GZ/SAR402671 in Combination With Cerezyme in Adult Patients With Gaucher Disease Type 3 (LEAP)

• ClinicalTrials.gov Identifier: NCT02843035
• Recruitment Status: Recruiting
• First Posted: July 25, 2016
• Last Update Posted: March 19, 2020
• Sponsor: Genzyme, a Sanofi Company
• Information provided by (Responsible Party): Sanofi ( Genzyme, a Sanofi Company )

Study Description

Brief Summary:

Primary Objective:

Part 1:

• Evaluate central nervous system (CNS) biomarkers in adult Gaucher disease (GD) Type 3 patients that distinguish GD3 from adult Gaucher disease Type 1 (GD1) patients.
• Screen adult GD3 patients who qualify for treatment with GZ/SAR402671 in Parts 2 and 3.

Parts 2 and 3:

• 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).

Secondary Objectives:

• Evaluate the pharmacokinetics of GZ/SAR402671 in adult GD3 patients (Part 2).
• 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 other exploratory CSF biomarkers in adult GD3 patients (Part 2 and 3)

Condition or disease	Intervention/treatment	Phase
Gaucher Disease Type 1-Gaucher Disease Type 3	Drug: GZ402671	Phase 2

Detailed Description:

The total duration for GD1 patients is 45 days (Part 1), while for GD3 patients, the total duration is up to 208 weeks, including 2 part-treatment of 52 weeks and 156 weeks, respectively.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 208-week Three-part,Open-label, Multicenter, Multinational Study of the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Exploratory Efficacy of GZ/SAR402671 in Combination With Cerezyme in Adult Patients With Gaucher Disease Type 3
• Actual Study Start Date: January 2017
• Estimated Primary Completion Date: May 2024
• Estimated Study Completion Date: May 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: GZ/SAR402671; Administered once a day orally for 208 weeks. Patients will continue their usual dose of Cerezyme throughout study.	Drug: GZ402671; Other Name: Venglustat

Outcome Measures

Primary Outcome Measures :

1. Number of patients with adverse events [ Time Frame: From screening through week 208 ]
2. Assessment of pharmacodynamic (PD) parameter: Lyso-glucosylceramide (lyso-GL1) and glucosylceramide (GL-1) in cerebrospinal fluid (CSF) [ Time Frame: From screening through week 52 ]
3. Assessment of pharmacodynamic (PD) parameter: Lyso-glucosylceramide (lyso-GL1) and glucosylceramide (GL-1) in plasma [ Time Frame: From screening through week 208 ]

Secondary Outcome Measures :

1. Assessment of pharmacokinetic parameter: Plasma maximum concentration (Cmax) [ Time Frame: Day 1, Week 4, Week 26, and Week 52 ]
2. Assessment of pharmacokinetic parameter: Time at Cmax (Tmax) [ Time Frame: Day 1, Week 4, Week 26, and Week 52 ]
3. Assessment of pharmacokinetic parameter: Area under the curve (AUC) [ Time Frame: Day 1, Week 4, Week 26, and Week 52 ]
4. Assessment of pharmacokinetic parameter: plasma trough concentration (Ctrough) [ Time Frame: Weeks 12 and 39 (Part 2), and on Weeks 78, 104, and 156 (for Part 3) ]
5. Assessment of pharmacokinetic parameter: CSF maximum concentration (Cmax) [ Time Frame: Day 1, Week 4, Week 26, and Week 52 ]
6. Assessment of pharmacokinetic parameter: CSF time at Cmax (Tmax) [ Time Frame: Day 1, Week 4, Week 26, and Week 52 ]
7. Assessment of pharmacokinetic parameter: CSF area under the curve (AUC) [ Time Frame: Day 1, Week 4, Week 26, and Week 52 ]
8. Immunogenicity testing as needed for IAR (Cerezyme) [ Time Frame: From screening to Day 45 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion criteria :

• The patient must provide written informed consent prior to any study-related procedures being performed.
• The patient 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:
• 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 the last year.
• The patient, if female and of childbearing potential, must have a negative pregnancy test [urine beta-human chorionic gonadotropin (β-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).
• Female patients 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 study drug.

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 (e.g., 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 >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.
• 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.
• The patient has had a major organ transplant (e.g., 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).

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Contacts and Locations

Contacts

Contact: Trial Transparency email recommended (Toll free number for US &; 800-633-1610 ext option 6; Contact-US@sanofi.com

Locations

United States, Connecticut

Investigational Site Number 840002; Recruiting

New Haven, Connecticut, United States, 06520

United States, Texas

Investigational Site Number 840001; Recruiting

Dallas, Texas, United States, 75226

Germany

Investigational Site Number 276001; Active, not recruiting

Mainz, Germany, 55131

Japan

Investigational Site Number 392001; Active, not recruiting

Minato-Ku, Japan

United Kingdom

Investigational Site Number 826003; Recruiting

Cambridge, United Kingdom, CB2 OQQ

Investigational Site Number 826001; Recruiting

London, United Kingdom, NW1 2PJ

Investigational Site Number 826002; Recruiting

Salford, United Kingdom, M6 8HD

Sponsors and Collaborators

Genzyme, a Sanofi Company

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

More Information

• Responsible Party: Genzyme, a Sanofi Company
• ClinicalTrials.gov Identifier: NCT02843035
• Other Study ID Numbers: PDY13949; 2014-002550-39 ( EudraCT Number ); U1111-1156-4278 ( Other Identifier: UTN )
• First Posted: July 25, 2016
• Last Update Posted: March 19, 2020
• Last Verified: March 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Individual participant data (IPD) and supporting clinical documents are available for request at clinicalstudydatarequest.com. While making information available Sanofi continues to protect the privacy of the participants in clinical trials and to remove commercially confidential information (CCI). Details on Data Sharing criteria and process for requesting access can be found at this web address: clinicalstudydatarequest.com

Additional relevant MeSH terms:

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