Venglustat in Combination With Cerezyme in Adult Patients With Gaucher Disease Type 3 With Venglustat Monotherapy Extension (LEAP)
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ClinicalTrials.gov Identifier: NCT02843035 |
Recruitment Status :
Active, not recruiting
First Posted : July 25, 2016
Last Update Posted : May 12, 2022
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Part 1: Biomarker evaluation/screening phase
Primary Objectives:
- Evaluate cerebrospinal fluid (CSF) biomarkers in adult Gaucher disease Type 3 (GD3) patients that distinguish GD3 from adult Gaucher disease Type 1 (GD1) patients
- Screen adult GD3 patients who qualify for treatment with venglustat in Parts 2, Part 3, and Part 4
Parts 2 and 3: Combination treatment phases
Primary objectives:
- Evaluate short-term (Part 2) and long-term (Part 3) safety and tolerability of venglustat in combination with Cerezyme in adult GD3 patients
- Evaluate the change in CSF central nervous system (CNS) biomarkers (glucosylceramide [GL-1] and lyso-glucosylceramide [lyso-GL-1]) from adult GD3 patients receiving venglustat in combination with Cerezyme (Part 2 only)
Part 4: Extended treatment phase with monotherapy
Primary objectives:
• Evaluate safety and tolerability of venglustat monotherapy in adult GD3 patients who have remained systemically stable on venglustat in combination with Cerezyme
Parts 2 and 3: Combination treatment phases
Secondary Objectives:
- Evaluate the pharmacokinetics (PK) of venglustat in adult GD3 patients
- Explore the efficacy of venglustat in combination with Cerezyme in infiltrative lung disease (ILD) in adult GD3 patients (Part 2 only)
- Explore the efficacy of venglustat in combination with Cerezyme in systemic disease in adult GD3 patients
- Explore the efficacy of venglustat in combination with Cerezyme on neurological function in adult GD3 patients
- 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
Secondary objectives:
- 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
Condition or disease | Intervention/treatment | Phase |
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Gaucher Disease Type 1 Gaucher Disease Type 3 | Drug: venglustat (GZ402671) Drug: imiglucerase | Phase 2 |
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 13 participants |
Allocation: | N/A |
Intervention Model: | Single Group Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | A 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 |
Actual Study Start Date : | January 4, 2017 |
Estimated Primary Completion Date : | September 25, 2025 |
Estimated Study Completion Date : | September 25, 2025 |

Arm | Intervention/treatment |
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Experimental: Open label (OL) venglustat
Administered once a day orally for up to approximately 8.7 years. Patients will continue their usual dose of Cerezyme during Part 1, Part 2 and Part 3. There is no administration of Cerezyme in Part 4 unless administrated as rescue treatment.
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Drug: venglustat (GZ402671)
Pharmaceutical form: capsule Route of administration: oral Drug: imiglucerase Pharmaceutical form: sterile lyophilized product Route of administration: intravenous Other Name: Cerezyme |
- Number of patients with Treatment Emergent Adverse Events (TEAEs) [ Time Frame: From screening up to end of study, up to approximately 8.7 years ]
- Assessment of pharmacodynamic (PD) parameter: Lyso-glucosylceramide (lyso-GL1) and glucosylceramide (GL-1) in cerebrospinal fluid (CSF) [ Time Frame: From screening through Week 52 ]
- Assessment of pharmacodynamic (PD) parameter: Lyso-glucosylceramide (lyso-GL1) and glucosylceramide (GL-1) in plasma [ Time Frame: From screening up to end of study, up to approximately 8.7 years ]Change from baseline in plasma lyso-GL1 and GL1
- Assessment of plasma pharmacokinetic parameter: Cmax [ Time Frame: Day 1, Week 4, Week 26, and Week 52 ]Plasma maximum concentration (Cmax)
- Assessment of plasma pharmacokinetic parameter: Tmax [ Time Frame: Day 1, Week 4, Week 26, and Week 52 ]Plasma time at Cmax (Tmax)
- Assessment of plasma pharmacokinetic parameter: AUC [ Time Frame: Day 1, Week 4, Week 26, and Week 52 ]Plasma area under the curve (AUC)
- Assessment of plasma pharmacokinetic parameter: Ctrough [ Time Frame: Weeks 12 and 39 (Part 2), and on Weeks 78, 104, and 156 (for Part 3) ]Plasma trough concentration (Ctrough)
- Assessment of CSF pharmacokinetic parameter: Cmax [ Time Frame: Day 1, Week 4, Week 26, and Week 52 ]CSF maximum concentration (Cmax)
- Assessment of pharmacokinetic parameter: CSF time at Cmax (Tmax) [ Time Frame: Day 1, Week 4, Week 26, and Week 52 ]
- Assessment of pharmacokinetic parameter: CSF area under the curve (AUC) [ Time Frame: Day 1, Week 4, Week 26, and Week 52 ]

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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
GD3 and GD1 patients must meet the following criteria to be eligible for this study:
- GD1 participant is ≥18 and ≤40 years of age.
- GD3 participant is ≥18 years of age.
- Participant must provide written informed consent prior to any study-related procedures being performed.
- Participant has a clinical diagnosis of Gaucher disease Type 1 (GD1) or Gaucher disease Type 3 (GD3) and documented deficiency of acid beta-glucosidase activity confirming this diagnosis.
- Participant has received ERT (Cerezyme or other ERT; as deemed appropriate by local regulations) for at least 3 years prior to enrollment, on a stable dose for at least 6 months and is within the therapeutic goals defined below, and is deemed clinically stable for at least 1 year by the Investigator.
- Participant has reached Gaucher disease therapeutic goals defined as all of the following:
- 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 (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.
- Participant, if female and of childbearing potential, must have a negative pregnancy test [urine beta-human chorionic gonadotropin (β-hCG)] at baseline.
- If participant 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 cytochrome P450 (CYP) 3A.
- Participant 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 venglustat and for the duration of the treatment period.
- Oculomotor apraxia characterized by a horizontal saccade abnormality.
- Female participants of childbearing potential and male 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 venglustat.
Exclusion Criteria:
Participants are excluded from the study if any of the following criteria apply:
- Substrate reduction therapy or chaperone therapy for GD within 6 months prior to enrollment.
- Participant has had a partial or total splenectomy within 3 years prior to randomization.
- Participant 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.
- Participant has any clinically significant disease, other than GD, including cardiovascular (congenital cardiac defect, coronary artery disease, valve disease or left sided heart failure; clinically significant arrhythmias or conduction defect), hepatic, gastrointestinal, pulmonary, neurologic, endocrine, metabolic (eg, hypokalemia, hypomagnesemia) or psychiatric disease, other medical conditions, or serious intercurrent illnesses that may preclude participation.
- Participant has renal insufficiency, as defined by an estimated glomerular filtration rate <30 mL/min/1.73m2 at the screening visit.
- Participant has received an investigational product within 30 days prior to enrollment.
- Participant has a history of cancer, with the exception of basal cell carcinoma.
- Participant has myoclonic seizures.
- Participant is pregnant or lactating.
- Participant has, according to World Health Organization (WHO) Grading, a cortical cataract > one-quarter 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.
- Participant requires use of invasive ventilatory support.
- Participant requires use of noninvasive ventilator support while awake for longer than 12 hours daily.
- Participant is unable to receive treatment with Cerezyme due to a known hypersensitivity or is unwilling to receive Cerezyme treatment to ensure maintenance of Gaucher treatment goals.
- Participant is currently receiving potentially cataractogenic medications (corticosteroids, psoralens used in dermatology with ultraviolet light therapy [PUVA], typical antipsychotics, and glaucoma medications) or any medication that may worsen the vision of a patient with cataract (eg, alphaadrenergic glaucoma medications).
- Participant has received strong or moderate inducers or inhibitors of CYP3A within 15 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 venglustat administration in Parts 2 and 3.
- Participant is scheduled for in-patient hospitalization including elective surgery, during the study.
- Participant has had a major organ transplant (e.g., bone marrow or liver).
- Participant, 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).

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02843035
United States, Connecticut | |
Investigational Site Number :840002 | |
New Haven, Connecticut, United States, 06520 | |
United States, Texas | |
Investigational Site Number :840001 | |
Dallas, Texas, United States, 75226 | |
United States, Virginia | |
Investigational Site Number :840003 | |
Fairfax, Virginia, United States, 22030 | |
Germany | |
Investigational Site Number :276001 | |
Mainz, Germany, 55131 | |
Japan | |
Investigational Site Number :392001 | |
Minato-ku, Tokyo, Japan, 105-8471 | |
United Kingdom | |
Investigational Site Number :826003 | |
Cambridge, Cambridgeshire, United Kingdom, CB2 OQQ | |
Investigational Site Number :826002 | |
Salford, Manchester, United Kingdom, M6 8HD |
Study Director: | Clinical Sciences & Operations | Sanofi |
Responsible Party: | Genzyme, a Sanofi Company |
ClinicalTrials.gov Identifier: | NCT02843035 |
Other Study ID Numbers: |
PDY13949 2014-002550-39 ( EudraCT Number ) U1111-1156-4278 ( Registry Identifier: ICTRP ) |
First Posted: | July 25, 2016 Key Record Dates |
Last Update Posted: | May 12, 2022 |
Last Verified: | May 1, 2022 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | Yes |
Plan Description: | Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
Gaucher Disease Sphingolipidoses Lysosomal Storage Diseases, Nervous System Brain Diseases, Metabolic, Inborn Brain Diseases, Metabolic Brain Diseases Central Nervous System Diseases Nervous System Diseases |
Metabolism, Inborn Errors Genetic Diseases, Inborn Lipidoses Lipid Metabolism, Inborn Errors Lysosomal Storage Diseases Metabolic Diseases Lipid Metabolism Disorders |