Mucopolysaccharidoses (MPS) are a group of rare inherited disorders characterized by a deficiency of lysosomal enzymes responsible for the normal degradation of glycosaminoglycans (GAGs). Medical need for treatment of MPS is still very high due to the poor penetration of the recombinant enzymes into the blood brain barrier as well as the ocular barriers and into tissues that are poorly vascularized, such as cartilages and bones. Odiparcil is an orally active compound that allows the synthesis of soluble glycosaminoglycans (GAGs), mainly chondroitin sulfate (CS) and dermatane sulfate (DS). The neosynthesized solubles GAGs are then excreted in urine. By diverting endogenous GAG synthesis to the synthesis of soluble odiparcil linked GAGs, odiparcil should decrease the intracellular pool of GAGs and consequently decrease the lysosomal GAG accumulation. The primary objective of the study is to assess the safety and efficacy of two doses of odiparcil in MPS VI patients and to provide evidence to enable the selection of the relevant dose of odiparcil for phase III study. The secondary objective of this study is to characterize the dose response, PK and PD of odiparcil.
Study design: This phase IIa study consists of 2 parts performed sequentially: a preliminary safety assessment followed by the core study with a double-blind, randomized, dose-ranged cohort of patients receiving Enzyme Replacement Therapy (ERT) and an open-label cohort of patients not receiving ERT. Preliminary safety assessment (N=2): open-label, escalating dose (2 doses) study. If acceptable safety profile is achieved, patients will be then included in the open-label arm of the core study. Core study Core study will be conducted on 2 populations in parallel: * A first cohort (N=18): MPS VI patients receiving ERT assigned in 3 arms: * Placebo (N=6) * Odiparcil 500 mg per day (250 mg BID) (N=6) * Odiparcil 1000 mg per day (500 mg BID) (N=6). * A second cohort (N=6): MPS VI patient not receiving ERT (odiparcil 1000 mg per day (500 mg BID)). Study duration: The overall study duration will be 20 months, including the 10-month enrolment period. For each patient, the study duration will be: * Preliminary safety assessment: 6 weeks including a 4-week run-in period followed by 2-week treatment period. Then, patients will go on treatment period in core study. * Core study: 34 weeks including a 4-week run-in period followed by 26-week treatment period and 4-week of follow-up.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
20
Hôpital Femme-Mère-Enfant
Bron, France
Villa Metabolica
Mainz, Germany
Centro Hospitalar S. João
Porto, Portugal
Royal Free Hospital
London, United Kingdom
Number of patients with modified clinical signs
Changes in physical examination and vital signs
Time frame: 26 weeks
Number of patients with modified biological values
Change from baseline in laboratory safety tests (coagulation, liver enzymes and crystalluria) 12-lead-ECG and bone biomarkers.
Time frame: 26 weeks
Incidence of AEs/SAEs
Incidence of AEs/SAEs, patient withdrawals from study due to AEs/SAEs,
Time frame: 26 weeks
12-lead ECG
Change from Baseline in ECG
Time frame: 26 weeks
Mobility: 6-minute walk test
Change from baseline in 6-minute walk test
Time frame: 26 weeks
Mobility: 9-hole PEG test
Change from baseline in 9-hole PEG test
Time frame: 26 weeks
Mobility: range of motion of the shoulder
Change from baseline in range of motion of the shoulder
Time frame: 26 weeks
Pain assessment
Change from Baseline in Brief Pain Inventory (BPI)
Time frame: 26 weeks
Respiratory function
Change from Baseline in FEV1
Time frame: 26 weeks
Respiratory function
Change from Baseline in FVC
Time frame: 26 weeks
Respiratory function
Change from Baseline in MVV
Time frame: 26 weeks
Cardiac and vascular function
Change from Baseline in echocardiogram
Time frame: 26 weeks
Cardiac and vascular function
Change from Baseline in carotid intima media thickness Odiparcil concentration remaining in patient plasma 12 hours following the last intake of investigational product at visits V4 and V7. An identification of odiparcil metabolites in plasma at visit V2.
Time frame: 26 weeks
Audiology assessments
Change from Baseline in pure tone audiometry
Time frame: 26 weeks
Audiology assessments
Change from Baseline in whisper voice test
Time frame: 26 weeks
Ophthalmology assessments
Change from Baseline in corneal opacification
Time frame: 26 weeks
Ophthalmology assessments
Change from Baseline in level of retinopathy
Time frame: 26 weeks
Ophthalmology assessments
Change from Baseline in optic nerve involvement,
Time frame: 26 weeks
Ophthalmology assessments
Change from Baseline in intra-ocular pressure
Time frame: 26 weeks
Ophthalmology assessments
Change from Baseline in visual acuity
Time frame: 26 weeks
Quality of life questionnaires
Change from Baseline in EQ-5D-5L questionnaires. 5 dimensions scored on a 5-point scale will be assessed: mobility, self-care, usual activities, pain/discomfort, anxiety/depression
Time frame: 26 weeks
Quality of life questionnaires
Change from Baseline in Zarit caregiver burden questionnaires. Scale in 22 items scored on a 5-point scale with 0 = never and 5 = nearly always
Time frame: 26 weeks
Quality of life questionnaires
Change from Baseline in Fatigue Severity Scale questionnaires. 9 questions scored on a 7-point scale with 1 = strongly disagree and 7= strongly agree
Time frame: 26 weeks
Pharmacokinetics: odiparcil concentration in plasma
Odiparcil concentration in plasma at visit V2 (up to 12 hours post dose).
Time frame: 12 hours
¨Pharmacodynamics: GAG concentrations
GAG concentration in leukocytes isolated from peripheral
Time frame: 26 weeks
¨Pharmacodynamics: GAG concentrations
GAG concentrations in urine
Time frame: 26 weeks
Pharmacodynamics: GAG concentrations
GAG concentrations in skin
Time frame: 26 weeks
¨Pharmacodynamics: anti-thrombin activity IIa
Change from Baseline in anti-thrombin activity IIa in plasma
Time frame: 26 weeks
¨Pharmacodynamics: Thrombin Generation Assay (TGA)
Change from Baseline in TGA in plasma
Time frame: 26 weeks
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