Clinical trial NCT02228460: Evaluate the Safety, Pharmacodynamics, Pharmacokinetics, and Exploratory Efficacy of GZ/SAR402671 in Treatment-naïve Adult Male Patients With Fabry Disease
Official title: A Phase 2 Study to Evaluate the Safety, Pharmacodynamics, Pharmacokinetics, and Exploratory Efficacy of GZ/SAR402671 in Enzyme Replacement Therapy (ERT) Treatment-naïve Adult Male Patients Diagnosed With Fabry Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Fabry Disease
Keywords: Venglustat
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2014-08-29
Enrollment: 11
Sex: MALE
Minimum age (years): 18
Maximum age (years): 49
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Primary Objective:

To assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and exploratory efficacy of GZ/SAR402671 in enzyme replacement therapy treatment-naïve adult male participants diagnosed with Fabry disease.

Detailed description: The total duration of study per participant was 7 to 8 months for participants who entered a planned extension study and approximately 13 to 14 months for participants who did not enter a planned extension study. A 2-year extension study was planned for eligible participants.

Eligibility criteria: Inclusion criteria:

* The participant was greater than equal to (\>=) 18 years of age and less than (\<) 50 years of age.
* The participant was male.
* The participant had provided a signed informed consent.
* The participant had a confirmed diagnosis of Fabry disease as documented by leukocyte α- Galactosidase A (αGAL) activity of \<4 nanomole/hour/milligram (nmol/hr/mg) leukocyte (preferred assay; results from a central laboratory) or plasma αGAL \<1.5 nanomole/hour/milliliter (nmol/hr/mL) (results from a central laboratory).
* The participant had a plasma globotriaosylsphingosine (lyso-GL3) \>=65 nanogram per milliliter (ng/mL).
* The participant had never been treated with a Fabry disease-specific treatment.
* If the participant was on renin-angiotensin-aldosterone system (RAAS) blockers and antidepressants, the dose should be stable (i.e., prescribed dose and frequency) for at least the immediate 3 months prior to screening.

Exclusion criteria:

* The participant had an estimated glomerular filtration rate (eGFR) \<60 mL/min/1.73 m\^2 using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI).
* The participant had a median urine protein/creatinine ratio (PCR) \>=0.5 gram per gram (g/g) (median of 3 overnight urine collections. Collection of each of the 3 samples must occur between 4 and 7 days of each other, and all samples must be collected within a 15 day period). All 3 samples must be collected regardless of the results and results available prior to Day 1.
* The participant had undergone a kidney transplant.
* The participant had either active or a history of clinically significant organic disease (with the exception of the symptoms related to Fabry disease), including clinically significant cardiovascular, hepatic, pulmonary, hematologic, neurological or renal disease, or other medical condition, serious inter-current illness, or extenuating circumstances that, in the opinion of the Investigator, would preclude participation in the trial.
* The participant had abnormal liver function (serum total bilirubin \> the upper limit of normal, or serum alanine aminotransferase (\[ALT\] and aspartate aminotransferase \[AST\] \>2.0 times the upper limit of normal).
* The participant had, according to World Health Organization (WHO) grading a cortical cataract (COR) \> one-quarter of the lens circumference (Grade COR-2) or a posterior subcapsular cataract (PSC) \>2 millimeter (mm) (Grade PSC-2). Participants with nuclear cataracts were not excluded.
* The participant was currently receiving potentially cataractogenic medications.
* The participant had received strong or moderate inducers or inhibitors of Cytochrome P450 3A4 (CYP3A4) per Food and Drug Administration (FDA) classification within 14 days prior to enrollment or within 5 times the elimination half-life or PD half-life of the medication, whichever is longer.
* The participant was scheduled for in-patient hospitalization, including elective surgery, during the study.
* The participant had a positive result on any of the following tests: hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (anti-HCV) antibodies, anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 and anti-HIV2 Ab). Participants with a positive hepatitis B surface antibody (HBsAb) test with a history of prior hepatitis B immunization were eligible if other criteria met (i.e., negative tests for: HBsAg, hepatitis B core antibody \[HBcAb\], and hepatitis C virus antibody \[HCVAb\]).
* The participant had participated in a study involving an investigational drug within the past 30 days of the start of the trial.
* The participant was unwilling to comply with the requirements of the protocol.
* The participant was a sexually active man who was not willing to use 2 forms of birth control including a barrier method during the study until 6 weeks after the last treatment with investigational medicinal product (IMP).
* The participant had a history or ongoing clinically significant cardiac arrhythmia, defined as either atrial fibrillation, sustained or non-sustained ventricular tachycardia.
* The participant had any contraindication to magnetic resonance imaging (MRI).
* The participant had one of the following central nervous system exclusion criteria:

  * Acute stroke, within 3 months of the screening visit.
  * History of seizures.

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

Primary outcomes:
measure: Change From Baseline at Week 26 in Skin Globotriaosylceramide (GL-3) Score in Superficial Skin Capillary Endothelium: Number of Participants in Categories of Shift in GL-3 Score From Baseline to Week 26
timeFrame: Baseline, Week 26
measure: Mean Change From Baseline at Week 26 in Skin GL-3 Score in Superficial Skin Capillary Endothelium
timeFrame: Baseline, Week 26
Secondary outcomes:
measure: Change From Baseline in Plasma GL-3 Concentration at Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline in Plasma Lyso Globotriaosylceramide (Lyso-GL-3) Concentration at Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline in Plasma Glucosylceramide (GL-1) Concentration at Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline at Week 26 in Skin GL-3 Score in Deep Vessels Endothelial Cells: Number of Participants in Categories of Shift in GL-3 Score From Baseline to Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline at Week 26 in Skin GL-3 Score in Deep Vessels Smooth Muscle Cells: Number of Participants in Categories of Shift in GL-3 Score From Baseline to Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline at Week 26 in Skin GL-3 Score in Perineurium Cells: Number of Participants in Categories of Shift in GL-3 Score From Baseline to Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline in Urine Globotriaosylceramide (GL-3) Concentration at Week 26
timeFrame: Baseline, Week 26
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
timeFrame: From Baseline up to 212 days
measure: Pharmacokinetics (PK): Maximum Plasma Drug Concentration (Cmax) of GZ/SAR402671
timeFrame: Day 1 (predose and 1, 2, 4, 8, and 24 hours post-dose); Day 182 (predose and 1, 2, 4, 8, and 24 hours post-dose)
measure: PK: Plasma Trough Concentration (Ctrough) of GZ/SAR402671
timeFrame: Predose on Days 14, 28, 56, 84, 126, and 182
measure: PK: Time to Reach Maximum Plasma Drug Concentration (Tmax) of GZ/SAR402671
timeFrame: Day 1 (predose and 1, 2, 4, 8, and 24 hours post-dose); Day 182 (predose and 1, 2, 4, 8, and 24 hours post-dose)
measure: PK: Area Under Plasma Concentration Versus Time Curve From 0 to 24 Hours (AUC0-24) of GZ/SAR402671
timeFrame: Day 1 (predose and 1, 2, 4, 8, and 24 hours post-dose); Day 182 (predose and 1, 2, 4, 8, and 24 hours post-dose)
measure: PK: Terminal Half-life (t1/2z) of GZ/SAR402671
timeFrame: Day 1 (predose and 1, 2, 4, 8, and 24 hours post-dose); Day 182 (predose and 1, 2, 4, 8, and 24 hours post-dose)
measure: PK: Apparent Total Body Clearance of GZ/SAR402671 at Steady State (CLss/F)
timeFrame: Predose and 1, 2, 4, 8, and 24 hours post-dose on Day 182
measure: PK: Apparent Volume of Distribution of GZ/SAR402671 (Vss/F) at Steady State
timeFrame: Predose and 1, 2, 4, 8, and 24 hours post-dose on Day 182
measure: PK: Cumulated Amount of GZ/SAR402671 Excreted in Urine From 0 to 24 Hours (Ae0-24)
timeFrame: 0-24 hours on Day 182
measure: PK: Percentage of Dose of GZ/SAR402671 Excreted in Urine From 0 to 24 Hours (fe0-24)
timeFrame: 0-24 hours on Day 182
measure: PK: Renal Clearance (CLR) of GZ/SAR402671 From 0 to 24 Hours
timeFrame: 0-24 hours on Day 182
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Investigational Site Number 840002
state: Georgia
city: Cincinnati
country: United States
facility: Investigational Site Number 840003
state: Ohio
city: Fairfax
country: United States
facility: Investigational Site Number 840001
state: Virginia
city: Garches
country: France
facility: Investigational Site Number 250001
city: Warszawa
country: Poland
facility: Investigational Site Number 616001
city: Moscow
country: Russian Federation
facility: Investigational Site Number 643002
city: Birmingham
country: United Kingdom
facility: Investigational Site Number 826003
city: Cambridge
country: United Kingdom
facility: Investigational Site Number 826002
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: