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Evaluate the Safety, Pharmacodynamics, Pharmacokinetics, and Exploratory Efficacy of GZ/SAR402671 in Treatment-naïve Adult Male Patients With Fabry Disease

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02228460
Recruitment Status : Completed
First Posted : August 29, 2014
Results First Posted : December 17, 2019
Last Update Posted : December 17, 2019
Sponsor:
Information provided by (Responsible Party):
Sanofi ( Genzyme, a Sanofi Company )

Tracking Information
First Submitted Date  ICMJE August 27, 2014
First Posted Date  ICMJE August 29, 2014
Results First Submitted Date  ICMJE November 26, 2019
Results First Posted Date  ICMJE December 17, 2019
Last Update Posted Date December 17, 2019
Actual Study Start Date  ICMJE November 2014
Actual Primary Completion Date September 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 26, 2019)
  • 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 [ Time Frame: Baseline, Week 26 ]
    Skin biopsies taken at Baseline and Week 26 were analyzed for cellular GL-3 accumulation (inclusions) by light microscopy. Three independent pathologists evaluated each biopsy using an inclusion severity score of 0 (none/trace), 1 (mild), 2 (moderate), and 3 (severe), where higher score indicated more severe condition. A single score per participant per time point was derived by taking the score rated by a majority of the pathologists; if a majority score could not be derived, the median score was used. Data were summarized and reported in terms of number of participants with shift from Baseline GL-3 score to Week 26 GL-3 score. Any shift category of Baseline score/Week 26 score that was not observed is not reported. Shift to lower score from Baseline to Week 26 indicates less severe condition at Week 26.
  • Mean Change From Baseline at Week 26 in Skin GL-3 Score in Superficial Skin Capillary Endothelium [ Time Frame: Baseline, Week 26 ]
    Skin biopsies taken at Baseline and Week 26 were analyzed for cellular GL-3 accumulation (inclusions) by light microscopy. Three independent pathologists evaluated each biopsy using an inclusion severity score of 0 (none/trace), 1 (mild), 2 (moderate), and 3 (severe), where higher score indicated more severe condition. A single score per participant per time point was derived by taking the score rated by a majority of the pathologists; if a majority score could not be derived, the median score was used. Change from Baseline in GL-3 score was obtained by subtracting Baseline value from post-baseline value at Week 26. A negative change from Baseline indicates less severe condition at Week 26.
Original Primary Outcome Measures  ICMJE
 (submitted: August 27, 2014)
Change from baseline in globotriaosylceramide (GL-3) scores as evaluated by light microscopy (LM) in superficial skin capillary [ Time Frame: 26 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 26, 2019)
  • Change From Baseline in Plasma GL-3 Concentration at Week 26 [ Time Frame: Baseline, Week 26 ]
    Change from Baseline in plasma GL-3 was obtained by subtracting Baseline value from post-baseline value at Week 26. Concentration of GL-3 in plasma was determined using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method.
  • Change From Baseline in Plasma Lyso Globotriaosylceramide (Lyso-GL-3) Concentration at Week 26 [ Time Frame: Baseline, Week 26 ]
    Change from Baseline in plasma Lyso-GL-3 was obtained by subtracting Baseline value from post-baseline value at Week 26. Concentration of lyso-GL-3 in plasma was determined using a validated LC-MS/MS method.
  • Change From Baseline in Plasma Glucosylceramide (GL-1) Concentration at Week 26 [ Time Frame: Baseline, Week 26 ]
    Change from Baseline in plasma GL-1 was obtained by subtracting Baseline value from post-baseline value at Week 26. Concentration of GL-1 in plasma was determined using a validated LC-MS/MS method.
  • 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 [ Time Frame: Baseline, Week 26 ]
    Skin biopsies taken at Baseline and Week 26 were analyzed for cellular GL-3 accumulation (inclusions) by light microscopy. Three independent pathologists evaluated each biopsy using an inclusion severity score of 0 (none/trace), 1 (mild), 2 (moderate), and 3 (severe), where higher score indicated more severe condition. A single score per participant per time point was derived by taking the score rated by a majority of the pathologists; if a majority score could not be derived, the median score was used. Data were summarized and reported in terms of number of participants with shift from Baseline GL-3 score to Week 26 GL-3 score. Any shift category of Baseline score/Week 26 score that was not observed is not reported. Shift to lower score from Baseline to Week 26 indicates less severe condition at Week 26.
  • 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 [ Time Frame: Baseline, Week 26 ]
    Skin biopsies taken at Baseline and Week 26 were analyzed for cellular GL-3 accumulation (inclusions) by light microscopy. Three independent pathologists evaluated each biopsy using an inclusion severity score of 0 (none/trace), 1 (mild), 2 (moderate), and 3 (severe), where higher score indicated more severe condition. A single score per participant per time point was derived by taking the score rated by a majority of the pathologists; if a majority score could not be derived, the median score was used. Data were summarized and reported in terms of number of participants with shift from Baseline GL-3 score to Week 26 GL-3 score. Any shift category of Baseline score/Week 26 score that was not observed is not reported. Shift to lower score from Baseline to Week 26 indicates less severe condition at Week 26.
  • 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 [ Time Frame: Baseline, Week 26 ]
    Skin biopsies taken at Baseline and Week 26 were analyzed for cellular GL-3 accumulation (inclusions) by light microscopy. Three independent pathologists evaluated each biopsy using an inclusion severity score of 0 (none/trace), 1 (mild), 2 (moderate), and 3 (severe), where higher score indicated more severe condition. A single score per participant per time point was derived by taking the score rated by a majority of the pathologists; if a majority score could not be derived, the median score was used. Data were summarized and reported in terms of number of participants with shift from Baseline GL-3 score to Week 26 GL-3 score. Any shift category of Baseline score/Week 26 score that was not observed is not reported. Shift to lower score from Baseline to Week 26 indicates less severe condition at Week 26.
  • Change From Baseline in Urine Globotriaosylceramide (GL-3) Concentration at Week 26 [ Time Frame: Baseline, Week 26 ]
    Change from Baseline in urine GL-3 was obtained by subtracting Baseline value from post-baseline value at Week 26. Concentration of GL-3 in urine was determined using a validated LC-MS/MS method.
  • Number of Participants With Treatment Emergent Adverse Events (TEAEs) [ Time Frame: From Baseline up to 212 days ]
    Any untoward medical occurrence in a participant who received study drug was considered an adverse event (AE) without regard to possibility of causal relationship with this treatment. TEAEs were defined as AEs that developed or worsened during on-treatment period (period from the first administration of study drug through the last administration of the study drug plus 30 days or end of study participation for participant, whichever occurs first).
  • Pharmacokinetics (PK): Maximum Plasma Drug Concentration (Cmax) of GZ/SAR402671 [ Time Frame: 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) ]
    Maximum plasma concentration observed for study drug was reported.
  • PK: Plasma Trough Concentration (Ctrough) of GZ/SAR402671 [ Time Frame: Predose on Days 14, 28, 56, 84, 126, and 182 ]
    Ctrough was defined as the plasma concentration of study drug observed just before treatment administration during repeated dosing.
  • PK: Time to Reach Maximum Plasma Drug Concentration (Tmax) of GZ/SAR402671 [ Time Frame: 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) ]
    Tmax was defined as time to reach maximum plasma concentration of study drug.
  • PK: Area Under Plasma Concentration Versus Time Curve From 0 to 24 Hours (AUC0-24) of GZ/SAR402671 [ Time Frame: 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) ]
    Area under the plasma concentration versus time curve of study drug from time 0 to 24 hours (AUC0-24) was calculated using the trapezoidal method over the dosing interval.
  • PK: Terminal Half-life (t1/2z) of GZ/SAR402671 [ Time Frame: 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) ]
    Plasma t1/2z was the time measured for the plasma concentration of drug to decrease by one half. The t1/2z was estimated based on 24-hour post-dose PK.
  • PK: Apparent Total Body Clearance of GZ/SAR402671 at Steady State (CLss/F) [ Time Frame: Predose and 1, 2, 4, 8, and 24 hours post-dose on Day 182 ]
    Apparent total body clearance at steady state was a quantitative measure of rate of clearance of drug from the blood following oral administration, and is described in terms of volume of fluid clear of drug per time unit (eg, mL/min).
  • PK: Apparent Volume of Distribution of GZ/SAR402671 (Vss/F) at Steady State [ Time Frame: Predose and 1, 2, 4, 8, and 24 hours post-dose on Day 182 ]
    Volume of distribution at steady state was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of drug.
  • PK: Cumulated Amount of GZ/SAR402671 Excreted in Urine From 0 to 24 Hours (Ae0-24) [ Time Frame: 0-24 hours on Day 182 ]
    Ae0-24 was the cumulated amount of study drug excreted in urine during the time interval of 0 to 24 hours.
  • PK: Percentage of Dose of GZ/SAR402671 Excreted in Urine From 0 to 24 Hours (fe0-24) [ Time Frame: 0-24 hours on Day 182 ]
    fe0-24 was the fraction of dose excreted in urine during the time interval of 0 to 24 hours.
  • PK: Renal Clearance (CLR) of GZ/SAR402671 From 0 to 24 Hours [ Time Frame: 0-24 hours on Day 182 ]
    CLR was calculated by dividing the cumulative amount of drug excreted in urine during the dosing interval of 0-24 hours by area under the plasma drug concentration time-curve during the dosing interval of 0-24 hours.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 27, 2014)
  • Change from baseline in plasma GL-3, lyso GL-3, and glucosylceramide (GL-1) [ Time Frame: 30 weeks ]
  • Change from baseline in scores of GL-3 from other cell types in skin biopsy using LM [ Time Frame: 30 weeks ]
  • Urine GL-3 change from baseline [ Time Frame: 30 weeks ]
  • Characterization of the safety profile of GZ402671, including the frequency, duration, and severity of adverse events (AEs) [ Time Frame: up to 54 weeks ]
  • Assessment PK parameters - peak concentration (Cmax), Dose-Corrected Observed Plasma Trough Concentrations (Ctrough), and time to reach max concentration (tmax) [ Time Frame: 26 weeks ]
  • Assessment of PK parameters - terminal half-life (t1/2z), area under the concentration-time curve from 0 to 24 hours (AUC0-24), and plasma clearance at steady state (CLss/F) [ Time Frame: 26 weeks ]
  • Assessment of PK parameters - volume of distribution at steady-state (Vss/F) and cumulated amount excreted in urine from 0 to 24 hours (Ae0-24) [ Time Frame: 26 weeks ]
  • Assessment of PK parameters- fraction of dose excreted in urine from 0 to 24 hours (Fe0-24) and renal clearance of the drug determined in 0 to 24 hours interval (CLr0-24) [ Time Frame: 26 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Evaluate the Safety, Pharmacodynamics, Pharmacokinetics, and Exploratory Efficacy of GZ/SAR402671 in Treatment-naïve Adult Male Patients With Fabry Disease
Official Title  ICMJE 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
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Fabry Disease
Intervention  ICMJE Drug: GZ/SAR402671
Pharmaceutical form: Capsule; Route of administration: Oral
Study Arms  ICMJE Experimental: GZ/SAR402671
GZ/SAR402671 15 milligram (mg) once daily orally for 26 weeks.
Intervention: Drug: GZ/SAR402671
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 Completed
Actual Enrollment  ICMJE
 (submitted: September 20, 2016)
11
Original Estimated Enrollment  ICMJE
 (submitted: August 27, 2014)
8
Actual Study Completion Date  ICMJE September 2016
Actual Primary Completion Date September 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years to 49 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France,   Poland,   Russian Federation,   United Kingdom,   United States
Removed Location Countries Czech Republic,   Czechia
 
Administrative Information
NCT Number  ICMJE NCT02228460
Other Study ID Numbers  ICMJE ACT13739
2013-005324-41
U1111-1152-1456 ( Other Identifier: UTN )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
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 September 2016

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