Clinical Trial Results:
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
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Summary
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EudraCT number |
2013-005324-41 |
Trial protocol |
GB CZ |
Global end of trial date |
06 Sep 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
21 Sep 2017
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First version publication date |
21 Sep 2017
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
ACT13739
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02228460 | ||
WHO universal trial number (UTN) |
U1111-1152-1456 | ||
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Sponsors
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Sponsor organisation name |
Genzyme Corporation
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Sponsor organisation address |
500 Kendall Street, Cambridge, MA, United States, 02142
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Public contact |
Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
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Scientific contact |
Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
23 Sep 2016
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
06 Sep 2016
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and exploratory efficacy of GZ402671/SAR402671 in enzyme replacement therapy (ERT) treatment-naïve adult male subjects diagnosed with Fabry disease (FD).
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Protection of trial subjects |
Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
11 Nov 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 1
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Country: Number of subjects enrolled |
France: 1
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Country: Number of subjects enrolled |
Russian Federation: 1
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Country: Number of subjects enrolled |
United States: 4
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Country: Number of subjects enrolled |
United Kingdom: 4
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Worldwide total number of subjects |
11
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EEA total number of subjects |
6
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
11
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Subjects were enrolled in the study at 8 centers in 5 countries between 11 November 2014 and 06 September 2016. A total of 14 subjects were screened in the study. | ||||||||||||
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Pre-assignment
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Screening details |
Out of 14 screened subjects, 11 subjects were enrolled and treated in the study. | ||||||||||||
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Period 1
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Period 1 title |
Overall period
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
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Arms
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Arm title
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GZ/SAR402671 | ||||||||||||
Arm description |
GZ/SAR402671 15 mg once daily, orally for 26 weeks. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
GZ/SAR402671
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
GZ/SAR402671 capsule, once daily for 26 weeks.
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Baseline characteristics reporting groups
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Reporting group title |
GZ/SAR402671
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Reporting group description |
GZ/SAR402671 15 mg once daily, orally for 26 weeks. | |||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
GZ/SAR402671
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Reporting group description |
GZ/SAR402671 15 mg once daily, orally for 26 weeks. | ||
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End point title |
Change From Baseline at Week 26 in Skin Globotriaosylceramide (GL-3) Score in Superficial Skin Capillary Endothelium: Number of Subjects in Categories of Shift in GL-3 Score From Baseline to Week 26 [1] | ||||||||||||||
End point description |
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). A single score per subject 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 subjects 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. Analysis was performed on Full Analysis Set (FAS) that included all subjects who received at least 1 dose of study treatment. Number of subjects analyzed=subjects with available data at both baseline and Week 26.
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End point type |
Primary
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End point timeframe |
Baseline, Week 26
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Single arm study. A McNemar test was used to assess the treatment effect based on paired pre-treatment and post-treatment (Week 26) frequencies of skin GL-3 score grouped into categories (0 to <2; 2 to 3) at the 5% significance level. p = 0.3173 |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Mean Change From Baseline at Week 26 in Skin GL-3 Score in Superficial Skin Capillary Endothelium [2] | ||||||||
End point description |
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). A single score per subject 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. Analysis was performed on FAS. Number of subjects analyzed=subjects with available data at both baseline and Week 26.
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End point type |
Primary
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End point timeframe |
Baseline, Week 26
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Single arm study. A Wilcoxon signed rank test was used to assess the mean change from baseline to Week 26 in skin GL-3 score at the 5% significance level. p = 0.625 |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Plasma GL-3 Concentration at Week 26 | ||||||||
End point description |
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. Analysis was performed on FAS. Number of subjects analyzed = subjects with available data at both baseline and Week 26.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Plasma Lyso Globotriaosylceramide (Lyso-GL-3) Concentration at Week 26 | ||||||||
End point description |
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. Analysis was performed on FAS. Number of subjects analyzed = subjects with available data at both baseline and Week 26.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Plasma Glucosylceramide (GL-1) Concentration at Week 26 | ||||||||
End point description |
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. Analysis was performed on FAS. Number of subjects analyzed = subjects with available data at both baseline and Week 26.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline at Week 26 in Skin GL-3 Score in Deep Vessels Endothelial Cells: Number of Subjects in Categories of Shift in GL-3 Score From Baseline to Week 26 | ||||||||||||
End point description |
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). A single score per subject 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 subjects 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. Analysis was performed on FAS. Number of subjects analyzed=subjects with available data at both baseline and Week 26.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline at Week 26 in Skin GL-3 Score in Deep Vessels Smooth Muscle Cells: Number of Subjects in Categories of Shift in GL-3 Score From Baseline to Week 26 | ||||||||||
End point description |
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). A single score per subject 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 subjects 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. Analysis was performed on FAS. Number of subjects analyzed=subjects with available data at both baseline and Week 26.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26
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| No statistical analyses for this end point | |||||||||||
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End point title |
Change From Baseline at Week 26 in Skin GL-3 Score in Perineurium Cells: Number of Subjects in Categories of Shift in GL-3 Score From Baseline to Week 26 | ||||||||||
End point description |
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). A single score per subject 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 subjects 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. Analysis was performed on FAS. Number of subjects analyzed=subjects with available data at both baseline and Week 26.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26
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| No statistical analyses for this end point | |||||||||||
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End point title |
Change From Baseline in Urine Globotriaosylceramide (GL-3) Concentration at Week 26 | ||||||||
End point description |
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 urine was determined using a validated LC-MS/MS method. Analysis was performed on FAS. Number of subjects analyzed = subjects with available data at both baseline and Week 26.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | ||||||
End point description |
Any untoward medical occurrence in a subject 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 subject, whichever occurs first). Analysis was performed on safety population defined as all enrolled subjects who received at least 1 dose of study drug.
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End point type |
Secondary
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End point timeframe |
Baseline up to 212 days
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| No statistical analyses for this end point | |||||||
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End point title |
Pharmacokinetics (PK): Maximum Plasma Drug Concentration (Cmax) of GZ/SAR402671 | ||||||||||||
End point description |
Maximum plasma concentration observed for study drug was reported. Analysis was performed on PK population defined as all subjects for whom the primary PK data were considered sufficient and interpretable. Here 'n' signifies number of subjects with available data for specified category.
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End point type |
Secondary
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End point timeframe |
Day 1 (predose and 1, 2, 4, 8, 24 hours post-dose); Day 182 (predose and 1, 2, 4, 8, 24 hours postdose)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
PK: Plasma Trough Concentration (Ctrough) of GZ/SAR402671 | ||||||||||||||||||||
End point description |
Ctrough was defined as the plasma concentration of study drug observed just before treatment administration during repeated dosing. Analysis was performed on PK population. Here 'n' signifies number of subjects with available data for specified category.
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End point type |
Secondary
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End point timeframe |
Predose on Day 14, 28, 56, 84, 126 and 182
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
PK: Time to Reach Maximum Plasma Drug Concentration (Tmax) of GZ/SAR402671 | ||||||||||||
End point description |
Tmax was defined as time to reach maximum plasma concentration of study drug. Analysis was performed on PK population. Here 'n' signifies number of subjects with available data for specified category.
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End point type |
Secondary
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End point timeframe |
Day 1 (predose and 1, 2, 4, 8, 24 hours post-dose); Day 182 (predose and 1, 2, 4, 8, 24 hours postdose)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
PK: Area Under Plasma Concentration Versus Time Curve From 0 to 24 Hours (AUC0-24) of GZ/SAR402671 | ||||||||||||
End point description |
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. Analysis was performed on PK population. Here 'n' signifies number of subjects with available data for specified category.
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End point type |
Secondary
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End point timeframe |
Day 1 (predose and 1, 2, 4, 8, 24 hours post-dose); Day 182 (predose and 1, 2, 4, 8, 24 hours postdose)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
PK: Terminal Half-life (t1/2z) of GZ/SAR402671 | ||||||||||||
End point description |
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. Analysis was performed on PK population. Here 'n' signifies number of subjects with available data for specified category.
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End point type |
Secondary
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End point timeframe |
Day 1 (predose and 1, 2, 4, 8, 24 hours post-dose); Day 182 (predose and 1, 2, 4, 8, 24 hours postdose)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
PK: Apparent Total Body Clearance of GZ/SAR402671 (CLss/F) | ||||||||
End point description |
Drug clearance was a quantitative measure of the rate at which a drug substance was removed from the blood. Analysis was performed on PK population. Number of subjects analyzed = subjects with available data for this end point.
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End point type |
Secondary
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End point timeframe |
Predose and 1, 2, 4, 8, 24 hours post-dose on Day 182
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| No statistical analyses for this end point | |||||||||
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End point title |
PK: Apparent Volume of Distribution of GZ/SAR402671 (Vss/F) at Steady State | ||||||||
End point description |
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. Since the percent extrapolation of AUC for all subjects was >30%, AUC could not be determined and hence, Vss/F could not be calculated.
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End point type |
Secondary
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End point timeframe |
Predose and 1, 2, 4, 8, 24 hours post-dose on Day 182
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| Notes [3] - Since percent extrapolation of AUC for all subjects was >30%, hence Vss/F could not be calculated. |
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| No statistical analyses for this end point | |||||||||
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End point title |
PK: Cumulated Amount of GZ/SAR402671 Excreted in Urine From 0 to 24 Hours (Ae0-24) | ||||||||
End point description |
Ae0-24 was the cumulated amount of study drug excreted in urine during the time interval of 0 to 24 hours. Analysis was performed on PK population. Number of subjects analyzed = subjects with available data for this end point.
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End point type |
Secondary
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End point timeframe |
0-24 hours on Day 182
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| No statistical analyses for this end point | |||||||||
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End point title |
PK: Percentage of Dose of GZ/SAR402671 Excreted in Urine From 0 to 24 Hours (fe0-24) | ||||||||
End point description |
fe0-24 was the fraction of dose excreted in urine during the time interval of 0 to 24 hours. Analysis was performed on PK population. Number of subjects analyzed = subjects with available data for this end point.
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End point type |
Secondary
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End point timeframe |
0-24 hours on Day 182
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| No statistical analyses for this end point | |||||||||
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End point title |
PK: Renal Clearance of GZ/SAR402671 From 0 to 24 Hours (CLR) | ||||||||
End point description |
Renal clearance (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. Analysis was performed on PK population. Number of subjects analyzed = subjects with available data for this end point.
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End point type |
Secondary
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End point timeframe |
0-24 hours on Day 182
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Baseline up to 212 days.
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Adverse event reporting additional description |
Reported AEs are TEAEs that is AEs developed/worsened during "on treatment period" (from first administration through last administration of study drug + 30 days or end of study participation for subject, whichever occurs first). Analysis was performed on safety population that included all enrolled subjects who received ≥1 dose of study drug.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.0
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Reporting groups
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Reporting group title |
GZ/SAR402671
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Reporting group description |
GZ/SAR402671 15 mg once daily, orally for 26 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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06 Aug 2014 |
Following changes were made: - Added ophthalmology exam at Week 12, as requested by the Medicines and Healthcare products Regulatory Agency; - Exclusion of the use of grapefruit, grapefruit juice, or grapefruit products for 72 hours prior to administration of first dose of study drug and for duration of 26-week treatment period. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
