Evaluate the Safety, Pharmacodynamics, Pharmacokinetics, and Exploratory Efficacy of GZ/SAR402671 in Treatment-naïve Adult Male Patients With Fabry Disease
- Registration Number
- NCT02228460
- Lead Sponsor
- Genzyme, a Sanofi Company
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Male
- Target Recruitment
- 11
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description GZ/SAR402671 GZ/SAR402671 GZ/SAR402671 15 milligram (mg) once daily orally for 26 weeks.
- Primary Outcome Measures
Name Time Method 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 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 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.
- Secondary Outcome Measures
Name Time Method Change From Baseline in Plasma GL-3 Concentration at Week 26 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 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 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 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 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 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 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.
Pharmacokinetics (PK): Maximum Plasma Drug Concentration (Cmax) of GZ/SAR402671 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.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) 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).
PK: Plasma Trough Concentration (Ctrough) of GZ/SAR402671 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: Area Under Plasma Concentration Versus Time Curve From 0 to 24 Hours (AUC0-24) of GZ/SAR402671 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: Time to Reach Maximum Plasma Drug Concentration (Tmax) of GZ/SAR402671 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: Terminal Half-life (t1/2z) of GZ/SAR402671 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) 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: Cumulated Amount of GZ/SAR402671 Excreted in Urine From 0 to 24 Hours (Ae0-24) 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: Renal Clearance (CLR) of GZ/SAR402671 From 0 to 24 Hours 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.
PK: Apparent Volume of Distribution of GZ/SAR402671 (Vss/F) at Steady State 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: Percentage of Dose of GZ/SAR402671 Excreted in Urine From 0 to 24 Hours (fe0-24) 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.
Trial Locations
- Locations (8)
Investigational Site Number 826003
🇬🇧Birmingham, United Kingdom
Investigational Site Number 643002
🇷🇺Moscow, Russian Federation
Investigational Site Number 250001
🇫🇷Garches, France
Investigational Site Number 616001
🇵🇱Warszawa, Poland
Investigational Site Number 826002
🇬🇧Cambridge, United Kingdom
Investigational Site Number 840002
🇺🇸Atlanta, Georgia, United States
Investigational Site Number 840003
🇺🇸Cincinnati, Ohio, United States
Investigational Site Number 840001
🇺🇸Fairfax, Virginia, United States