Venglustat in Combination with Cerezyme in Adult Patients with Gaucher Disease Type 3 with venglustat monotherapy extension

• Register: EUCTR
• Last refreshed on: 15 January 2024
• Main ID: EUCTR2014-002550-39-DE
• Date of registration: 25/04/2016
• Prospective Registration: Yes
• Primary sponsor: Genzyme Corporation
• Public title: Venglustat in Combination with Cerezyme in Adult Patients with Gaucher Disease Type 3 with venglustat monotherapy extension
• Scientific title: 4-part, open-label, multicenter, multinational study of the safety, tolerability, pharmacokinetics, pharmacodynamic, and exploratory efficacy of venglustat in combination with Cerezyme in adult patients with Gaucher disease Type 3 with venglustat monotherapy extension - LEAP
• Date of first enrolment: 20/10/2016
• Target sample size: 18
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-002550-39
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Germany, Japan, United Kingdom, United States

Contacts

• Affiliation: Sanofi-Aventis Deutschland GmbH

• Affiliation: Sanofi-Aventis Deutschland GmbH

Key inclusion & exclusion criteria

Inclusion criteria:
-The patient must provide written informed consent prior to any studyrelated procedures being performed.
-Has a clinical diagnosis of Gaucher Disease Type 1 (GD1) or Gaucher Disease Type 3 GD3 and documented deficiency of acid beta-glucosidase activity.
-The patient has received treatment with enzyme repalcement therapy for at least 3 years. For at least 6 months prior to enrollment, the Patient has received Cerezyme at a stable monthly dose and must continue at the same monthly dose during the study.
-The patient has reached Gaucher disease therapeutic goals defined as all of the following to be eligible for this study:
-Hemoglobin level of =11.0 g/dL for females and =12.0 g/dL for males.
-Platelet count =100 000/mm^3.
-Spleen volume <10 multiples of normal (MN)MN), or total splenectomy (provided the splenectomy occurred >3 years prior to randomization).
-Liver volume <1.5 MN.
-No bone crisis and free of symptomatic bone disease such as bone pain attributable to osteonecrosis and/or pathological fractures within 3 months prior to screening.
- The patient has maintained GD therapeutic goals defined as all of the following to be eligible for entering Part 4 of this study:
- Hemoglobin level of =11.0 g/dL for females and =12.0 g/dL for males
- Platelet count =100,000/mm3
- Spleen volume <10 multiples of normal (MN), or total splenectomy
- Liver volume <1.5 MN
- No bone crisis and free of symptomatic bone disease such as bone pain attributable to osteonecrosis and/or pathological fractures within 3 months prior to entering Part 4
- The patient, if female and of childbearing potential must have a negative pregnancy test (urine beta-human chorionic gonadotropin [ß-hCG]) at baseline.
-If the patient has a history of seizures, except for myoclonic seizures, they are well controlled under appropriate medication not identified as a strong or moderate inducer or inhibitor of CYP3A.
Adult GD1 cohort only:
-GD1 patient is =18 and =40 years of age.
Adult GD3 cohort only:
-GD3 patient is =18 years of age.
-The patient is willing to abstain from consumption of grapefruit, grapefruit juice, or grapefruit containing products for 72 hours prior to administration of the first dose of GZ/SAR402671 and for the duration of the 156 week treatment period.
-Oculomotor apraxia characterized by a horizontal saccade abnormality.
-Cerezyme treatment every 2 weeks (minimum dose 30 U/kg every 2 weeks).
-Females patients of childbearing potential and males patients must be willing to practice true abstinence in line with their preferred and usual lifestyle, or use 2 acceptable effective methods of contraception for the duration of the study and for at least 6 weeks for females and 90 days for males following their last dose of study drug.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 18
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
-Substrate reduction therapy or chaperone therapy for GD within 6 months prior to enrollment.
-The patient has had a partial or total splenectomy within 3 years Prior to randomization.
-The patient is blood transfusion-dependent.
-Prior esophageal varices or liver infarction or current liver enzymes (alanine aminotransferase [ALT]/aspartate aminotransferase [AST]) or total bilirubin >2 times the upper limit of normal, unless the patient has a diagnosis of Gilbert Syndrome.
-Clinically significant congenital cardiac defect, coronary artery disease, valve disease or left sided heart failure; clinically significant arrhythmias or conduction defect.
-The patient has any clinically significant disease, other than GD, including cardiovascular, renal, hepatic, gastrointestinal, pulmonary, neurologic, endocrine, metabolic (eg, hypokalemia, hypomagnesemia), or psychiatric disease, other medical conditions, or serious intercurrent illnesses that may preclude participation.
-The patient has received an investigational product within 30 days Prior to enrollment.
-The patient has a history of cancer, with the exception of basal cell carcinoma.
-The patient has myoclonic seizures.
-The patient is pregnant or lactating.
-The patient has, according to World Health Organization (WHO) Grading, a cortical cataract >onequarter of the lens circumference (Grade cortical cataract-2) or a posterior subcapsular cataract >2 mm (Grade posterior subcapsular cataract-2). Patients with nuclear cataracts will not be excluded.
-The patient requires use of invasive ventilatory support.
-The patient requires use of noninvasive ventilator support while awake for longer than 12 hours daily.
-The patient is unable to receive treatment with Cerezyme due to a known hypersensitivity or is unwilling to receive Cerezyme Treatment every 2 weeks.
-The patient is currently receiving potentially cataractogenic medications as listed in Section 8.8.2.
-The patient has received strong or moderate inducers or inhibitors of Cytochrome p450 Isoform 3A within 30 days or 5 half-lives from screening, whichever is longer, prior to enrolment in Part 2. This also includes the consumption of grapefruit, grapefruit juice, or Grapefruit containing products within 72 hours of starting GZ/SAR402671 administration in Parts 2 and 3.
-The patient is scheduled for in-patient hospitalization including elective surgery, during the study.
-Has had a major organ transplant (eg, bone marrow or liver).
-The patient, in the opinion of the Investigator, is unable to adhere to the requirements of the study or unable to undergo study assessments (e.g., contraindications for magnetic resonance imaging).


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

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Gaucher disease
MedDRA version: 24.1 Level: PT Classification code 10075699 Term: Gaucher's disease type III System Organ Class: 10010331 - Congenital, familial and genetic disorders
MedDRA version: 24.1 Level: PT Classification code 10075697 Term: Gaucher's disease type I System Organ Class: 10010331 - Congenital, familial and genetic disorders

Intervention(s)

Product Name: Venglustat
Product Code: GZ402671
Pharmaceutical Form: Capsule
CAS Number: 1401090-53-6
Current Sponsor code: SAR402671A / GZ402671
Other descriptive name: Genz-682452-AU
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 15-

Product Name: Venglustat
Product Code: GZ402671
Pharmaceutical Form: Tablet
CAS Number: 1401090-53-6
Current Sponsor code: SAR402671A / GZ402671
Other descriptive name: Genz-682452-AU
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 2-

Primary Outcome(s)

Main Objective: Part 1:
-Evaluate central nervous system (CNS) biomarkers in adult Gaucher disease (GD) type 3 that distinguish GD3 from adult Gaucher disease type 1 (GD1) patients.
-Screen adult GD3 patients who qualify for treatment with
venglustat in Parts 2,3 and Part 4

Part 2 and 3: Combination treatment phases
-Evaluate short-term (Part 2) and long-term (Part 3) safety and
tolerability of GZ/SAR402671 in combination with Cerezyme in adult GD3 patients.
-Evaluate the change in cerebrospinal fluid (CSF) CNS biomarkers (glucosylceramide [GL-1] and lyso-glucosylceramide [lyso-GL1]) from adult GD3 patients receiving GZ/SAR402671 in combination with Cerezyme (Part 2 only).
Part 4: Extended treatment phase with monotherapy
- Evaluate safety and tolerability of venglustat monotherapy in adult
GD3 patients who have remained systemically stable on venglustat in
combination with Cerezyme

Primary end point(s): 1) Number of patients with adverse events
2) Assessment of pharmacodynamic (PD) parameter: Lysoglucosylceramide
(lyso-GL1) and glucosylceramide (GL-1) in
cerebrospinal fluid (CSF) ; Change from baseline in CSF lyso-GL1 and GL1

Timepoint(s) of evaluation of this end point: 1 - From screening up to end of study, up to approximately 8.7 years

2 - From screening through Week 52

Secondary Objective: Parts 2 and 3: Combination treatment phases
-Evaluate the pharmacokinetics of GZ/SAR402671 in adult GD3 patients (Part2).
-Explore the efficacy of GZ/SAR402671 in combination with Cerezyme in infiltrative lung disease (IDL) in adult GD3 patients (Part 2 and 3).
-Explore the efficacy of GZ/SAR402671 in combination with Cerezyme in systemic disease in adult GD3 patients (Part 2 and 3).
-Explore the efficacy of GZ/SAR402671 in combination with Cerezyme in neurological function and on exploratory CSF biomarkers in adult GD3 patients (Part 2 and 3).
- Explore plasma biomarkers (lyso-GL-1 and GL-1) in adult GD3 patients
- Explore CSF biomarkers other than lyso-GL-1 and GL-1 in adult GD3
patients (Part 2 only)
Part 4: Extended treatment phase with monotherapy
- Explore the efficacy of venglustat in systemic disease in adult GD3
patients
- Explore the efficacy of venglustat on neurological function in adult GD3
patients
- Explore plasma biomarkers (lyso-GL-1 and GL-1) in adult GD3 patients

Secondary Outcome(s)

Secondary end point(s): 1 - Assessment of pharmacodynamic (PD) parameter: Lysoglucosylceramide
(lyso-GL1) and glucosylceramide (GL-1) in plasma ;
Change from baseline in plasma lyso-GL1 and GL1
2 - Assessment of plasma pharmacokinetic parameter: Cmax ; Plasma
maximum concentration (Cmax)
3 - Assessment of plasma pharmacokinetic parameter: Tmax ; Plasma
time at Cmax (Tmax)
4 - Assessment of plasma pharmacokinetic parameter: AUC ;Plasma area
under the curve (AUC)
5 - Assessment of plasma pharmacokinetic parameter: Ctrough ; Plasma
trough concentration (Ctrough)
6 - Assessment of CSF pharmacokinetic parameter: Cmax ; CSF maximum
concentration (Cmax)
7 - Assessment of pharmacokinetic parameter: CSF time at Cmax (Tmax)
8 - Assessment of pharmacokinetic parameter: CSF area under the curve
(AUC)

Timepoint(s) of evaluation of this end point: 1 - From screening up to end of study, up to approximately 8.7 years
2, 3, 4, 6, 7, 8 - Day 1, Week 4, Week 26, and Week 52
5 - Weeks 12 and 39 (Part 2), and on Weeks 78, 104, and 156 (for Part
3)

Secondary ID(s)

PDY13949

Source(s) of Monetary Support

Genzyme Corporation

Ethics review

Status: Approved
Approval date: 20/10/2016
Contact: