Study to investigate the fate of odiparcil since its administration up to the point is completely eliminated, its safety and efficacy in patients 16 years and above with mucopolysaccharidosis (MPS) type VI

• Register: EUCTR
• Last refreshed on: 11 May 2020
• Main ID: EUCTR2017-002158-35-PT
• Date of registration: 23/07/2018
• Prospective Registration: Yes
• Primary sponsor: Inventiva S.A.
• Public title: Study to investigate the fate of odiparcil since its administration up to the point is completely eliminated, its safety and efficacy in patients 16 years and above with mucopolysaccharidosis (MPS) type VI
• Scientific title: A phase IIa study to investigate safety, pharmacokinetics, and efficacy of odiparcil in patients 16 years and above with mucopolysaccharidosis (MPS) type VI.
• Date of first enrolment: 14/01/2019
• Target sample size: 20
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-002158-35
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: no Open: no Single blind: no Double blind: no Parallel group: no Cross over: no Other: yes Other trial design description: Preliminary safety assessment is open-label. Core study will be double blind and open label. If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 4
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

France, Germany, Portugal, United Kingdom

Contacts

• Name: Véronique BERGER
• Affiliation: Inventiva S.A

• Name: Véronique BERGER
• Affiliation: Inventiva S.A

Key inclusion & exclusion criteria

Inclusion criteria:
1. Male or female gender.
2. Age =16 years.
3. Diagnosis of MPS VI.
4. Urine GAG above upper limit of normal (ULN) based on historical data.
5. Willing and able to provide written, dated, signed informed consent, or in the case of subjects age < 18 years, provide written assent (if required) and written informed consent by a legally authorized representative after the nature of the study has been explained, and prior to any research-related procedures or study assessment.
6. Able to comply with all study procedures.
7. Women with childbearing potential must agree to use a highly effective method of birth control during the study and at least 10 weeks after last administration. The following can be considered to be examples of highly effective methods of contraception preferably with low user dependency:
- Combined (estrogen and progestogen containing hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal)
- Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
- Intrauterine device (IUD)
- Intrauterine hormone-releasing system (IUS)
- Bilateral tubal occlusion
- Vasectomised partner
- Sexual abstinence
If the hormonal contraception method is used, it must be supplemented with a barrier method (preferably male condom).

Inclusion criteria for Enzyme Replacement Therapy (ERT) receiving group
1. Patients with MPS Type VI receiving enzyme replacement therapy (Naglazyme) for at least 6 months on the licensed dosage or as per local guidelines.

Inclusion criteria for not ERT receiving group:
Patients with MPS Type VI not receiving enzyme replacement therapy for the following reasons:
1. Patients not treated with ERT (treatment naïve) or previously treated with ERT but having discontinued for more than 3 months before inclusion, either due to medical decision or to personal choice (e.g. for quality of life preferences). Under no circumstances patients will be taken of ERT for the only purpose of participating to the study. Reason for not receiving ERT should be specified by the investigator.
2. Patients allergic to ERT therapy.
3. Patients that have had a previous hematopoietic stem cell transplant (HSCT).
Are the trial subjects under 18? yes
Number of subjects for this age range: 8
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 12
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
Exclusion criteria for the entire cohort
1. Use of any investigational product or investigational medical device within 30 days prior to screening. This will include product bought over the counter specifically compounds like genistein and pentosane polysulphate which may not be considered as investigational products by patients and some health care professionals.
2. Concurrent disease or condition that would interfere with study participation or pose a safety concern. For example patient with: severe cardiac insufficiency as define NYHA class > II, severe respiratory insufficiency as reflected by by either FEV1 < 30% predicted (GOLD classification stage 4 - very severe) or ventilation-dependency more than 8 hours a day, renal insufficiency levels 4 or 5 reflected by an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 ( eGFR based on the abbreviated Modification of Diet in Renal Disease (MDRD) formula).
3. Subjects who had surgery within 3 months before study starts, or for whom surgery is planned during study period.
4. Patient with spinal cord compression requiring surgical intervention.
5. Subjects with the following liver test abnomalies: any ALT, AST > 3 x ULN or bilirubin >1.5 x ULN (except if Gilbert syndrome) at screening visit.
6. Evidence of an immunosuppressive state, including known HIV infection, agammaglubilinemias, T-Cell deficiencies.
7. Subjects with history of chronic infections, including but not limited to subjects with history of viral hepatitis C, or B, with recent history of serious or life-threatening infection or any current signs or symptoms that may indicate infection at visit V-1 of study as per investigators clinical judgement.
8. History of malignant cancer except of cervical carcinoma in situ, basal cell carcinoma, dermatological squamous cell carcinoma.
9. Subjects with significant haematologic abnormalities, such as hemoglobin <8 g/dL, or WBC<2000 /mm3 or absolute neutrophil count <1300 /mm3, or platelet <30.000 /mm3.
Subjects with other haematological abnormalities not corresponding to the above criteria should not be included in preliminary safety assessment.
10. International Normalized Ratio (INR), activated partial thromboplastin time (aPTT) or thrombin time (TT) values above the central laboratory reference range at screening considered as clinically significant by the investigator. For patients on anti-coagulants, they should be within their target effect on INR and be stable.
Subjects under anticoagulants should not be included in preliminary safety assessment.
11. Any history of bleeding diathesis.
12. Patient with coexistence of corneal pathologies other than corneal clouding (e.g. exposure keratopathy)
13. An unwillingness on the part of male patients to abstain from sexual intercourse with pregnant or lactating women; or an unwillingness to use highly effective form of birth control if engaging in sexual intercourse with a woman who could become pregnant from the time of the first dose of study medication until completion of follow-up procedures.
14. An unwillingness on the part of female patients to use highly effective form of birth control if engaging in sexual intercourse and to have a monthly pregnancy test during treatment and until completion of follow-up procedures.
15. Pregnant or lactating women.
16. Have a known hypersensitivity to any of the ingredients or excipients of the IMP including: Microcrystalline Cellulose, Povidone, Sodium starch glycol

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Mucopolysaccharidosis (MPS) type VI.
MedDRA version: 20.1 Level: PT Classification code 10056892 Term: Mucopolysaccharidosis VI System Organ Class: 10010331 - Congenital, familial and genetic disorders

Therapeutic area: Body processes [G] - Genetic Phenomena [G05]

Intervention(s)

Product Name: Odiparcil
Product Code: IVA 336
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Odiparcil
CAS Number: 137215-12-4
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 250-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: 1. Preliminary safety assessment
V-1, V0, Va (D1), Vb (D7), Vc (D14)
2. Core study
a. Safety:
a1. V-1, V0, V1, V2, V4, V5, V6, V7 and V8
a2.1 V-1, V0, V2, V4, V7 and V8
a2.2 V0 and V7

b. Efficacy outcomes:
b1. V-1, V0, V2, V4, V7 and V8
b2. V0, V7
b3. V-1, V0 and V7
b4. V0 and V7
b5. V0 and V7
b6. V0 and V7
b7. V-1, V0, V4 and V7

c. Pharmacokinetic endpoints:
c1. V2 (0, 0.5, 1, 2, 3, 4, 8, 12 h post dose)
c2. V4 and V7
c3. V2

d. Pharmacodynamic endpoints
d1. V-1, V0, V2, V4, V7 and V8
d2. V6 and V7
d3. V-1, V0, V2, V4, V7 and V8
d4. V-1, V0, V1, V2, V4, V7 and V8

Primary end point(s): 1. Preliminary safety assessment
The goal of preliminary safety assessment is to focus on clinical tolerance and lab safety such as coagulation, liver enzymes and cristalluria.
2. Core study
a. Safety outcomes:
a1. Safety outcomes will be evaluated on the following safety variables: incidence of AEs/SAEs, patient withdrawals from study due to AEs/SAEs, change from baseline in laboratory safety test, change from baseline in vital signs parameters.
a2.1 Twelve-lead-ECG
a2.2 Bone biomarkers (osteocalcin, beta-crosslaps, bone-specific alkaline phosphatase (BSAP), N-terminal propeptide of type 1 collagen (P1NP)).

b. Efficacy outcomes:
b1. Mobility: 6-minute walk test, 9-hole PEG test, range of motion of the shoulder
b2. Pain assessment: Brief Pain Inventory BPI
b3. Respiratory function: FEV1, FVC, MVV
b4. Cardiac and vascular tests: echochardiogram and carotid intima media thickness
b5. Audiology assessments: pure tone audiometry and whisper voice test
b6. Ophthalmology assessments: corneal opacification, level of retinopathy and optic nerve involvement, intra-ocular pressure, and visual acuity
b7. Questionnaires: EQ-5D-5L, Zarit caregiver burden, Fatigue Severity Scale

c. Pharmacokinetic endpoints:
c1. Odiparcil concentration in plasma and its metabolites.
c2. Pre-dose samples will be collected to measure the odiparcil concentration remaining
c3. Metabolite identification
?
d. Pharmacodynamic endpoints:
d1. GAG concentrations in urine and leukocytes isolated from peripheral blood
d2. GAG content in skin biopsies
d3. Anti-thrombin IIa activity in plasma
d4. Thrombin generation assay (TGA)

Secondary Objective: The secondary objective of this study is to characterize the dose response, PK and PD of odiparcil.

Main Objective: 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.

Secondary Outcome(s)

Secondary end point(s): Not applicable

Timepoint(s) of evaluation of this end point: Not applicable

Secondary ID(s)

2017-002158-35-GB

IVA_01_ODI_HMPS_17_002

Source(s) of Monetary Support

Inventiva S.A.

Ethics review

Status: Approved
Approval date: 14/01/2019
Contact: