Charcot-Marie-Tooth Disease, Genetic Disorders, Hereditary Neuropathy With Liability to Pressure Palsies
Conditions
Keywords
PXT3003, Charcot-Marie-Tooth Disease, Hereditary Motor and Sensory Neuropathies
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.
Interventions
DRUGPXT3003 Low dose
Liquid,5 ml, twice a day, 12-month treatment
DRUGPXT3003 Intermediate Dose
Liquid,5 ml, twice a day, 12-month treatment
DRUGPXT3003 High Dose
Liquid,5 ml, twice a day, 12-month treatment
OTHERPlacebo
Liquid,5 ml, twice a day, 12-month treatment
Sponsors
Pharnext S.C.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of PXT3003 | Screening, randomization, 1-, 3-, 6-, 9-, 12-month treatment and 1-month follow-up | 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
| Measure | Time frame | Description |
|---|---|---|
| To Obtain Preliminary Data on the Efficacy of PXT3003 on Clinical Scores and Functional Tests | Screening, randomization, 3-, 6-, 9- and 12-months treatment | 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 | Randomization and 12-month treatment | 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 | Screening, randomization, 3-, 6-, 9- and 12-month treatment | 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 | Randomization and 3-month treatment | Dosages of biochemical biomarkers in plasma. Change from baseline after 3-month of treatment. |
| To Assess the Plasma Concentrations of PXT3003 | Randomization, 1-, 6- and 12-month treatment | PXT3003 plasmatic concentrations after one administration (randomization) and after 1-,6-and 12-months of treatment. |
Countries
France
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PXT3003 Low Dose Oral Liquid formulation, 1/100, bid, 12 months
PXT3003: Liquid,5 ml, twice a day, 12-month treatment | 21 |
| PXT3003 Intermediate Dose Oral Liquid formulation, 1/50, bid, 12 months
PXT3003: Liquid,5 ml, twice a day, 12-month treatment | 21 |
| PXT3003 High Dose Oral Liquid formulation, 1/10, bid, 12 months
PXT3003: Liquid,5 ml, twice a day, 12-month treatment | 19 |
| Placebo Oral Liquid formulation, bid, 12 months
Placebo: Liquid,5 ml, twice a day, 12-month treatment | 19 |
| Total | 80 |
Baseline characteristics
| Characteristic | PXT3003 Intermediate Dose | PXT3003 High Dose | PXT3003 Low Dose | Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 21 Participants | 19 Participants | 21 Participants | 19 Participants | 80 Participants |
| Age, Continuous | 44.3 years | 44.6 years | 47.9 years | 43.2 years | 45.1 years |
| Region of Enrollment France | 21 participants | 19 participants | 21 participants | 19 participants | 80 participants |
| Sex: Female, Male Female | 13 Participants | 10 Participants | 14 Participants | 11 Participants | 48 Participants |
| Sex: Female, Male Male | 8 Participants | 9 Participants | 7 Participants | 8 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 12 / 21 | 10 / 21 | 13 / 19 | 11 / 19 |
| serious Total, serious adverse events | 2 / 21 | 0 / 21 | 0 / 19 | 0 / 19 |
Outcome results
Primary
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.
Time frame: Screening, randomization, 1-, 3-, 6-, 9-, 12-month treatment and 1-month follow-up
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PXT3003 Low Dose | Safety and Tolerability of PXT3003 | 21 Participants |
| PXT3003 Intermediate Dose | Safety and Tolerability of PXT3003 | 21 Participants |
| PXT3003 High Dose | Safety and Tolerability of PXT3003 | 19 Participants |
| Placebo | Safety and Tolerability of PXT3003 | 19 Participants |
Secondary
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.
Time frame: Randomization and 3-month treatment
Secondary
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.
Time frame: Randomization and 12-month treatment
Secondary
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.
Time frame: Screening, randomization, 3-, 6-, 9- and 12-month treatment
Secondary
To Assess the Plasma Concentrations of PXT3003
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
Secondary
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.
Time frame: Screening, randomization, 3-, 6-, 9- and 12-months treatment