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Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A

Primary Purpose

Charcot-Marie-Tooth Disease, Hereditary Neuropathy With Liability to Pressure Palsies, Genetic Disorders

Status

Completed

Phase

Phase 2

Locations

France

Study Type

Interventional

Intervention

PXT3003 Low dose

PXT3003 Intermediate Dose

PXT3003 High Dose

Placebo

About this trial

This is an interventional treatment trial for Charcot-Marie-Tooth Disease focused on measuring PXT3003, Charcot-Marie-Tooth Disease, Hereditary Motor and Sensory Neuropathies

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

DNA proven CMT1A
Muscle weakness in at least foot dorsiflexion (clinical assessment)
Age between 18 and 65 years
Male or non pregnant, non breastfeeding female
CMT neuropathy score at screening ≤ 20
Agrees to perform electrorophysiological studies and two cutaneous biopsies for determination of PMP22 expression and histology
Providing signed written informed consent to participate in the study and willing and able to comply with all study procedures and scheduled visits

Exclusion Criteria:

Patients with another neurological disease
Patients using unauthorized concomitant treatments, ascorbic acid, opioids, levothyroxine and potentially neurotoxic drugs. Patients who can/agree to stop these medications 4 weeks before randomization can be included
Patients who have participated in another trial of investigational drug within the past 30 days
Concomitant major systemic disease
Clinically significant history of unstable medical illness over the last 30 days (unstable angina…)
History of significant hematologic, kidney, liver disease, or insulin-dependent diabetes
Clinically significant abnormalities on the prestudy laboratory evaluation, physical evaluation, electrocardiogram (ECG)
ASAT/ALAT levels above the upper limit of normal (ULN). However, patients with an isolated elevation of either ASAT or ALAT (<1.5 ULN) can be included at investigators" discretion if the remaining liver function tests are normal and if ASAT or ALAT value is stable at 2 distinct evaluations in the month prior to inclusion
Serum creatinine levels above the upper limit of normal
Limited mental capacity or psychiatric disease rendering the subject unable to provide written informed consent or comply with evaluation procedures
History of recent alcohol or drug abuse or non-adherence with treatment or other experimental protocols
Female of childbearing potential (apart of patient using adequate contraceptive measures), pregnant or breast feeding
Suspected inability to complete the study follow-up (foreign workers, transient visitors, tourists or any others for whom follow-up evaluation is not assured)
Limb surgery in the six months before randomization or planned before completion of the trial
Known hypersensitivity to any of the individual components of PXT3003
Porphyria

Sites / Locations

Hôpital Roger Salengro
CHU Dupuytren
CHU Lyon Sud
Hôpital La Timone
Hôtel Dieu
Groupe Hospitalier Pitié-Salpétrière

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Arm Label

PXT3003 Low dose

PXT3003 Intermediate dose

PXT3003 High dose

Placebo

Arm Description

Oral Liquid formulation, 1/100, bid, 12 months

Oral Liquid formulation, 1/50, bid, 12 months

Oral Liquid formulation, 1/10, bid, 12 months

Oral Liquid formulation, bid, 12 months

Outcomes

Primary Outcome Measures

Safety and Tolerability of PXT3003

The Primary Objective is to assess the clinical and laboratory safety and tolerability of three doses of PXT3003 administered orally for 12 months to CMT1A patients versus placebo. Number of participants with adverse events in each arm.

Secondary Outcome Measures

To Obtain Preliminary Data on the Efficacy of PXT3003 on Clinical Scores and Functional Tests

Efficacy scores and functional tests will be assessed CMTNS/CMTES:ONLS, VAS, fatigue, pain, six minute walk test (6MWT), nine-hole peg test, quantified muscular testing (QMT; hand grip and foot dorsiflexion), CGI. For each test or score, change from baseline after 3-,6-, 9- and 12-months of treatment.

To Assess the Pharmacodynamic Effect of PXT3003 on PMP22 mRNA Levels and Intra-epidermal Axon Density in Cutaneous Biopsy

A cutaneous biopsy (consisting in 2 small punch biopsies) will be performed to assess PMP22 mRNA expression and intra-epidermal axon density. Change from baseline after 12-month of treatment.

To Assess the Pharmacodynamic Effect of PXT3003 on Selected Neurophysiological Parameters

Electrophysiological examination will be performed to assess sensory and motor responses of the median and ulnar nerves (non-dominant side) including: NCV, compound muscle action potential (CMAP) and SNAP. Change from baseline after 3-,6-, 9- and 12-months of treatment.

To Assess the Pharmacodynamic Effect of PXT3003 on a Series of Biochemical Biomarkers

Dosages of biochemical biomarkers in plasma. Change from baseline after 3-month of treatment.

To Assess the Plasma Concentrations of PXT3003

PXT3003 plasmatic concentrations after one administration (randomization) and after 1-,6-and 12-months of treatment.

Full Information

NCT ID

NCT01401257

First Posted

July 20, 2011

Last Updated

October 19, 2017

Sponsor

Pharnext SA

1. Study Identification

Unique Protocol Identification Number

NCT01401257

Brief Title

Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A

Official Title

A Phase II, Randomized, Placebo-controlled Trial of the Safety, Efficacy, Pharmacodynamics and Pharmacokinetics of PXT3003 in Patients With Charcot-Marie-Tooth Disease Type 1A.

Study Type

Interventional

2. Study Status

Record Verification Date

October 2017

Overall Recruitment Status

Completed

Study Start Date

December 2010 (undefined)

Primary Completion Date

October 2011 (Actual)

Study Completion Date

December 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Pharnext SA

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The present trial is a randomized, placebo-controlled study evaluating 3 different doses of PXT3003 in patients with CMT1A disease.

Detailed Description

In addition to the safety and tolerability of the treatment, clinical, electrophysiological and biological endpoints (PMP22 mRNA, skin biopsy histology and plasma biomarkers) will be assessed. Standard laboratory tests and drug plasma concentrations will also be measured. Because of the slow progression of the disease and the nature of the observed symptoms, a minimum duration of 12 months of treatment is required in order to observe a potential improvement in any of the efficacy parameters.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Charcot-Marie-Tooth Disease, Hereditary Neuropathy With Liability to Pressure Palsies, Genetic Disorders

Keywords

PXT3003, Charcot-Marie-Tooth Disease, Hereditary Motor and Sensory Neuropathies

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

80 (Actual)

8. Arms, Groups, and Interventions

Arm Title

PXT3003 Low dose

Arm Type

Experimental

Arm Description

Oral Liquid formulation, 1/100, bid, 12 months

Arm Title

PXT3003 Intermediate dose

Arm Type

Experimental

Arm Description

Oral Liquid formulation, 1/50, bid, 12 months

Arm Title

PXT3003 High dose

Arm Type

Experimental

Arm Description

Oral Liquid formulation, 1/10, bid, 12 months

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Oral Liquid formulation, bid, 12 months

Intervention Type

Drug

Intervention Name(s)

PXT3003 Low dose

Other Intervention Name(s)

Pleocompound PXT3003

Intervention Description

Liquid,5 ml, twice a day, 12-month treatment

Intervention Type

Drug

Intervention Name(s)

PXT3003 Intermediate Dose

Other Intervention Name(s)

Pleocompound PXT3003

Intervention Description

Liquid,5 ml, twice a day, 12-month treatment

Intervention Type

Drug

Intervention Name(s)

PXT3003 High Dose

Other Intervention Name(s)

Pleocompound PXT3003

Intervention Description

Liquid,5 ml, twice a day, 12-month treatment

Intervention Type

Other

Intervention Name(s)

Placebo

Other Intervention Name(s)

Pleocompound PXT3003

Intervention Description

Liquid,5 ml, twice a day, 12-month treatment

Primary Outcome Measure Information:

Title

Safety and Tolerability of PXT3003

Description

Time Frame

Screening, randomization, 1-, 3-, 6-, 9-, 12-month treatment and 1-month follow-up

Secondary Outcome Measure Information:

Title

To Obtain Preliminary Data on the Efficacy of PXT3003 on Clinical Scores and Functional Tests

Description

Time Frame

Screening, randomization, 3-, 6-, 9- and 12-months treatment

Title

To Assess the Pharmacodynamic Effect of PXT3003 on PMP22 mRNA Levels and Intra-epidermal Axon Density in Cutaneous Biopsy

Description

A cutaneous biopsy (consisting in 2 small punch biopsies) will be performed to assess PMP22 mRNA expression and intra-epidermal axon density. Change from baseline after 12-month of treatment.

Time Frame

Randomization and 12-month treatment

Title

To Assess the Pharmacodynamic Effect of PXT3003 on Selected Neurophysiological Parameters

Description

Time Frame

Screening, randomization, 3-, 6-, 9- and 12-month treatment

Title

To Assess the Pharmacodynamic Effect of PXT3003 on a Series of Biochemical Biomarkers

Description

Dosages of biochemical biomarkers in plasma. Change from baseline after 3-month of treatment.

Time Frame

Randomization and 3-month treatment

Title

To Assess the Plasma Concentrations of PXT3003

Description

PXT3003 plasmatic concentrations after one administration (randomization) and after 1-,6-and 12-months of treatment.

Time Frame

Randomization, 1-, 6- and 12-month treatment

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: DNA proven CMT1A Muscle weakness in at least foot dorsiflexion (clinical assessment) Age between 18 and 65 years Male or non pregnant, non breastfeeding female CMT neuropathy score at screening ≤ 20 Agrees to perform electrorophysiological studies and two cutaneous biopsies for determination of PMP22 expression and histology Providing signed written informed consent to participate in the study and willing and able to comply with all study procedures and scheduled visits Exclusion Criteria: Patients with another neurological disease Patients using unauthorized concomitant treatments, ascorbic acid, opioids, levothyroxine and potentially neurotoxic drugs. Patients who can/agree to stop these medications 4 weeks before randomization can be included Patients who have participated in another trial of investigational drug within the past 30 days Concomitant major systemic disease Clinically significant history of unstable medical illness over the last 30 days (unstable angina…) History of significant hematologic, kidney, liver disease, or insulin-dependent diabetes Clinically significant abnormalities on the prestudy laboratory evaluation, physical evaluation, electrocardiogram (ECG) ASAT/ALAT levels above the upper limit of normal (ULN). However, patients with an isolated elevation of either ASAT or ALAT (<1.5 ULN) can be included at investigators" discretion if the remaining liver function tests are normal and if ASAT or ALAT value is stable at 2 distinct evaluations in the month prior to inclusion Serum creatinine levels above the upper limit of normal Limited mental capacity or psychiatric disease rendering the subject unable to provide written informed consent or comply with evaluation procedures History of recent alcohol or drug abuse or non-adherence with treatment or other experimental protocols Female of childbearing potential (apart of patient using adequate contraceptive measures), pregnant or breast feeding Suspected inability to complete the study follow-up (foreign workers, transient visitors, tourists or any others for whom follow-up evaluation is not assured) Limb surgery in the six months before randomization or planned before completion of the trial Known hypersensitivity to any of the individual components of PXT3003 Porphyria

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Shahram ATTARIAN, MD

Organizational Affiliation

Hôpital La Timone

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Viviane BERTRAND, PhD

Organizational Affiliation

Pharnext SA

Official's Role

Study Director

Facility Information:

Facility Name

Hôpital Roger Salengro

City

Lille

ZIP/Postal Code

59037

Country

France

Facility Name

CHU Dupuytren

City

Limoges

ZIP/Postal Code

87042

Country

France

Facility Name

CHU Lyon Sud

City

Lyon

ZIP/Postal Code

69495

Country

France

Facility Name

Hôpital La Timone

City

Marseille

ZIP/Postal Code

13385

Country

France

Facility Name

Hôtel Dieu

City

Nantes

ZIP/Postal Code

44093

Country

France

Facility Name

Groupe Hospitalier Pitié-Salpétrière

City

Paris

ZIP/Postal Code

75013

Country

France

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

25519680

Citation

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

Results Reference

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Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A

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