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

Fabry Disease Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02228460
• Other study ID #: ACT13739
• Secondary ID: 2013-005324-41U1
• Status: Completed
• Phase: Phase 2
• Start date: November 2014
• Est. completion date: September 2016

Study information

• Verified date: September 2016
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 11
• Est. completion date: September 2016
• Est. primary completion date: September 2016
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 49 Years

Eligibility

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 a- Galactosidase A (aGAL) activity of <4 nanomole/hour/milligram (nmol/hr/mg) leukocyte (preferred assay; results from a central laboratory) or plasma aGAL <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.

Related Conditions & MeSH terms

• Fabry Disease

Intervention

Drug:
• GZ/SAR402671
Pharmaceutical form: Capsule; Route of administration: Oral

Locations

Country	Name	City	State
France	Investigational Site Number 250001	Garches
Poland	Investigational Site Number 616001	Warszawa
Russian Federation	Investigational Site Number 643002	Moscow
United Kingdom	Investigational Site Number 826003	Birmingham
United Kingdom	Investigational Site Number 826002	Cambridge
United States	Investigational Site Number 840002	Atlanta	Georgia
United States	Investigational Site Number 840003	Cincinnati	Ohio
United States	Investigational Site Number 840001	Fairfax	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
Genzyme, a Sanofi Company

Countries where clinical trial is conducted

United States,  France,  Poland,  Russian Federation,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.	Baseline, Week 26
Primary	Mean Change From Baseline at Week 26 in Skin GL-3 Score in Superficial Skin Capillary Endothelium	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.	Baseline, Week 26
Secondary	Change From Baseline in Plasma GL-3 Concentration at 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.	Baseline, Week 26
Secondary	Change From Baseline in Plasma Lyso Globotriaosylceramide (Lyso-GL-3) Concentration at 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.	Baseline, Week 26
Secondary	Change From Baseline in Plasma Glucosylceramide (GL-1) Concentration at 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.	Baseline, Week 26
Secondary	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	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.	Baseline, Week 26
Secondary	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	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.	Baseline, Week 26
Secondary	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	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.	Baseline, Week 26
Secondary	Change From Baseline in Urine Globotriaosylceramide (GL-3) Concentration at 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.	Baseline, Week 26
Secondary	Number of Participants With Treatment Emergent Adverse Events (TEAEs)	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).	From Baseline up to 212 days
Secondary	Pharmacokinetics (PK): Maximum Plasma Drug Concentration (Cmax) of GZ/SAR402671	Maximum plasma concentration observed for study drug was reported.	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)
Secondary	PK: Plasma Trough Concentration (Ctrough) of GZ/SAR402671	Ctrough was defined as the plasma concentration of study drug observed just before treatment administration during repeated dosing.	Predose on Days 14, 28, 56, 84, 126, and 182
Secondary	PK: Time to Reach Maximum Plasma Drug Concentration (Tmax) of GZ/SAR402671	Tmax was defined as time to reach maximum plasma concentration of study drug.	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)
Secondary	PK: Area Under Plasma Concentration Versus Time Curve From 0 to 24 Hours (AUC0-24) of GZ/SAR402671	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.	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)
Secondary	PK: Terminal Half-life (t1/2z) of GZ/SAR402671	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.	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)
Secondary	PK: Apparent Total Body Clearance of GZ/SAR402671 at Steady State (CLss/F)	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).	Predose and 1, 2, 4, 8, and 24 hours post-dose on Day 182
Secondary	PK: Apparent Volume of Distribution of GZ/SAR402671 (Vss/F) at Steady State	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.	Predose and 1, 2, 4, 8, and 24 hours post-dose on Day 182
Secondary	PK: Cumulated Amount of GZ/SAR402671 Excreted in Urine From 0 to 24 Hours (Ae0-24)	Ae0-24 was the cumulated amount of study drug excreted in urine during the time interval of 0 to 24 hours.	0-24 hours on Day 182
Secondary	PK: Percentage of Dose of GZ/SAR402671 Excreted in Urine From 0 to 24 Hours (fe0-24)	fe0-24 was the fraction of dose excreted in urine during the time interval of 0 to 24 hours.	0-24 hours on Day 182
Secondary	PK: Renal Clearance (CLR) of GZ/SAR402671 From 0 to 24 Hours	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.	0-24 hours on Day 182