Clinical Trials Register

Summary
EudraCT Number:	2020-004805-30
Sponsor's Protocol Code Number:	CLN-PXT3003-06
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2021-02-05
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2020-004805-30

A.3

Full title of the trial

A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Phase III Study to Assess the Efficacy, Safety, and Tolerability of PXT3003 in Charcot-Marie-Tooth type 1A (CMT1A)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Phase 3 trial of PXT3003 in Charcot-Marie-Tooth (CMT) Type 1A patients

A.4.1

Sponsor's protocol code number

CLN-PXT3003-06

A.5.4

Other Identifiers

Name:

IND number

Number:

122505

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Pharnext SCA
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Pharnext SCA
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Pharnext SCA
B.5.2	Functional name of contact point	Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	9 rue des Filles Saint-Thomas
B.5.3.2	Town/ city	Paris
B.5.3.3	Post code	75002
B.5.3.4	Country	France
B.5.4	Telephone number	+19178853598
B.5.5	Fax number	+33141092231
B.5.6	E-mail	misrael@pharnext.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/14/1260
D.3 Description of the IMP
D.3.1	Product name	NA
D.3.2	Product code	PXT3003
D.3.4	Pharmaceutical form	Oral solution in sachet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BACLOFEN
D.3.9.1	CAS number	1134-47-0
D.3.9.3	Other descriptive name	(RS)-baclofen
D.3.9.4	EV Substance Code	SUB05667MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.6
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NALTREXONE
D.3.9.1	CAS number	16590-41-3
D.3.9.3	Other descriptive name	naltrexone hydrochloride
D.3.9.4	EV Substance Code	SUB09143MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.07
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Sorbitol
D.3.9.1	CAS number	50-70-4
D.3.9.3	Other descriptive name	D-SORBITOL
D.3.9.4	EV Substance Code	SUB20837
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	21
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Oral solution in sachet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Charcot Marie Tooth Type 1A

E.1.1.1

Medical condition in easily understood language

Hereditary Motor and Sensory Neuropathy

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10008414
E.1.2	Term	Charcot-Marie-Tooth disease
E.1.2	System Organ Class	100000004850

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the efficacy of treatment with PXT3003 (a fixed-dose combination of (RS)-baclofen, naltrexone hydrochloride, and D-sorbitol) compared to placebo in subjects with CMT1A

E.2.2

Secondary objectives of the trial

To evaluate the safety and tolerability of PXT3003 treatment in subjects with CMT1A

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Male and non-pregnant female subjects, aged 16 to 65 years with a genetically proven diagnosis of CMT1A. Notes: a) A report of a genetic test confirming PMP22 duplication and therefore a diagnosis of CMT1A must be available in the subject's record at the clinical site. b) In the absence of a report of a genetic test confirming PMP22 duplication in the subject's medical record, a confirmatory genetic test must be conducted via the central laboratory as part of Screening. c) In the exceptional case wherein subject was randomized into the study without meeting (a) or (b), an unscheduled confirmatory genetic test will be performed. In the event of a negative genetic test result, the subject will be withdrawn
from the study.
2) Able to provide written informed consent/assent and comply with study procedures
3) Mild-to-moderate severity assessed by CMTNS-v2 score >2 and ≤18
4) Muscle weakness in at least foot dorsiflexion on clinical assessment
5) Ulnar nerve motor conduction time of at least 15m/s
6) If taking prescribed psychoactive drug(s) (eg, antidepressants, stimulants, tranquilizers, anti-epileptics) for CMT1A, should be on a stable dose for at least 4 weeks prior to randomization, which is not planned to be changed.
7) If taking prescribed or 'over-the-counter' analgesic medication(s) (eg, paracetamol/acetaminophen, nonsteroidal anti-inflammatory drugs) for CMT1A, should be on a stable dose for at least 2 weeks prior to randomization, which is not planned to be changed.
8) If female, subject must be: (a) Surgically sterilized via hysterectomy, bilateral oophorectomy, or bilateral tubal ligation; or (b) Of childbearing potential and using a birth control method such as:
• Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
o Oral
o Intravaginal
o Transdermal
• Progestogen-only hormonal contraception associated with inhibition of ovulation:
o Oral
o Injectable
o Implantable
• IUD
• IUS
• Bilateral tubal occlusion
• Vasectomized partner
• Sexual abstinence;
or (c) Of non-childbearing potential (i.e., no menses for ≥12 consecutive months without any other underlying medical cause)
9) If male, the subject must have had a vasectomy or must use a reliable method of birth control with their partner or total abstinence from sexual intercourse. The subject must agree to continue using their selected method of birth control with their sexual partner during the study and for 120 days after study completion.

For subjects consenting to enter the OLE Period, the following Inclusion
criteria will be confirmed/reassessed on Screening Day (SV6) of the OLE
Period:
1. Able to provide written informed consent/assent and comply with
study procedures.
2. If female, subject must be (a) surgically sterilized via hysterectomy,
bilateral oophorectomy, or bilateral tubal ligation; or (b) of childbearing
potential and using a birth control method such as:
• Combined (estrogen and progestogen containing) hormonal
contraception
associated with inhibition of ovulation:
o Oral
o Intravaginal
o Transdermal
• Progestogen-only hormonal contraception associated with inhibition
of ovulation:
o Oral
o Injectable
o Implantable
•IUD
•IUS
• Bilateral tubal occlusion
• Vasectomized partner
• Sexual abstinence
or (c) of non-childbearing potential (ie, no menses for =12 consecutive
months without any other underlying medical cause).
3. If male, the subject must have had a vasectomy or must use a reliable method of birth control with their partner or total abstinence from sexual intercourse. The subject must agree to continue using their selected method of birth control with their sexual partner during the study and for 120 days after study completion.

E.4

Principal exclusion criteria

1.Subjects previously enrolled in any PXT3003 study.
2.Subjects living in the same household and enrolled in a PXT3003 study (due to potential lack of adequate storage for study material, risk of mixing treatments and potential unblinding).
3.CMT of any subtype other than 1A.
4.ONLS score of 0.
5.Known clinically significant motor or sensory abnormalities secondary to a different neurological cause. Note: subjects with diagnosis of unilateral carpal tunnel syndrome at least 1 year prior to Screening Visit, that is asymptomatic at the time of Screening Visit, will not be excluded from participating in this study.
6.Subjects who have had any surgery or have a concomitant disorder that reduces the mobility of the ankle or wrist making it, in the opinion of the investigator, difficult to assess the efficacy of the treatment. Note: subjects with surgical repair of unilateral carpal tunnel syndrome will not be excluded from participating in this study.
7.Known peripheral neuropathy, myopathy, or neuromuscular disorder of any other kind. Note: subjects with diagnosis of unilateral carpal tunnel syndrome at least 1 year prior to Screening Visit, that is asymptomatic at the time of Screening Visit, will not be excluded from participating in this study.
8.Any other clinically significant and/or uncontrolled medical condition that, in the opinion of the investigator, could be a confound, may increase subject’s risk, or may preclude successful participation or completion of the study.
9.Known hypersensitivity or intolerance to PXT3003 (or matching placebo), including any of its active ingredients, and/or any of its excipients.
10.Concomitant treatments including but not limited to baclofen, naltrexone, sorbitol (pharmaceutical form), opioids, potent central nervous system depressants, and potentially neurotoxic drugs such as amiodarone, chloroquine, and chemotherapeutics capable of inducing peripheral neuropathy. Subjects able to stop these medications at least 2 weeks before randomization and for the study duration may be included. Subjects with positive urine drug screen at Baseline Visit will be excluded, except for permitted use of codeine and benzodiazepines.
11.History of porphyria.
12.Diagnosis or history of substance use disorder by DSM-V criteria within the past 12 months.
13.Medical or recreational use of marijuana in the 3 months prior to the Screening Visit.
14.Active suicidality
15.Currently active major depression, as determined by a BDI-II score ≥20.
16.Currently lactating, pregnant, or planning on becoming pregnant during the study.
17.ALT or AST levels greater than 2 times the ULN.
18.Significant renal impairment as determined by GFR of less than 50 mL/min.
19.Subject has participated in an investigational drug or device study within 30 days prior to the Screening Visit or plans to participate in an investigational drug or device study during the course of this study.
20.Subject is a dependent and/or relative of the Sponsor or Principal Investigator.
For subjects consenting to enter the OLE Period, the following criteria
will be confirmed/reassessed on SV6 of the OLE Period
1.Any clinically significant and/or uncontrolled medical condition that, in the opinion of the investigator, could be a confound factor, may increase subject's risk, or may preclude successful participation or completion of the study.
2.Concomitant treatments including but not limited to baclofen,
naltrexone, sorbitol (pharmaceutical form) other than PXT3003 taken in the Double-blind Treatment Period of this study, opioids, potent CNS depressants, and potentially neurotoxic drugs such as amiodarone, chloroquine, and chemotherapeutics capable of inducing peripheral neuropathy. Subjects able to stop these medications at least 2 weeks before randomization and for the study duration may be included.
3.Diagnosis or history of substance use disorder by Diagnostic and
Statistical Manual of Mental Disorders-5th Edition criteria within the past 12 months.
4.Active suicidality
5.Currently active major depression, as determined by a BDI-II score =20.
6.Currently lactating, pregnant, or planning on becoming pregnant
during the study.
7.ALT or AST levels greater than 2 × ULN relative to Baseline.1
8.Estimated GFR of less than 50 mL/min.
1.Note: If the laboratory values are not normal (out of range), the
subjects will be contacted, and therapy will be stopped.
Note: PXT3003 will be dispensed to all subjects before laboratory results are available, and if the laboratory results are out of range, ie, subject meeting the exclusion criteria, the subject will be called immediately to stop taking PXT3003. One retest within 4 weeks may be performed in consultation with the Medical Monitor if any of the above laboratory abnormalities are found. In case of eligibility determination after the retest, subjects will restart taking 2 weeks of half dose of PXT3003.

E.5 End points

E.5.1

Primary end point(s)

The change in the modified Overall Neuropathy Limitation Scale (mONLS) between baseline and the Month 15 visit.

E.5.1.1

Timepoint(s) of evaluation of this end point

Month 15 visit

E.5.2

Secondary end point(s)

The change from baseline to month 15 in the following outcome measures in hierarchical order:
1) 10-Meter Walk Test (10mWT)
2) CMTNS-V2
3) Patient Global Impression of Severity (PGI-S)
4) Patient Global Impression of Change (PGI-C)*
5) Quantified Muscular Testing (hand grip)
6) Quantified Muscular Testing (bilateral foot dorsiflexion dynamometry)
* Because the PGI-C is already a change assessment, the change from Baseline is not needed for this endpoint.

E.5.2.1

Timepoint(s) of evaluation of this end point

Month 15 visit

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Canada

Israel

United States

Belgium

Denmark

France

Germany

Italy

Spain

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

For Double-blind Treatment Period -LVLS- completion of the Month 15 Visit by the last subject.

The duration of OLE Period will be up to two years and will be based on Sponsor discretion. Justification of a potential extension beyond the two-year period will be evaluated and agreed upon with the competent authorities of Germany (BfArM)

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

381

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Minors aged 16 and older.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

183

F.4.2.2

In the whole clinical trial

387

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-06-15

Ethics Committee Opinion of the trial application

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2023-12-12

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