Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 1 of 1 for:    NCT02843035
Previous Study | Return to List | Next Study

Venglustat in Combination With Cerezyme in Adult and Pediatric Patients With Gaucher Disease Type 3 (LEAP2IT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02843035
Recruitment Status : Recruiting
First Posted : July 25, 2016
Last Update Posted : June 2, 2021
Sponsor:
Information provided by (Responsible Party):
Sanofi ( Genzyme, a Sanofi Company )

Tracking Information
First Submitted Date  ICMJE July 20, 2016
First Posted Date  ICMJE July 25, 2016
Last Update Posted Date June 2, 2021
Actual Study Start Date  ICMJE January 4, 2017
Estimated Primary Completion Date January 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 8, 2021)
  • Lyso-glucosylceramide (lyso-GL1) levels in cerebrospinal fluid (CSF) (Cohort 1 Part 1) [ Time Frame: 45 days (Part 1 - screening phase) ]
  • Number of participants with Treatment Emergent Adverse Events (TEAEs) (Cohort 2 Part 2 and 3) [ Time Frame: Up to Week 208 (up to Week 260 for US participants) ]
  • Lyso-GL1 and glucosylceramide (GL-1) in CSF (Cohort 2 Part 2) [ Time Frame: Up to Week 52 ]
  • Change in Scale for Assessment and Rating of Ataxia (SARA) modified total score from baseline to Week 52 (Cohort 3 Part 2) [ Time Frame: Baseline and Week 52 ]
  • Change in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total scale index score from baseline to Week 52 (Cohort 3 Part 2) [ Time Frame: Baseline and Week 52 ]
Original Primary Outcome Measures  ICMJE
 (submitted: July 20, 2016)
  • Number of patients with adverse events [ Time Frame: From screening through week 52 ]
  • Change from baseline in biomarker levels [ Time Frame: From screening through week 52 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 8, 2021)
  • Maximum venglustat plasma concentration (Cmax) (Cohort 2 Part 2) [ Time Frame: Day 1 pre-dose and 1, 2, 4, 8 and 24 hours post-dose ]
  • Time to maximum venglustat plasma concentration (tmax) (Cohort 2 Part 2) [ Time Frame: Day 1 pre-dose and 1, 2, 4, 8 and 24 hours post-dose ]
  • Area under the venglustat plasma concentration versus time curve from time 0 to 24 hours (AUC0-24) (Cohort 2 Part 2) [ Time Frame: Day 1 pre-dose and 1, 2, 4, 8 and 24 hours post-dose ]
  • Trough venglustat plasma concentration (Ctrough) (Cohort 2 Part 2 and 3) [ Time Frame: Pre-dose at Day 2 and Week 12, 39, 78, 104, 156 ]
  • Venglustat CSF concentration (Cohort 2 Part 2) [ Time Frame: Day 1 (pre-dose) and Week 4, 26 and 52 ]
  • Percent Change in CSF Lyso-GL1 levels from baseline to Week 52 (Cohort 3 Part 2) [ Time Frame: Baseline and Week 52 ]
  • Change in Modified Friedreich´s Ataxia Rating Scale - Activities of Daily Living (FARS-ADL) score from baseline to Week 52 (Cohort 3 Part 2) [ Time Frame: Baseline and Week 52 ]
  • Change in connectivity between vision perception (resting state networks 3) and action execution (resting state network 6) areas by task-free blood oxygenation level-dependent (BOLD) fMRI from baseline to Week 52 (Cohort 3 Part 2) [ Time Frame: Baseline and Week 52 ]
  • Change in dual-energy X-ray absorptiometry (DXA) lumbar spine bone mineral density (BMD) T-score from baseline to Week 52 (Cohort 3 Part 2) [ Time Frame: Baseline and Week 52 ]
  • Change in bone MRI bone marrow burden (BMB) total score from baseline to Week 52 (Cohort 3 Part 2) [ Time Frame: Baseline and Week 52 ]
  • Number of participants with TEAEs (Cohort 3 Part 2 and 3) [ Time Frame: Up to Week 182 ]
  • Growth rate (Cohort 3 Part 2 and 3) [ Time Frame: Up to Week 182 ]
  • Bone age by hand X-ray (Cohort 3 Part 2 and 3) [ Time Frame: Up to Week 182 ]
  • Sexual maturation (Tanner stage) (Cohort 3 Part 2 and 3) [ Time Frame: Up to Week 182 ]
  • Immunogenicity testing to assess possible infusion associated reaction (IAR) to Cerezyme (Cohort 2 Part 1) [ Time Frame: 45 days (Part 1 - screening phase) ]
  • Immunogenicity testing to assess possible IAR to Cerezyme (Cohort 3 Part 1) [ Time Frame: 60 days (Part 1 - screening phase) ]
  • Beck Depression Inventory-II (BDI-II) (Cohort 2 Part 2 and 3) [ Time Frame: Up to Week 208 (up to Week 260 for US participants) ]
  • Beck Depression Inventory-II (BDI-II) (Cohort 3 Part 2 and 3) [ Time Frame: Up to Week 182 ]
  • Maximum venglustat plasma concentration (Cmax) (Cohort 3 Part 2) [ Time Frame: Day 1 pre-dose and 1, 2, 4, 8 and 24 hours post-dose ]
  • Time to maximum venglustat plasma concentration (tmax) (Cohort 3 Part 2) [ Time Frame: Day 1 pre-dose and 1, 2, 4, 8 and 24 hours post-dose ]
  • Area under the venglustat plasma concentration versus time curve from time 0 to 24 hours (AUC0-24) (Cohort 3 Part 2) [ Time Frame: Day 1 pre-dose and 1, 2, 4, 8 and 24 hours post-dose ]
  • Trough venglustat plasma concentration (Ctrough) (Cohort 3 Part 2 and 3) [ Time Frame: Pre-dose at Day 2 and Week 4, 52, 78, 104, 156 ]
  • Venglustat CSF concentration (Cohort 3 Part 2) (only participants ≥18 years of age) [ Time Frame: Week 52 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: July 20, 2016)
  • Assessment of pharmacokinetic parameter: Plasma maximum concentration (Cmax) [ Time Frame: Day 1, Week 4, Week 26, and Week 52 ]
  • Assessment of pharmacokinetic parameter: Time at Cmax (Tmax) [ Time Frame: Day 1, Week 4, Week 26, and Week 52 ]
  • Assessment of pharmacokinetic parameter: Area under the curve (AUC) [ Time Frame: Day 1, Week 4, Week 26, and Week 52 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Venglustat in Combination With Cerezyme in Adult and Pediatric Patients With Gaucher Disease Type 3
Official Title  ICMJE A 3-part Study to Evaluate the Efficacy and Safety of Venglustat in Combination With Cerezyme in Adult and Pediatric Patients With Gaucher Disease Type 3 (GD3) With Open-label Long-term Treatment
Brief Summary

Primary Objectives:

Part 1:

Cohorts 1, 2 and 3

  • Evaluate cerebrospinal fluid (CSF) biomarkers in adult Gaucher disease (GD) Type 3 patients that distinguish GD3 from adult Gaucher disease Type 1 (GD1) patients.
  • Screen adult and pediatric GD3 patients who qualify for treatment with venglustat in Parts 2 and 3.

Parts 2 and 3:

Cohort 2

  • 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-GL1]) from adult GD3 patients receiving venglustat in combination with Cerezyme (Part 2 only).

Cohort 3

  • Evaluate the efficacy of venglustat in combination with Cerezyme in adult and pediatric GD3 patients by assessing:

    • Ataxia using the Scale for the Assessment and Rating of Ataxia (SARA)
    • Cognition using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)

Secondary Objectives:

Parts 2 and 3:

Cohort 2

  • Evaluate the pharmacokinetics (PK) of venglustat in adult GD3 patients.

Cohort 3

  • Evaluate the efficacy of venglustat in combination with Cerezyme in adult and pediatric GD3 patients by assessing:

    • CSF Lyso-GL1 levels
    • Modified Friedreich´s Ataxia Rating Scale - Activities of Daily Living (FARS-ADL)
    • Brain resting-state functional Magnetic Resonance Imaging (rs-fMRI) reflecting connectivity between parieto-occipital areas
    • Bone disease manifestations
  • Evaluate safety and tolerability of venglustat in combination with Cerezyme in adult and pediatric GD3 patients
  • Evaluate PK of venglustat in adult and pediatric GD3 patients.
Detailed Description The total duration for GD1 participants is 45 days (Part 1), while for GD3 participants the total duration is up to 4.2 years for Cohort 2 (up to 5.2 years for US participants) and up to 3.7 years for Cohort 3.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Cohort 3 Part 2 is 12-month double-blind treatment period. Open label venglustat is administered in Cohort 3 Part 3 (long-term treatment) and Cohort 2 Part 2 (12-month treatment) and 3 (long-term treatment).
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Gaucher Disease Type 1-Gaucher Disease Type 3
Intervention  ICMJE
  • Drug: placebo

    Pharmaceutical form: tablet

    Route of administration: oral

  • Drug: venglustat (GZ402671)

    Pharmaceutical form: tablet or capsule

    Route of administration: oral

  • Drug: imiglucerase

    Pharmaceutical form: sterile lyophilized product

    Route of administration: intravenous

    Other Name: Cerezyme
Study Arms  ICMJE
  • Experimental: Adult GD1 participants: No venglustat treatment (Cohort 1)

    Part 1 only (45 days): Biomarker evaluation/screening phase. No venglustat administered.

    During Part 1 participants will continue their routine total monthly Cerezyme dose or, if received another enzyme replacement therapy (ERT) prior to study, will switch to a defined corresponding Cerezyme dose regimen.

    Intervention: Drug: imiglucerase
  • Experimental: Adult GD3 participants: OL venglustat (Cohort 2)

    Part 1 (45 days): Biomarker evaluation/screening phase. No venglustat administered.

    Part 2: Open label (OL) venglustat administered once a day orally for 12 months.

    Part 3: OL venglustat administered once a day orally for up to 3 years (up to 4 years for US participants).

    During Parts 1-3 study participants will continue their routine total monthly Cerezyme dose or, if received another ERT prior to study, will switch to a defined corresponding Cerezyme dose regimen.

    Interventions:
    • Drug: venglustat (GZ402671)
    • Drug: imiglucerase
  • Experimental: Adult/pediatric GD3 participants: DB venglustat (Cohort 3)

    Part 1 (60 days): Biomarker evaluation/screening phase. No venglustat administered.

    Part 2: Double-blind (DB) venglustat administered once a day orally for 12 months.

    Part 3: OL venglustat administered once a day orally for up to 2.5 years.

    During Parts 1-3 study participants will continue their routine total monthly Cerezyme dose or, if received another ERT prior to study, will switch to a defined corresponding Cerezyme dose regimen.

    Interventions:
    • Drug: venglustat (GZ402671)
    • Drug: imiglucerase
  • Placebo Comparator: Adult/pediatric GD3 participants: DB placebo (Cohort 3)

    Part 1 (60 days): Biomarker evaluation/screening phase. No venglustat administered.

    Part 2: DB placebo administered once a day orally for 12 months.

    Part 3: OL venglustat administered once a day orally for up to 2.5 years.

    During Parts 1-3 study participants will continue their routine total monthly Cerezyme dose or, if received another ERT prior to study, will switch to a defined corresponding Cerezyme dose regimen.

    Interventions:
    • Drug: placebo
    • Drug: venglustat (GZ402671)
    • Drug: imiglucerase
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 28, 2020)
49
Original Estimated Enrollment  ICMJE
 (submitted: July 20, 2016)
10
Estimated Study Completion Date  ICMJE January 2023
Estimated Primary Completion Date January 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria:

  • For participants ≥18 years of age: Participant must provide written informed consent prior to any study-related procedures being performed.
  • For participants ≥12 and <18 years of age: Parent(s)/legal guardian(s) must provide written informed consent prior to any study related procedures being performed. If the patient is considered able by local regulation, assent will also be obtained before any study related procedures are 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.

Cohort 1 only:

  • GD1 participant is ≥18 and ≤40 years of age.

Cohort 2 only:

  • GD3 participant is ≥18 years of age.

Cohort 3 only:

  • GD3 adult participant ≥18 years of age.
  • GD3 pediatric participant is ≥12 years of age <18 years and ≥30 kg of weight. For male patients 12 to <18 years of age: There is a potential risk for venglustat to impact male fertility particularly when used in patients who have not reached a certain stage of sexual maturation. If a patient has not reached Tanner Stage 3 by the screening visit, the Investigator should assess and discuss with the patient the potential benefits and risks when considering eligibility for study participation. In this benefit/risk assessment-discussion, the parent(s)/legal guardian(s), the patient (if considered able by local regulation), and the Sponsor's medical representative (if considered appropriate) shall be consulted.

Exclusion criteria:

  • 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, alpha-adrenergic 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).

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Trial Transparency email recommended (Toll free number for US & 800-633-1610 ext option 6 Contact-US@sanofi.com
Listed Location Countries  ICMJE Germany,   Japan,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02843035
Other Study ID Numbers  ICMJE PDY13949
2014-002550-39 ( EudraCT Number )
U1111-1156-4278 ( Other Identifier: UTN )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
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
Responsible Party Sanofi ( Genzyme, a Sanofi Company )
Study Sponsor  ICMJE Genzyme, a Sanofi Company
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Sciences & Operations Sanofi
PRS Account Sanofi
Verification Date June 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP