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
Sponsored by
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
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
Experimental
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
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
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.
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
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.
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
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.
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
No
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
No
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
derived
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Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
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