Clinical Trials Register

Summary
EudraCT Number:	2015-002379-81
Sponsor's Protocol Code Number:	CLN-PXT3003-03
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2017-04-07
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

Spain - AEMPS

A.2

EudraCT number

2015-002379-81

A.3

Full title of the trial

International, multi-center, double blind 9-month FOLLOW-UP extension study assessing the long term safety and tolerability of PXT3003 in patients with Charcot-Marie-Tooth Disease type 1A.

Estudio de extensión del seguimiento internacional, multicéntrico, doble ciego de 9 meses de duración para evaluar la seguridad y tolerabilidad a largo plazo de PXT3003 en pacientes con enfermedad de Charcot-Marie-Tooth de tipo 1A.

A.3.1

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

An International, multi-center, 9-month FOLLOW-UP extension study to study the long term safety of PXT3003 in patients with Charcot-Marie-Tooth Disease type 1A.

Estudio internacional, multicéntrico de extensión del seguimiento de 9 meses para estudiar la seguridad a largo plazo de PXT3003 en pacientes con enfermedad de Charcot-Marie-Tooth de tipo 1A.

A.4.1

Sponsor's protocol code number

CLN-PXT3003-03

A.5.4

Other Identifiers

Name:

US IND

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
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
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
B.5.2	Functional name of contact point	Agnes Daoust
B.5.3	Address:
B.5.3.1	Street Address	11, rue des Peupliers
B.5.3.2	Town/ city	Issy-Les-Moulineaux
B.5.3.3	Post code	92130
B.5.3.4	Country	France
B.5.4	Telephone number	+34916307447
B.5.5	Fax number	33141092231
B.5.6	E-mail	adaoust@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.3.2	Product code	PXT3003 Dose 1
D.3.4	Pharmaceutical form	Oral solution
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.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
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	16676-29-2
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NALTREXONE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB14629MIG
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.3.9.2	Current sponsor code	NA
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.IMP: 2
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.3.2	Product code	PXT3003 Dose 2
D.3.4	Pharmaceutical form	Oral solution
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.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
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	1.2
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	16676-29-2
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NALTREXONE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB14629MIG
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	0.14
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.3.9.2	Current sponsor code	NA
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	42
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

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 Disease type 1A

Enfermedad de Charcot-Marie-Tooth de tipo 1A

E.1.1.1

Medical condition in easily understood language

Charcot-Marie-Tooth Disease type 1A

Enfermedad de Charcot-Marie-Tooth de tipo 1A

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	19.1
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

The main objective of the study is to assess the long-term safety and tolerability of PXT3003 up to 2 years, and to increase the exposed population receiving PXT3003 for at least 9 months.

El objetivo principal del estudio es evaluar la seguridad y la tolerabilidad a largo plazo de PXT3003 durante un máximo de 2 años, así como aumentar la población de pacientes expuestos que reciban PXT3003 durante al menos 9 meses.

E.2.2

Secondary objectives of the trial

To gather up-to-2-year data to estimate the long term effect of PXT3003 on clinical, functional and electrophysiological endpoints;
- To compare the effect of PXT3003 in patients receiving PXT3003 active dose from the start of the primary study to patients assigned to a delayed start (i.e., who received placebo during the primary study) in order to show if PXT3003 slows the progression of the disease
- To assess the evolution of potential blood biomarkers and molecular changes in skin biopsy on longer term.

- Recopilar datos de hasta 2 años para calcular el efecto a largo plazo de PXT3003 en los criterios de valoración clínicos, funcionales y lectrofisiológicos
- Comparar el efecto de PXT3003 en pacientes que reciben una dosis activa de PXT3003 desde el principio del estudio principal con pacientes asignados a un inicio tardío (es decir, los que recibieron placebo durante el estudio principal) a fin de demostrar si PXT3003 ralentiza la progresión de la enfermedad
- Evaluar la evolución de posibles biomarcadores sanguíneos y cambios moleculares en la biopsia de piel a largo plazo.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

- Skin Biopsy (ancillary sub-study) for molecular biology will be done at the end of the study (9-month visit)
- MRI measure (ancillary sub-study) of muscle/fat index in the leg (by MRI quantification of lower limb muscles and fatty muscle infiltration) will be performed at the end of the study (9-month visit).

- Biopsia de piel (sub-estudio opcional) para biología molecular, que se hará al final del estudio (visita de los 9 meses)
- RMN (sub-estudio opcional) de músculo/índice de grasa en la pierna (por RMN de cuantificación en los músculos de las extremidades inferiores e infiltración de grasa en los músculos), que se hará al final del estudio (visita de los 9 meses)

E.3

Principal inclusion criteria

Male or female patients with all of the following inclusion criteria will be considered for randomization:
1. Patient previously randomized to the initial PLEO-CMT study (protocol CLN-PXT3003-02) and having completed 15 months of double-blind treatment in that study, including all procedures required at the Study Termination visit (V6)
2. Patient providing a signed written informed consent to participate in the extension study and willing and able to comply with all study procedures and scheduled visits.
3. Female patients must agree to continue using an approved method of birth control throughout the extension study

Pacientes varones o mujeres con todos los siguientes criterios de inclusión para ser considerados para aleatorización en el ensayo:
- Los pacientes deben haber recibido tratamiento doble ciego durante 15 meses en el estudio principal CLN-PXT3003-02, incluidos todos los procedimientos necesarios en la
visita de finalización del estudio (V6).
- Las pacientes deberán aceptar seguir utilizando un método anticonceptivo aprobado a lo largo de todo el estudio de extensión.
- Para participar en este estudio, los pacientes deberán firmar un consentimiento informado por escrito, específico para el estudio de extensión. En el caso de menores de entre 16 y 18 años, deberá recogerse el consentimiento tanto del padre/madre como del menor.

E.4

Principal exclusion criteria

Patients with any of the following criteria will be excluded from entry:
1. Presenting any clinically significant change in health status that, in the opinion of the Investigator, would prevent the subject from participating in this study or successfully completing this study.
2. Any unauthorized concomitant treatments, as study CLN-PXT3003-02.

Los pacientes con alguno de los siguientes criterios serán excluidos
- Todo cambio clínicamente significativo en el estado de salud que, a criterio del investigador, impediría que el paciente participara en el estudio o que lo finalizara de forma satisfactoria.
- Todo tratamiento concomitante no autorizado, como en el estudio CLN-PXT3003-02

E.5 End points

E.5.1

Primary end point(s)

To assess the safety and tolerability of PXT3003 in CMT1A patients during a long term period, the primary endpoint will be the incidence of Treatment-Emergent Adverse Events (TEAEs) Related to the Investigational Product during the follow-up, in patients exposed to PXT3003 for 24 months or 9 months.
The incidence of TEAEs in the two groups P / D1-9m and P/ D2-9m will be compared to the first 9-month placebo period in the primary study.
The incidence of TEAEs in the two groups D1-24m, D2-24m will be compared to the first 9-month period in the primary study for their corresponding group.

Evaluar la seguridad y tolerabilidad de PXT3003 en pacientes con CMT1A durante un período prolongado. El criterio de valoración principal será la incidencia de acontecimientos adversos de aparición durante el tratamiento (AAAT) relacionados con el producto en investigación durante el seguimiento en pacientes expuestos a PXT3003 durante 24 meses o 9 meses.
La incidencia de AAAT en los dos grupos P/D1-9m y P/D2-9m se comparará con el primer período con placebo de 9 meses del estudio principal.
La incidencia de AAAT en los dos grupos D1-24m y D2-24m se comparará con el primer período de 9 meses del estudio principal para el grupo correspondiente.

E.5.1.1

Timepoint(s) of evaluation of this end point

The incidence of TEAEs in the two groups P/ D1-9m and P / D2-9m will be compared to the first 9-month placebo period in the primary study.
The incidence of TEAEs in the two groups D1-24m, D2-24m will be compared to the first 9-month period in the primary study for their corresponding group

La incidencia de AAAT en los dos grupos P/D1-9m y P/D2-9m se comparará con el primer período con placebo de 9 meses del estudio principal.
La incidencia de AAAT en los dos grupos D1-24m y D2-24m se comparará con el primer período de 9 meses del estudio principal para el grupo correspondiente.

E.5.2

Secondary end point(s)

Secondary safety endpoints will be:
- The incidence of all Treatment-Emergent Adverse Events (TEAEs) and evaluation of their type/nature, severity/intensity, seriousness, duration, relationship to study drug, and outcome;
- The incidence of AEs leading to withdrawal of study drug;
- The changes in laboratory parameters, ECGs, vital signs and physical examinations;

Se evaluarán otros criterios de valoración de la seguridad:
- Incidencia de todos los AAAT y su evaluación en cuanto a tipo/naturaleza, intensidad,
gravedad, duración, relación con el fármaco del estudio y desenlace;
- Incidencia de AA que den lugar a la retirada del fármaco del estudio;
- Cambio en los parámetros analíticos, ECG, constantes vitales y exploraciones físicas;

E.5.2.1

Timepoint(s) of evaluation of this end point

For the patients receiving 24 months of active dose along the two successive studies (from groups D1-24m and D2-24m) the clinical response will be assessed by the change from V1/baseline of each endpoint.
For the patients who received placebo during the 15-month primary study and active drug during the 9-month extension study (from groups P/D1-9m and P/D2-9m) the clinical response will be assessed after 9 months of PXT3003 treatment by the change from V6/baseline.
The Percentage of responders to PXT3003 defined as a patients improving on ONLS at end of treatment (V9) will be assessed in the patients receiving the active dose of PXT3003 during 24 months (from groups D1-24m, D2-24m).

Par los pacientes que reciban 24 meses de dosis activa en los 2 estudios sucesivos (de los grupos D1-24m y D2-24m), la respuesta clínica se evaluará mediante el cambio respecto a la V1/inicio de cada criterio de valoración.
Par los pacientes que recibieron placebo durante el estudio principal de 15 meses y fármaco activo durante el estudio de extensión de 9 meses grupos P/D1-9m y P/D2-9m), la respuesta clínica se evaluará tras 9 meses de tratamiento con PXT3003 mediante el cambio respecto a la V6/inicio
El % de pacientes con respuesta a PXT3003, definido como los pacientes cuya puntuación en ONLS mejora al final del tratamiento (V9), se evaluará en los pacientes que reciben la dosis activa de PXT3003 durante 24 meses (de los grupos D1-24m y D2-24m)

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

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

E.8.1.1

Randomised