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    Clinical Trial Results:
    A Phase 3, Randomized, Multi-Center, Multi-National, Open-Label, Active Comparator Study to Evaluate the Efficacy and Safety of Genz-112638 in Patients With Gaucher Disease Type 1 Who Have Reached Therapeutic Goals With Enzyme Replacement Therapy (ENCORE)

    Summary
    EudraCT number
    		 2008-005223-28
    Trial protocol
    		 NL   GB   FR   DE   ES   CZ   IT  
    Global end of trial date
    02 Jun 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    27 Oct 2016
    First version publication date
    02 Jun 2016
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Correction of subjects disposition data
    Summary report(s)
    		 GZGD02607

    Trial information

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    Trial identification
    Sponsor protocol code
    GZGD02607/EFC12812
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00943111
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Study Name: ENCORE
    Sponsors
    Sponsor organisation name
    Genzyme, a Sanofi Company
    Sponsor organisation address
    500 Kendall Street, Cambridge, MA, United States, 02142
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Jun 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy and safety of eliglustat compared with Cerezyme® (imiglucerase) after 52 weeks of treatment in subjects with Gaucher disease type 1 (GD1) who had reached therapeutic goals with enzyme replacement therapy (ERT).
    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.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Sep 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Argentina: 28
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Brazil: 27
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Egypt: 5
    Country: Number of subjects enrolled
    Russian Federation: 9
    Country: Number of subjects enrolled
    United States: 68
    Worldwide total number of subjects
    159
    EEA total number of subjects
    18
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    157
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 209 subjects were screened of which 46 subjects were screen failure and 3 subjects withdrew prior to randomization. A total of 160 subjects were enrolled in this study.

    Pre-assignment
    Screening details
    		 All enrolled subjects received eliglustat or imiglucerase in 52 week primary analysis period (PAP). After 52- weeks PAP, all subjects who remained on-study received eliglustat in the long-term treatment period (LTTP) for up to 5 years. One subject randomized to imiglucerase group but did not receive treatment.

    Period 1
    Period 1 title
    52-Weeks Primary Analysis Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Eliglustat: PAP
    Arm description
    		 Eliglustat tartrate (Genz-112638) 50 mg twice daily (BID) from Day 1 to Week 4 followed by eliglustat tartrate 50 mg or 100 mg BID up to Week 8, and then eliglustat tartrate 50 mg or 100 mg or 150 mg BID up to Week 52.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eliglustat tartrate
    Investigational medicinal product code
    Genz-112638/GZ385660
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    The dose adjustments after Week 4 and Week 8 were based on Genz-99067 (active moiety of eliglustat tartrate in plasma) trough plasma concentrations. If Genz-99067 trough plasma concentration was < 5 ng/mL, the next higher dose was administered whereas if the Genz-99067 trough plasma concentration was >= 5 ng/mL, the same dose was continued. The pharmacokinetic (PK) assessment at Week 2 and Week 6 were used for dose adjustment after Week 4 and Week 8, respectively.

    Arm title
    		 Imiglucerase: PAP
    Arm description
    		 Imiglucerase every other week (q2w) up to Week 52 in doses equivalent to subject’s past ERT dose prior to any unanticipated treatment interruption, dose reduction, or regimen change.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Imiglucerase
    Investigational medicinal product code
    Other name
    Cerezyme®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Imiglucerase intravenous infusion q2w up to Week 52.

    Number of subjects in period 1
    		Eliglustat: PAP Imiglucerase: PAP
    Started
    106
    53
    Completed
    104
    52
    Not completed
    2
    1
         Adverse Event
    2
    1
    Period 2
    Period 2 title
    5 Years Long-term Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Eliglustat: LTTP
    Arm description
    		 Subjects from both the arms of PAP who completed PAP were included in this arm of LTTP. Subjects originally randomized to eliglustat in PAP continued to receive eliglustat dose, based on their Genz 99067 plasma trough concentration at Week 6. Subjects originally randomized to imiglucerase received eliglustat tartrate 50 mg BID from Week 52+1 Day to Week 56 followed by eliglustat tartrate 50 mg or 100 mg BID up to Week 60, and then eliglustat tartrate 50 mg or 100 mg or 150 mg BID up to 5 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eliglustat tartrate
    Investigational medicinal product code
    Genz-112638/GZ385660
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    The dose adjustments after Week 56 and Week 60 were based on Genz-99067 (active moiety of eliglustat tartrate in plasma) trough plasma concentrations. If Genz-99067 trough plasma concentration was <5 ng/mL next higher dose was administered whereas if the Genz-99067 trough plasma concentration was >=5 ng/mL the same dose was continued. PK assessment at Week 54 and Week 58 were used for dose adjustment after Week 56 and Week 60, respectively.

    Number of subjects in period 2 [1]
    		Eliglustat: LTTP
    Started
    152
    Completed
    77
    Not completed
    75
         Adverse Event
    9
         Pregnancy
    4
         Transition to commercial eliglustat
    51
         Other than specified
    2
         Withdrawal by Subject
    8
         Lost to follow-up
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Subjects from both the arms of PAP who completed PAP and remained on-study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Eliglustat: PAP
    Reporting group description
    		 Eliglustat tartrate (Genz-112638) 50 mg twice daily (BID) from Day 1 to Week 4 followed by eliglustat tartrate 50 mg or 100 mg BID up to Week 8, and then eliglustat tartrate 50 mg or 100 mg or 150 mg BID up to Week 52.

    Reporting group title
    Imiglucerase: PAP
    Reporting group description
    		 Imiglucerase every other week (q2w) up to Week 52 in doses equivalent to subject’s past ERT dose prior to any unanticipated treatment interruption, dose reduction, or regimen change.

    Reporting group values
    		 Eliglustat: PAP Imiglucerase: PAP Total
    Number of subjects
    		 106 53 159
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 37.6 ( 14.17 ) 37.5 ( 14.92 ) -
    Gender categorical
    Units: Subjects
        Female
    		 59 28 87
        Male
    		 47 25 72
    Race
    Units: Subjects
        White
    		 98 48 146
        Black or African American
    		 6 4 10
        Asian
    		 1 1 2
        White/American Indian
    		 1 0 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 42 19 61
        Not Hispanic or Latino
    		 64 34 98
    Body Mass Index (BMI)
    BMI was calculated as ([weight in kg] divided by [height in cm multiplied by 0.01]^2).
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 25.2 ( 5.24 ) 24.5 ( 4.51 ) -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 70.8 ( 16.82 ) 67.8 ( 14.44 ) -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 167.6 ( 9.92 ) 166.2 ( 9.56 ) -

    End points

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    End points reporting groups
    Reporting group title
    Eliglustat: PAP
    Reporting group description
    		 Eliglustat tartrate (Genz-112638) 50 mg twice daily (BID) from Day 1 to Week 4 followed by eliglustat tartrate 50 mg or 100 mg BID up to Week 8, and then eliglustat tartrate 50 mg or 100 mg or 150 mg BID up to Week 52.

    Reporting group title
    Imiglucerase: PAP
    Reporting group description
    		 Imiglucerase every other week (q2w) up to Week 52 in doses equivalent to subject’s past ERT dose prior to any unanticipated treatment interruption, dose reduction, or regimen change.
    Reporting group title
    Eliglustat: LTTP
    Reporting group description
    		 Subjects from both the arms of PAP who completed PAP were included in this arm of LTTP. Subjects originally randomized to eliglustat in PAP continued to receive eliglustat dose, based on their Genz 99067 plasma trough concentration at Week 6. Subjects originally randomized to imiglucerase received eliglustat tartrate 50 mg BID from Week 52+1 Day to Week 56 followed by eliglustat tartrate 50 mg or 100 mg BID up to Week 60, and then eliglustat tartrate 50 mg or 100 mg or 150 mg BID up to 5 years.

    Primary: Percentage of Subjects Who Remained Stable for 52 Weeks During the Primary Analysis Period

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    End point title
    		 Percentage of Subjects Who Remained Stable for 52 Weeks During the Primary Analysis Period
    End point description
    For a subject to be classified as stable, the subject must have remained stable in hematological parameters (hemoglobin levels and platelet counts) and organ volumes (spleen, when applicable, and liver volumes in multiples of normal [MN]). Stable hematological parameters were defined as hemoglobin level did not decrease >1.5 g/dL from baseline and platelet count did not decrease >25% from baseline. Stable organ volumes were defined as spleen volume (in MN) did not increase >25% from baseline, if applicable, and liver volume (in MN) did not increase >20% from baseline. Analysis was performed on per protocol population for PAP included subjects who were at least 80% compliant with treatment during PAP, had no major protocol deviations, and did not exhibit hematological decline as a result of medically determined etiologies other than Gaucher disease.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 Eliglustat: PAP Imiglucerase: PAP
    Number of subjects analysed
    99
    47
    Units: percentage of subjects
        number (confidence interval 95%)
    84.8 (76.2 to 91.3)
    93.6 (82.5 to 98.7)
    Statistical analysis title
    		 Eliglustat: PAP vs. Imiglucerase: PAP
    Comparison groups
    Eliglustat: PAP v Imiglucerase: PAP
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Difference in Percentage Stable
    Point estimate
    -8.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.6
         upper limit
    		 4.2
    Notes
    [1] - The sample size for study was based on expected stability rates of 95% for the Imiglucerase group and 85% for the Eliglustat group, power of 85%, a one-sided significance level of 0.025, a non-inferiority margin of 25%, and a 20% non-evaluable/dropout rate. Eliglustat was declared non-inferior to Imiglucerase if the lower-bound of the 95% confidence interval for the difference was within the non inferiority margin of 25%.

    Primary: Percentage of Subjects Remaining Stable Annually for 4 Years During the LTTP

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    End point title
    		 Percentage of Subjects Remaining Stable Annually for 4 Years During the LTTP [2]
    End point description
    For a subject to be classified as stable, the subject must have remained stable in hematological parameters (hemoglobin levels and platelet counts) and organ volumes (spleen, when applicable, and liver volumes in MN). Stable hematological parameters were defined as hemoglobin level did not decrease >1.5 g/dL from baseline and platelet count did not decrease >25% from baseline. Stable organ volumes were defined as spleen volume (in MN) did not increase >25% from baseline, if applicable, and liver volume did not increase >20% from baseline. Analysis was performed on FAS population for LTTP: included all subjects who received at least 1 dose of eliglustat in the extension study period. Number of subjects analyzed= subjects at risk at specified time-points. Here 'n' signifies number of subjects with available data for specified time-points.
    End point type
    Primary
    End point timeframe
    Week 52 up to Week 208
    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: Due to EudraCT system constraint, the statistical analysis could not be provided for single arm.
    End point values
    		 Eliglustat: LTTP
    Number of subjects analysed
    152
    Units: percentage of subjects
    number (not applicable)
        Year 1 (n=127)
    83.6
        Year 2 (n= 115)
    75.65
        Year 3 (n= 92)
    60.53
        Year 4 (n= 41)
    26.97
    No statistical analyses for this end point

    Secondary: Total T-Scores for Bone Mineral Density

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    End point title
    		 Total T-Scores for Bone Mineral Density
    End point description
    Images of the spine and bilateral femur were obtained by dual-energy X-ray absorptiometry (DXA) to determine T-score for each bone area and total bone mineral density. T-score compares subject's bone density with that of healthy young subject. The T-score bone density categories are: normal (score >-1), osteopenia (score -2.5 to <=-1), and osteoporosis (score <=-2.5). Analysis was performed on per protocol population for PAP. Number of subjects analyzed = subjects with baseline T-score assessment. Here, 'n' signifies subjects with baseline T-score assessment for specified bone area.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Eliglustat: PAP Imiglucerase: PAP
    Number of subjects analysed
    81
    38
    Units: T-score
    arithmetic mean (standard deviation)
        Lumbar Spine T-Score (n=81, 38)
    -0.56 ( 1.309 )
    -0.33 ( 1.169 )
        Femur T-Score (n=80, 37)
    -0.11 ( 1.08 )
    -0.47 ( 1.293 )
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Total T-Scores for Bone Mineral Density at Week 52

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    End point title
    		 Absolute Change From Baseline in Total T-Scores for Bone Mineral Density at Week 52
    End point description
    Images of the spine and bilateral femur were obtained by DXA to determine T-score for each bone area and total bone mineral density. T-score compares subject's bone density with that of healthy young subject. The T-score bone density categories are: normal (score >-1), osteopenia (score -2.5 to <=-1), and osteoporosis (score <= -2.5). Absolute change = T-score at Week 52 minus T-score at baseline. Analysis was performed on per protocol population for PAP. Number of subjects analyzed = subjects with both baseline and Week 52 T-score assessment. Here, 'n' signifies subjects with both baseline and Week 52 T-score assessment for specified bone area. Eliglustat subjects switching to imiglucerase were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Eliglustat: PAP Imiglucerase: PAP
    Number of subjects analysed
    81
    38
    Units: T-score
    least squares mean (standard error)
        Change in Lumbar Spine T-Score (n=81, 38)
    0.04 ( 0.03 )
    0.03 ( 0.05 )
        Change in Femur T-Score (n=80, 37)
    0 ( 0.02 )
    -0.03 ( 0.03 )
    No statistical analyses for this end point

    Secondary: Total Z-Scores for Bone Mineral Density

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    End point title
    		 Total Z-Scores for Bone Mineral Density
    End point description
    Images of the spine and bilateral femur were obtained by DXA to determine Z-score for each bone area and total bone mineral density. The Z-score bone density categories are: normal (score >-2) and below normal (score <=-2). Per protocol population for PAP. Number of subjects analyzed = subjects with baseline Z-score assessment. Here, 'n' signifies subjects with baseline Z-score assessment for specified bone area.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Eliglustat: PAP Imiglucerase: PAP
    Number of subjects analysed
    94
    45
    Units: Z-score
    arithmetic mean (standard deviation)
        Lumbar Spine Z-Score (n=94, 45)
    -0.35 ( 1.26 )
    -0.14 ( 1.108 )
        Femur Z-Score (n=93, 44)
    0.09 ( 1.02 )
    -0.18 ( 1.122 )
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Total Z-Scores for Bone Mineral Density at Week 52

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    End point title
    		 Absolute Change From Baseline in Total Z-Scores for Bone Mineral Density at Week 52
    End point description
    Images of the spine and bilateral femur were obtained by DXA to determine Z-score for each bone area and total bone mineral density. The Z-score bone density categories are: normal (score >-2) and below normal (score <=-2). Absolute change = Z-score at Week 52 minus Z-score at baseline. Analysis was performed on per protocol population for PAP. Number of subjects analyzed = subjects with both baseline and Week 52 Z-score assessment. Here, 'n' signifies subjects with both baseline and Week 52 Z-score assessment for specified bone area. Eliglustat subjects switching to imiglucerase were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Eliglustat: PAP Imiglucerase: PAP
    Number of subjects analysed
    94
    45
    Units: Z-score
    least squares mean (standard error)
        Change in Lumbar Spine Z-Score (n=94, 45)
    0.06 ( 0.03 )
    0.06 ( 0.04 )
        Change in Femur Z-Score (n=93, 44)
    0.03 ( 0.02 )
    0.02 ( 0.02 )
    No statistical analyses for this end point

    Secondary: Hemoglobin Level

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    End point title
    		 Hemoglobin Level
    End point description
    Analysis was performed on per protocol population for PAP. Number of subjects analyzed = subjects with baseline hemoglobin assessment.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Eliglustat: PAP Imiglucerase: PAP
    Number of subjects analysed
    98
    47
    Units: g/dL
    arithmetic mean (standard deviation)
        Hemoglobin Level
    13.592 ( 1.2467 )
    13.797 ( 1.2234 )
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Hemoglobin Levels at Week 52

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    End point title
    		 Absolute Change From Baseline in Hemoglobin Levels at Week 52
    End point description
    Absolute change = hemoglobin level at Week 52 minus hemoglobin level at baseline. Analysis was performed on per protocol population for PAP. Number of subjects analyzed = subjects with both baseline and Week 52 hemoglobin assessment. Eliglustat subjects switching to imiglucerase were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Eliglustat: PAP Imiglucerase: PAP
    Number of subjects analysed
    98
    47
    Units: g/dL
        least squares mean (standard error)
    -0.22 ( 0.07 )
    0.05 ( 0.1 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Platelet Counts at Week 52

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    End point title
    		 Percent Change From Baseline in Platelet Counts at Week 52
    End point description
    Percent change in platelet counts = ([platelet count at Week 52 minus platelet count at baseline] divided by [platelet count at baseline]) multiplied by 100. Analysis was performed on per protocol population for PAP. Number of subjects analyzed = subjects with both baseline and Week 52 platelet assessment. Eliglustat subjects switching to imiglucerase were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Eliglustat: PAP Imiglucerase: PAP
    Number of subjects analysed
    98
    47
    Units: percent change
        least squares mean (standard error)
    3.93 ( 1.71 )
    2.63 ( 2.47 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Spleen Volume (in MN) at Week 52

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    End point title
    		 Percent Change From Baseline in Spleen Volume (in MN) at Week 52
    End point description
    Percent change in spleen volume = ([spleen volume at Week 52 minus spleen volume at baseline] divided by [spleen volume at baseline]) multiplied by 100, where all volumes are in MN. Analysis was performed on per protocol population for PAP. Number of subjects analyzed = subjects with both baseline and Week 52 spleen volume assessment. Eliglustat subjects switching to imiglucerase were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Eliglustat: PAP Imiglucerase: PAP
    Number of subjects analysed
    70
    39
    Units: percent change
        least squares mean (standard error)
    -6.05 ( 1.57 )
    -3.22 ( 2.13 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Liver Volume (in MN) at Week 52

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    End point title
    		 Percent Change From Baseline in Liver Volume (in MN) at Week 52
    End point description
    Percent change in liver volume = ([liver volume at Week 52 minus liver volume at baseline] divided by [liver volume at baseline]) multiplied by 100, where all volumes are in multiples of normal. Analysis was performed on per protocol population for PAP. Number of subjects analyzed = subjects with both baseline and Week 52 liver volume assessment. Eliglustat subjects switching to imiglucerase were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Eliglustat: PAP Imiglucerase: PAP
    Number of subjects analysed
    98
    47
    Units: percent change
        least squares mean (standard error)
    1.99 ( 0.94 )
    3.13 ( 1.36 )
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Total T-Scores for Bone Mineral Density at Week 208

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    End point title
    		 Absolute Change From Baseline in Total T-Scores for Bone Mineral Density at Week 208
    End point description
    Images of the spine and bilateral femur were obtained by DXA to determine T-score for each bone area and total bone mineral density. T-score compares subject's bone density with that of healthy young subject. The T-score bone density categories are: normal (score >-1), osteopenia (score -2.5 to <=-1), and osteoporosis (score <= -2.5). Absolute change = T-score at Week 208 minus T-score at baseline. Number of subjects analyzed = subjects with both baseline and Week 208 T-score assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 208
    End point values
    		 Eliglustat: LTTP
    Number of subjects analysed
    36
    Units: T-Score
    arithmetic mean (standard deviation)
        Total Spine
    0.22 ( 0.405 )
        Total Femur
    -0.03 ( 0.345 )
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Total Z-Scores for Bone Mineral Density at Week 208

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    End point title
    		 Absolute Change From Baseline in Total Z-Scores for Bone Mineral Density at Week 208
    End point description
    Images of the spine and bilateral femur were obtained by DXA to determine Z-score for each bone area and total bone mineral density. The Z-score bone density categories are: normal (score >-2) and below normal (score <=-2). Absolute change = Z-score at Week 208 minus Z-score at baseline. Analysis was performed on FAS population for LTTP. Number of subjects analyzed = subjects with both baseline and Week 208 Z-score assessment. Here, 'n' signifies subjects with both baseline and Week 208 Z-score assessment for specified bone area.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 208
    End point values
    		 Eliglustat: LTTP
    Number of subjects analysed
    42
    Units: Z-score
    arithmetic mean (standard deviation)
        Total Spine
    0.29 ( 0.358 )
        Total Femur
    0.03 ( 0.381 )
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Hemoglobin Levels at Week 208

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    End point title
    		 Absolute Change From Baseline in Hemoglobin Levels at Week 208
    End point description
    Absolute change = hemoglobin level at Week 208 minus hemoglobin level at baseline. Analysis was performed on FAS population for LTTP. Number of subjects analyzed = subjects with both baseline and Week 208 hemoglobin assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 208
    End point values
    		 Eliglustat: LTTP
    Number of subjects analysed
    45
    Units: g/dL
        arithmetic mean (standard deviation)
    0.297 ( 0.7472 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Platelet Counts at Week 208

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    End point title
    		 Percent Change From Baseline in Platelet Counts at Week 208
    End point description
    Percent change in platelet counts = ([platelet count at Week 208 minus platelet count at baseline] divided by [platelet count at baseline]) multiplied by 100. Analysis was performed on FAS population for LTTP. Number of subjects analyzed = subjects with both baseline and Week 208 platelet assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 208
    End point values
    		 Eliglustat: LTTP
    Number of subjects analysed
    45
    Units: percent change
        arithmetic mean (standard deviation)
    6.99 ( 20.4382 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Spleen Volume (in MN) at Week 208

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    End point title
    		 Percent Change From Baseline in Spleen Volume (in MN) at Week 208
    End point description
    Percent change in spleen volume = ([spleen volume at Week 208 minus spleen volume at baseline] divided by [spleen volume at baseline]) multiplied by 100, where all volumes are in MN. Analysis was performed on FAS population for LTTP. Number of subjects analyzed = subjects with both baseline and Week 208 spleen volume assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 208
    End point values
    		 Eliglustat: LTTP
    Number of subjects analysed
    33
    Units: percent change
        arithmetic mean (standard deviation)
    -14.768 ( 17.9435 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Liver Volume (in MN) at Week 208

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    End point title
    		 Percent Change From Baseline in Liver Volume (in MN) at Week 208
    End point description
    Percent change in liver volume = ([liver volume at Week 208 minus liver volume at baseline] divided by [liver volume at baseline]) multiplied by 100, where all volumes are in multiples of normal. Analysis was performed on FAS population for LTTP. Number of subjects analyzed = subjects with both baseline and Week 208 liver volume assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 208
    End point values
    		 Eliglustat: LTTP
    Number of subjects analysed
    46
    Units: percent change
        arithmetic mean (standard deviation)
    -2.345 ( 12.8795 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signature of informed consent up to 30-37 days after the last dose of treatment (last dose = up to Week 104)
    Adverse event reporting additional description
    Safety set included all subjects who received at least 1 dose of study drug (Eliglustat or Imiglucerase). In the event a single subject experienced both serious and non-serious forms of same adverse events (AE), individual was included in numerator (number of subjects affected) of each AE table.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Imiglucerase
    Reporting group description
    		 PAP: Imiglucerase q2w up to Week 52 in doses equivalent to subject's past ERT dose prior to any unanticipated treatment interruption, dose reduction, or regimen change. LTTP: Subjects originally randomized to imiglucerase received eliglustat tartrate 50 mg BID from Week 52+1 Day to Week 56 followed by eliglustat tartrate 50 mg or 100 mg BID up to Week 60, and then eliglustat tartrate 50 mg or 100 mg or 150 mg BID up to 5 years. The dose adjustments after Week 56 and Week 60 were based on Genz­99067 (active moiety of eliglustat tartrate in plasma) trough plasma concentrations.

    Reporting group title
    Eliglustat
    Reporting group description
    		 PAP: Eliglustat tartrate 50 mg BID from Day 1 to Week 4, followed by eliglustat tartrate 50, 100 or 150 mg BID up to Week 52. Dose adjustments after Week 4 and Week 8 were based on Genz­99067 (active moiety of eliglustat tartrate in plasma) trough plasma concentrations. LTTP: Subjects originally randomized to eliglustat in PAP continued to receive eliglustat dose, based on their Genz 99067 plasma trough concentration at Week 6.

    Serious adverse events
    		 Imiglucerase Eliglustat
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 53 (13.21%)
    18 / 106 (16.98%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign Ovarian Tumour
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic Renal Cell Carcinoma
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine Leiomyoma
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic Carcinoma Metastatic
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Injury
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint Dislocation
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Mammoplasty
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Neuropathy Peripheral
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 106 (2.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Polycythaemia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Device Malfunction
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis Ischaemic
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary Colic
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal Septum Deviation
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Imiglucerase Eliglustat
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 53 (71.70%)
    91 / 106 (85.85%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 53 (1.89%)
    6 / 106 (5.66%)
         occurrences all number
    1
    6
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 53 (1.89%)
    10 / 106 (9.43%)
         occurrences all number
    1
    10
    Chest Pain
         subjects affected / exposed
    1 / 53 (1.89%)
    9 / 106 (8.49%)
         occurrences all number
    1
    9
    Fatigue
         subjects affected / exposed
    7 / 53 (13.21%)
    20 / 106 (18.87%)
         occurrences all number
    7
    20
    Pain
         subjects affected / exposed
    3 / 53 (5.66%)
    6 / 106 (5.66%)
         occurrences all number
    3
    6
    Peripheral Swelling
         subjects affected / exposed
    1 / 53 (1.89%)
    6 / 106 (5.66%)
         occurrences all number
    1
    6
    Pyrexia
         subjects affected / exposed
    3 / 53 (5.66%)
    2 / 106 (1.89%)
         occurrences all number
    3
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 53 (3.77%)
    11 / 106 (10.38%)
         occurrences all number
    2
    11
    Epistaxis
         subjects affected / exposed
    1 / 53 (1.89%)
    7 / 106 (6.60%)
         occurrences all number
    1
    7
    Oropharyngeal Pain
         subjects affected / exposed
    3 / 53 (5.66%)
    7 / 106 (6.60%)
         occurrences all number
    3
    7
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 53 (1.89%)
    10 / 106 (9.43%)
         occurrences all number
    1
    10
    Depression
         subjects affected / exposed
    3 / 53 (5.66%)
    3 / 106 (2.83%)
         occurrences all number
    3
    3
    Investigations
    Mean Cell Volume Abnormal
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 106 (0.00%)
         occurrences all number
    3
    0
    Blood Creatine Phosphokinase Increased
         subjects affected / exposed
    3 / 53 (5.66%)
    16 / 106 (15.09%)
         occurrences all number
    3
    16
    Nerve Conduction Studies Abnormal
         subjects affected / exposed
    3 / 53 (5.66%)
    7 / 106 (6.60%)
         occurrences all number
    3
    7
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 53 (3.77%)
    7 / 106 (6.60%)
         occurrences all number
    2
    7
    Laceration
         subjects affected / exposed
    1 / 53 (1.89%)
    7 / 106 (6.60%)
         occurrences all number
    1
    7
    Ligament Sprain
         subjects affected / exposed
    0 / 53 (0.00%)
    8 / 106 (7.55%)
         occurrences all number
    0
    8
    Limb Injury
         subjects affected / exposed
    0 / 53 (0.00%)
    6 / 106 (5.66%)
         occurrences all number
    0
    6
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    3 / 53 (5.66%)
    8 / 106 (7.55%)
         occurrences all number
    3
    8
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 53 (7.55%)
    18 / 106 (16.98%)
         occurrences all number
    4
    18
    Headache
         subjects affected / exposed
    9 / 53 (16.98%)
    26 / 106 (24.53%)
         occurrences all number
    9
    26
    Paraesthesia
         subjects affected / exposed
    1 / 53 (1.89%)
    7 / 106 (6.60%)
         occurrences all number
    1
    7
    Hypoaesthesia
         subjects affected / exposed
    1 / 53 (1.89%)
    6 / 106 (5.66%)
         occurrences all number
    1
    6
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    6 / 53 (11.32%)
    14 / 106 (13.21%)
         occurrences all number
    6
    14
    Abdominal Pain Lower
         subjects affected / exposed
    0 / 53 (0.00%)
    6 / 106 (5.66%)
         occurrences all number
    0
    6
    Abdominal Pain Upper
         subjects affected / exposed
    3 / 53 (5.66%)
    26 / 106 (24.53%)
         occurrences all number
    3
    26
    Constipation
         subjects affected / exposed
    6 / 53 (11.32%)
    10 / 106 (9.43%)
         occurrences all number
    6
    10
    Diarrhoea
         subjects affected / exposed
    2 / 53 (3.77%)
    20 / 106 (18.87%)
         occurrences all number
    2
    20
    Gastritis
         subjects affected / exposed
    5 / 53 (9.43%)
    6 / 106 (5.66%)
         occurrences all number
    5
    6
    Dyspepsia
         subjects affected / exposed
    4 / 53 (7.55%)
    15 / 106 (14.15%)
         occurrences all number
    4
    15
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    2 / 53 (3.77%)
    13 / 106 (12.26%)
         occurrences all number
    2
    13
    Nausea
         subjects affected / exposed
    7 / 53 (13.21%)
    18 / 106 (16.98%)
         occurrences all number
    7
    18
    Toothache
         subjects affected / exposed
    3 / 53 (5.66%)
    7 / 106 (6.60%)
         occurrences all number
    3
    7
    Vomiting
         subjects affected / exposed
    0 / 53 (0.00%)
    10 / 106 (9.43%)
         occurrences all number
    0
    10
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    3 / 53 (5.66%)
    5 / 106 (4.72%)
         occurrences all number
    3
    5
    Skin and subcutaneous tissue disorders
    Dry Skin
         subjects affected / exposed
    4 / 53 (7.55%)
    5 / 106 (4.72%)
         occurrences all number
    4
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    13 / 53 (24.53%)
    38 / 106 (35.85%)
         occurrences all number
    13
    38
    Back Pain
         subjects affected / exposed
    6 / 53 (11.32%)
    23 / 106 (21.70%)
         occurrences all number
    6
    23
    Bone Pain
         subjects affected / exposed
    3 / 53 (5.66%)
    9 / 106 (8.49%)
         occurrences all number
    3
    9
    Muscle Spasms
         subjects affected / exposed
    1 / 53 (1.89%)
    6 / 106 (5.66%)
         occurrences all number
    1
    6
    Musculoskeletal Pain
         subjects affected / exposed
    3 / 53 (5.66%)
    8 / 106 (7.55%)
         occurrences all number
    3
    8
    Myalgia
         subjects affected / exposed
    2 / 53 (3.77%)
    6 / 106 (5.66%)
         occurrences all number
    2
    6
    Pain In Extremity
         subjects affected / exposed
    5 / 53 (9.43%)
    21 / 106 (19.81%)
         occurrences all number
    5
    21
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 53 (3.77%)
    8 / 106 (7.55%)
         occurrences all number
    2
    8
    Gastroenteritis
         subjects affected / exposed
    2 / 53 (3.77%)
    11 / 106 (10.38%)
         occurrences all number
    2
    11
    Influenza
         subjects affected / exposed
    6 / 53 (11.32%)
    20 / 106 (18.87%)
         occurrences all number
    6
    20
    Nasopharyngitis
         subjects affected / exposed
    10 / 53 (18.87%)
    28 / 106 (26.42%)
         occurrences all number
    10
    28
    Upper Respiratory Tract Infection
         subjects affected / exposed
    7 / 53 (13.21%)
    21 / 106 (19.81%)
         occurrences all number
    7
    21
    Sinusitis
         subjects affected / exposed
    3 / 53 (5.66%)
    20 / 106 (18.87%)
         occurrences all number
    3
    20
    Urinary Tract Infection
         subjects affected / exposed
    3 / 53 (5.66%)
    16 / 106 (15.09%)
         occurrences all number
    3
    16

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Oct 2009
    - Treatment duration for the PAP was increased to 52 weeks in response to regulatory agency feedback. - Changed to a non-inferiority study design (versus Cerezyme) in response to regulatory agency feedback. - Nerve conduction assessments and analysis were added to the safety analyses. - Inclusion/exclusion criteria were modified to ensure study conduct in subjects receiving long-term Cerezyme treatment. - An Independent Adjudication Board (IAB) was added to confirm whether failure to meet the primary endpoint during the 52-week PAP could be attributed to a decline in GD. - Prior and concomitant medication guidelines were revised, including the following: added restrictions for cytochrome P450 (CYP) 3A4 inducers and CYP3A4 strong inhibitors in all subjects.
    05 May 2010
    - The duration of study participation was extended for individual subjects. - Enrollment to a broader subject population was expanded based on subject age, including subjects who were >65 years of age, and prior ERT therapy; i.e, subjects previously receiving Cerezyme or velaglucerase were eligible for the study. - Prior and concomitant medication guidelines were revised, including the following: Restrictions related to ingestion of grapefruit or grapefruit juice 72 hours prior to the first dose of study medication; Inducers of CYP3A4 were prohibited in all subjects; Strong CYP3A4 inhibitors were prohibited in subjects who were CYP2D6 poor metabolizers; An exception was added for temporary use of CYP3A4 inducers and strong inhibitors of CYP2D6 and CYP3A4 after completion of dose adjustment in each treatment period, and an exception for new chronic use of these medications after completion of dose adjustment in the LTTP.
    29 Nov 2010
    - The exclusion of subjects who received ERT therapy with taliglucerase was removed based on preliminary data indicating subjects were able to maintain GD therapeutic goals on taliglucerase. - Subjects without historical X-ray or magnetic resonance imaging (MRI) scans but whose screening images confirmed that any bone findings were not acute in origin were eligible for inclusion in the study. - The analysis of organ volume measurements in subjects who had a repeat measurement was modified such that only the repeat measurement was to be used in statistical analyses, rather than the average of the original and repeat measurements. This change was made because the original percent increase in organ volume could potentially be due to a transient condition unrelated to GD or treatment response.
    06 Jul 2011
    - It included the implementation of additional monitoring in subjects with a peak plasma concentration ≥150 ng/mL. - Planned enrollment was reduced from 186 subjects to 132 subjects. The underlying sample size assumptions were unchanged, and the study remained adequately powered for the primary efficacy endpoint (80% power for 132 subjects compared with a previous estimate of 90% power for 186 subjects) and all secondary endpoints. - US Food and Drug Administration (FDA)-recommended efficacy endpoint was added for the non-inferiority analysis as the percentage change in spleen volume (in MN) from baseline to Week 52. - Prior and concomitant medication guidelines were revised, including the following: Grapefruit products were added to the list of restricted medications prior to first dose of treatment; An exception was added for temporary use of medications known to prolong QTc interval, after completion of the dose adjustment in either treatment period.
    13 Mar 2012
    - Sample size, which had been adjusted downward to 132 subjects in previous amendment, was reverted to 150 subjects. - Clarified the length of time subjects randomized to eliglustat were to be followed in the study after any clinical decline requiring Cerezyme therapy. - Prior and concomitant medication guidelines were revised, including the following: A definition of concomitant medications was added; Requirements were added to notify the Sponsor's Medical Monitor in the event of temporary use of a CYP3A4 inducer and to interrupt the dose of eliglustat during temporary use of strong inhibitors of CYP2D6 or CYP3A4. - A statement about the potential for eliglustat to increase the exposure of P-glycoprotein substrate drugs was added. - Clarified that CYP2D6 non-poor metabolizer subjects could be on chronic therapy with a strong inhibitor of CYP2D6 or CYP3A4 (but not both) when entering the LTTP. Chronic therapy with strong CYP3A4 inhibitors remained prohibited in CYP2D6 poor metabolizers.
    31 Jan 2013
    - Added text was updated to include moderate CYP2D6 and CYP3A4 inhibitors. - Text was added to include specific PK sampling points for subjects who started or changed current chronic treatment of these medications. - Information on taliglucerase was added. - The eliglustat benefits/risk summary was updated to include results of the metropol study. - Added text was revised to include effects of Genz-112638 on CYP2D6 substrates. - Updated yexy was added to provide guidance regarding use of concomitant medications as of the date of this amendment.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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