urinary tract infection
subjects affected / exposed	3 / 113 (2.65%)	1 / 109 (0.92%)	2 / 101 (1.98%)
occurrences all number	5	1	2
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	3 / 113 (2.65%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences all number	3	0	1
Vitamin D deficiency
subjects affected / exposed	1 / 113 (0.88%)	0 / 109 (0.00%)	3 / 101 (2.97%)
occurrences all number	1	0	3

More information

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Were there any global substantial amendments to the protocol? Yes

01 Sep 2015

The study protocol was updated from version 1.0 dated 22 May 2015 to version 1.1 dated 01 September 2015 to add an interim analysis and minor changes in the presentation of the protocol to harmonize all protocols for all countries.

19 Jan 2016

The study protocol was updated from version 1.1 dated 01 September 2015 to version 1.2 dated 19 January 2016, the main change was the following: Calf MRI changes in leg MRI and added possibility to perform the PMP22 duplication genetic test if not already documented in patient history (only for US).

14 Oct 2016

The study protocol was updated from version 1.2 dated 19 January 2016 to version 1.3 dated 14 October 2016, the main changes were the following: Removing of SynteractHCR CRO name on the cover page, correction Typo error in section 13.1, 2nd§: written 6β-naltrexol instead of 6β-naltrexone.

18 Jan 2017

The study protocol was updated from version 1.3 dated 14 October 2016 to version 1.4 dated 18 January 2017, the main changes were the following: the wording of “a total of 300 patients” is replaced by a “total of at least 300 patients” to cover the fact that a total of 323 patients were actually randomized in the study. Due to the high number of screened patients, it was deemed appropriate to keep screened and eligible patients to participate in the study. This adaptation is applied in the following sections: Synopsis (in the 2 sub-sections “total expected number of patients” and “Statistical considerations”) and in 8.3, 9, 14.3.

05 Dec 2017

The study protocol was updated from version 1.4 dated 18 January 2017 to version 1.5 dated 05 December 2017, the main changes were the followings: due to an unexpected investigational medicinal product (IMP) quality event, without safety concerns, the use of dose 2 IMP is discontinued from the pivotal phase III study CLN-PXT3003-02 upon Sponsor decision (September 18th, 2017). The stability testing at Quay Pharma (UK) observed the occurrence of crystals in one stability batch of PXT3003 dose 2 at month 18 (September 14th, 2017), whereas this was not the case at month 12. This new finding is inconsistent with the dose 2 IMP release criteria and therefore does not meet the ICH Harmonized Tripartite Guideline for Stability Testing of New Drug Substances and Products. Hence, the patient arm of PXT3003 dose 2 will early terminate the study. They will be offered to enter the extension study CLNPXT3003-03 to receive the equivalent of dose 2 (5 mL per administration), by using of its equivalent dose, i.e. twice the dose 1 IMP (2x5 mL, i.e. 10 mL) per administration. Furthermore, all patients using dose 1 IMP or placebo will continue to receive dose 1 IMP or placebo (5 mL per administration) in the pivotal phase III study CLN-PXT3003-02 as planned.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
27 Jun 2017	In March 2017, during the course of the clinical study, crystals were reported by patients in some vials of the Dose 2 Investigational Medicinal Product. Based on that , the study was put on hold in Germany by BfArM in July 2017. The crystals were subsequently confirmed in an 18-month stability testing of the Dose 2 formulation of PXT3003 on September 14, 2017. Despite the lack of safety concerns reported by the data safety monitoring board on September 5, 2017, the Sponsor's decision was to discontinue the Dose 2 arm patients still under treatment on September 18, 2017. The remaining patients on Dose 1 and Placebo continued the study in a blinded fashion. Patients of the PXT3003 dose 2 arm terminated the study early and were offered to enter the extension study CLN-PXT3003-03. They received the equivalent of dose 2 (5 mL per administration), by using twice the dose 1 IMP (2x5 mL, i.e. 10 mL) per administration.	-

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

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

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Clinical trials

Clinical Trial Results: International, multi-center, randomized, double-blind, placebo-controlled phase III study assessing in parallel groups the efficacy and safety of 2 doses of PXT3003 in patients with Charcot-Marie-Tooth Disease type 1A treated for 15 months

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Mean of the ONLS total score at Month 12 and Month 15

Primary: Mean of the ONLS total score at Month 12 and Month 15

Secondary: Mean change of the Ten Meter Walking Test (10MWT) score

Secondary: Mean change of the Ten Meter Walking Test (10MWT) score

Secondary: Mean change of the CMTNS-v2 Sensory Score

Secondary: Mean change of the CMTNS-v2 Sensory Score

Secondary: Mean change of the CMTNS-v2 Examination Score

Secondary: Mean change of the CMTNS-v2 Examination Score

Secondary: Mean change of the results at the Nine-Hole Peg Test

Secondary: Mean change of the results at the Nine-Hole Peg Test

Secondary: Incidence of all TEAEs

Secondary: Incidence of all TEAEs

Secondary: Incidence of AE leading to withdrawal of study drug

Secondary: Incidence of AE leading to withdrawal of study drug

Secondary: Incidence of SAEs

Secondary: Incidence of SAEs

Other pre-specified: Plasma concentrations of baclofen at trough and at peak

Other pre-specified: Plasma concentrations of baclofen at trough and at peak

Other pre-specified: Plasma concentrations of naltrexone at trough and at peak

Other pre-specified: Plasma concentrations of naltrexone at trough and at peak

Other pre-specified: Plasma concentrations of 6β-naltrexol at trough and at peak

Other pre-specified: Plasma concentrations of 6β-naltrexol at trough and at peak

Other pre-specified: Mean change CMTNS-v2 Sensory Symptoms

Other pre-specified: Mean change CMTNS-v2 Sensory Symptoms

Other pre-specified: ONLS Therapy Response 1

Other pre-specified: ONLS Therapy Response 1

Other pre-specified: ONLS Therapy Response 2

Other pre-specified: ONLS Therapy Response 2

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
International, multi-center, randomized, double-blind, placebo-controlled phase III study assessing in parallel groups the efficacy and safety of 2 doses of PXT3003 in patients with Charcot-Marie-Tooth Disease type 1A treated for 15 months