A Study in MPS VI to Assess Safety and Efficacy of Odiparcil
- Registration Number
- NCT03370653
- Lead Sponsor
- Inventiva Pharma
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 20
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Double-blind - odiparcil 1000 mg per day Odiparcil 2 tablets of odiparcil 250 mg per os, twice daily (BID) Double-blind - odiparcil 500 mg per day Placebo 1 tablet of placebo and 1 tablet of odiparcil 250 mg per os, twice daily (BID) Double-blind - placebo Placebo 2 tablets of placebo per os, twice daily (BID) Double-blind - odiparcil 500 mg per day Odiparcil 1 tablet of placebo and 1 tablet of odiparcil 250 mg per os, twice daily (BID) Open Label - odiparcil 1000 mg per day Odiparcil 2 tablets of odiparcil 250 mg per os, twice daily (BID)
- Primary Outcome Measures
Name Time Method Incidence of AEs/SAEs 26 weeks Incidence of AEs/SAEs, patient withdrawals from study due to AEs/SAEs,
12-lead ECG 26 weeks Change from Baseline in ECG
Number of patients with modified clinical signs 26 weeks Changes in physical examination and vital signs
Number of patients with modified biological values 26 weeks Change from baseline in laboratory safety tests (coagulation, liver enzymes and crystalluria) 12-lead-ECG and bone biomarkers.
- Secondary Outcome Measures
Name Time Method Quality of life questionnaires 26 weeks Change from Baseline in Fatigue Severity Scale questionnaires. 9 questions scored on a 7-point scale with 1 = strongly disagree and 7= strongly agree
Mobility: 6-minute walk test 26 weeks Change from baseline in 6-minute walk test
Mobility: range of motion of the shoulder 26 weeks Change from baseline in range of motion of the shoulder
Audiology assessments 26 weeks Change from Baseline in whisper voice test
Ophthalmology assessments 26 weeks Change from Baseline in visual acuity
¨Pharmacodynamics: GAG concentrations 26 weeks GAG concentrations in urine
Pharmacodynamics: GAG concentrations 26 weeks GAG concentrations in skin
¨Pharmacodynamics: anti-thrombin activity IIa 26 weeks Change from Baseline in anti-thrombin activity IIa in plasma
Mobility: 9-hole PEG test 26 weeks Change from baseline in 9-hole PEG test
Pain assessment 26 weeks Change from Baseline in Brief Pain Inventory (BPI)
Respiratory function 26 weeks Change from Baseline in MVV
Pharmacokinetics: odiparcil concentration in plasma 12 hours Odiparcil concentration in plasma at visit V2 (up to 12 hours post dose).
¨Pharmacodynamics: Thrombin Generation Assay (TGA) 26 weeks Change from Baseline in TGA in plasma
Cardiac and vascular function 26 weeks 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.
Trial Locations
- Locations (4)
Hôpital Femme-Mère-Enfant
🇫🇷Bron, France
Royal Free Hospital
🇬🇧London, United Kingdom
Centro Hospitalar S. João
🇵🇹Porto, Portugal
Villa Metabolica
🇩🇪Mainz, Germany