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    Clinical Trial Results:
    An Open-label Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of REPLAGAL® in Treatment-naïve Chinese Subjects with Fabry Disease

    Summary
    EudraCT number
    		 2022-004246-35
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    03 Jan 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Jul 2024
    First version publication date
    18 Jul 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TAK-675-3001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04974749
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    95 Hayden Avenue, Lexington, United States, MA 02421
    Public contact
    Study Director, Takeda, TrialDisclosures@takeda.com
    Scientific contact
    Study Director, Takeda, TrialDisclosures@takeda.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Jan 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jan 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of this study is to assess the safety of REPLAGAL in treatment-naïve Chinese participants with Fabry disease.
    Protection of trial subjects
    Each participant signed an informed consent form (ICF) before participating in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 May 2022
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    China: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    0
    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)
    2
    Adolescents (12-17 years)
    5
    Adults (18-64 years)
    13
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at 6 investigative sites in China from 1 May 2022 to 3 January 2024.

    Pre-assignment
    Screening details
    		 A total of 20 participants with Fabry disease were enrolled in this study to receive REPLAGAL for 52 weeks.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 REPLAGAL
    Arm description
    		 Participants received REPLAGAL 0.2 milligrams per kilogram (mg/kg) body weight, intravenous (IV) infusion, every other week (EOW) from Day 1 (Week 0) up to Week 52.
    Arm type
    		 Experimental

    Investigational medicinal product name
    REPLAGAL
    Investigational medicinal product code
    Other name
    Agalsidase Alfa, TAK-675
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received REPLAGAL 0.2 mg/kg body weight, infusion, IV, EOW for 52 weeks.

    Number of subjects in period 1
    		REPLAGAL
    Started
    20
    Completed
    17
    Not completed
    3
         Consent withdrawn by subject
    2
         Gestation
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    REPLAGAL
    Reporting group description
    		 Participants received REPLAGAL 0.2 milligrams per kilogram (mg/kg) body weight, intravenous (IV) infusion, every other week (EOW) from Day 1 (Week 0) up to Week 52.

    Reporting group values
    		 REPLAGAL Total
    Number of subjects
    		 20
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 30.1 ( 14.90 ) -
    Gender categorical
    Units: Subjects
        Female
    		 12 12
        Male
    		 8 8
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 20 20
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 0 0
        White
    		 0 0
        More than one race
    		 0 0
        Unknown or Not Reported
    		 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0
        Not Hispanic or Latino
    		 20 20
        Unknown or Not Reported
    		 0 0
    Height
    Units: centimeters (cm)
        arithmetic mean (standard deviation)
    		 160.47 ( 9.271 ) -
    Weight
    Units: kilograms (kg)
        arithmetic mean (standard deviation)
    		 53.88 ( 10.370 ) -
    Body Mass Index (BMI)
    BMI = weight (kg)/[height (m)^2]
    Units: kilograms per meter square (kg/m^2)
        arithmetic mean (standard deviation)
    		 20.87 ( 3.674 ) -

    End points

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    End points reporting groups
    Reporting group title
    REPLAGAL
    Reporting group description
    		 Participants received REPLAGAL 0.2 milligrams per kilogram (mg/kg) body weight, intravenous (IV) infusion, every other week (EOW) from Day 1 (Week 0) up to Week 52.

    Primary: Number of Participants With Serious Treatment-emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Participants With Serious Treatment-emergent Adverse Events (TEAEs) [1]
    End point description
    An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that did not necessarily have a causal relationship with this investigational product (IP) or medicinal product. Serious AE was any untoward medical occurrence (whether considered to be related to investigational product or not) that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital abnormality/birth defect, and was an important medical event. A TEAE was defined as any event emerging at or after the initiation of treatment with an IP or any existing event that worsened in either intensity or frequency following exposure to the IP until the end of the safety follow-up period. Safety Analysis Set included all participants in the ITT Set who received at least 1 dose of REPLAGAL.
    End point type
    Primary
    End point timeframe
    From start of study drug administration up to 14 days after end of treatment (EOT) [up to Week 54]
    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: Only descriptive analysis was planned for this endpoint.
    End point values
    		 REPLAGAL
    Number of subjects analysed
    20
    Units: participants
    2
    No statistical analyses for this end point

    Secondary: Number of Participants With TEAEs

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    End point title
    		 Number of Participants With TEAEs
    End point description
    An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that did not necessarily have a causal relationship with this investigational product or medicinal product. A TEAE was defined as any event emerging at or after the initiation of treatment with an IP or any existing event that worsened in either intensity or frequency following exposure to the IP until the end of the safety follow-up period. Safety Analysis Set included all participants in the Intent-to-treat (ITT) Set who received at least 1 dose of REPLAGAL.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 14 days after EOT (up to Week 54)
    End point values
    		 REPLAGAL
    Number of subjects analysed
    20
    Units: participants
    20
    No statistical analyses for this end point

    Secondary: Number of Participants With Infusion-related Reactions (IRRs)

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    End point title
    		 Number of Participants With Infusion-related Reactions (IRRs)
    End point description
    An IRR was defined as an event that began either during or within 24 hours after the start of the infusion, and was judged as related to treatment with the IP. An IRR could be serious or non-serious. Adverse events that were considered IRRs were noted as such in the participant’s source documentation. Other AEs which occurred prior to the infusion, along with AEs associated with protocol-defined testing and assessments (example, laboratory testing and physical examinations), which were performed prior to the infusion, were not considered as IRRs. Safety Analysis Set included all participants in the ITT Set who received at least 1 dose of REPLAGAL.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to Week 52
    End point values
    		 REPLAGAL
    Number of subjects analysed
    20
    Units: participants
    5
    No statistical analyses for this end point

    Secondary: Number of Participants With Clinically Meaningful Changes in Laboratory Parameters

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    End point title
    		 Number of Participants With Clinically Meaningful Changes in Laboratory Parameters
    End point description
    Laboratory assessment included parameters of serum chemistry, hematology, and urinalysis. Clinically meaningful laboratory parameters assessment was based on investigator interpretation. Number of participants with clinically meaningful changes in laboratory parameters were reported. Safety Analysis Set included all participants in the ITT Set who received at least 1 dose of REPLAGAL.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to Week 52
    End point values
    		 REPLAGAL
    Number of subjects analysed
    20
    Units: participants
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in eGFR Values at Weeks 8, 16, 28, and 40

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    End point title
    		 Change From Baseline in eGFR Values at Weeks 8, 16, 28, and 40
    End point description
    The eGFR was calculated by CKD-EPI formula for ≥18 years participants, eGFR = 141 x min (Scr/κ,1)^(α) x max(Scr/κ,1)^(-1.209) x 0.993^(Age) x 1.018 (if female) x 1.159 (if black) where: Scr is serum creatinine (mg/dL); κ is 0.7 for females and 0.9 for males; α is -0.329 for females and -0.411 for males; min indicates the minimum of Scr/κ or 1; max indicates the maximum of Scr /κ or 1. For <18 years participants, Counahan-Barratt equation was used for calculation of eGFR. eGFR = (0.43 × height in cm)/Scr where, Scr is serum creatinine (mg/dL). mITT Set included all enrolled participants who had received at least 1 dose of investigational product and completed at least 1 post-baseline efficacy assessment of the endpoints. 'n' denotes the number of participants with data available for analysis at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 8, 16, 28, and 40
    End point values
    		 REPLAGAL
    Number of subjects analysed
    19
    Units: mL/min/1.73m^2
    arithmetic mean (standard deviation)
        Week 8 (n=18)
    -1.2 ( 15.66 )
        Week 16 (n=18)
    -0.4 ( 13.67 )
        Week 28 (n=17)
    5.1 ( 11.25 )
        Week 40 (n=16)
    0.3 ( 13.17 )
    No statistical analyses for this end point

    Secondary: Number of Participants With Positive Anti-drug Antibodies (ADA) to REPLAGAL

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    End point title
    		 Number of Participants With Positive Anti-drug Antibodies (ADA) to REPLAGAL
    End point description
    Number of participants with positive ADA to REPLAGAL were reported. Safety Analysis Set included all participants in the ITT Set who received at least 1 dose of REPLAGAL.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 REPLAGAL
    Number of subjects analysed
    20
    Units: participants
    6
    No statistical analyses for this end point

    Secondary: Number of Participants With Clinically Meaningful Changes in Vital Signs

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    End point title
    		 Number of Participants With Clinically Meaningful Changes in Vital Signs
    End point description
    Vital sign assessment included pulse, blood pressure, respiratory rate, and temperature. Clinically meaningful vital signs assessment was based on investigator interpretation. Number of participants with clinically meaningful abnormalities in vital signs were reported. Safety Analysis Set included all participants in the ITT Set who received at least 1 dose of REPLAGAL.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to Week 52
    End point values
    		 REPLAGAL
    Number of subjects analysed
    20
    Units: participants
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Clinically Meaningful Changes in Electrocardiogram (ECG) Parameters

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    End point title
    		 Number of Participants With Clinically Meaningful Changes in Electrocardiogram (ECG) Parameters
    End point description
    ECG parameters included assessment of heart rate, sinus rhythm, atrial or ventricular hypertrophy, and assessment of PR, QRS, QT, and corrected QT intervals. Clinically meaningful ECG assessment was based on investigator interpretation. Number of participants with clinically meaningful abnormalities in 12-lead ECG were reported. Safety Analysis Set included all participants in the ITT Set who received at least 1 dose of REPLAGAL.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to Week 52
    End point values
    		 REPLAGAL
    Number of subjects analysed
    20
    Units: participants
    0
    No statistical analyses for this end point

    Secondary: Renal Function as Assessed by Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 52

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    End point title
    		 Renal Function as Assessed by Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 52
    End point description
    Renal function was assessed by eGFR using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula for ≥18 years participants, eGFR = 141 x min (Scr/κ,1)^(α) x max(Scr/κ,1)^(-1.209) x 0.993^(Age) x 1.018 (if female) x 1.159 (if black) where: Scr is serum creatinine (milligram per deciliter [mg/dL]); κ is 0.7 for females and 0.9 for males; α is -0.329 for females and -0.411 for males; min indicates the minimum of Scr/κ or 1; max indicates the maximum of Scr /κ or 1. For <18 years participants, Counahan-Barratt equation was used for calculation of eGFR. eGFR = (0.43 × height in centimeter [cm])/Scr where, Scr is serum creatinine (mg/dL). Renal function as assessed by eGFR was expressed using the unit: milliliters/minute/1.73 meter square (mL/min/1.73m^2). Modified Intent-to-treat (mITT) Set included all enrolled participants who had received at least 1 dose of investigational product and completed at least 1 post-baseline efficacy assessment of the endpoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 REPLAGAL
    Number of subjects analysed
    19
    Units: mL/min/1.73m^2
        arithmetic mean (standard deviation)
    4.1 ( 12.48 )
    No statistical analyses for this end point

    Secondary: Number of Participants With Positive Neutralizing Antibodies (NAb) to REPLAGAL

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    End point title
    		 Number of Participants With Positive Neutralizing Antibodies (NAb) to REPLAGAL
    End point description
    Number of participants with positive NAb to REPLAGAL were reported. Safety Analysis Set included all participants in the ITT Set who received at least 1 dose of REPLAGAL.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 REPLAGAL
    Number of subjects analysed
    20
    Units: participants
    5
    No statistical analyses for this end point

    Secondary: Change From Baseline in Left Ventricular Mass Index (LVMI) at Weeks 16 and 52

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    End point title
    		 Change From Baseline in Left Ventricular Mass Index (LVMI) at Weeks 16 and 52
    End point description
    LVMI was measured by echocardiography at the clinical sites, and LVMI was derived using the following formula: LVM [grams] = 0.8×[1.04×{(LVDd + IVSTd + PWTd)^3 – LVDd^3}] + 0.6, where: LVDd is left ventricular internal diameter (diastolic) (cm), IVSTd is intraventricular septum thickness (diastolic) (cm), and PWTd is posterior wall thickness (diastolic) (cm). LVM indexed to height (LVMI) = LVM/height^2.7 (g/m^2.7), where height was measured in meter. mITT Set included all enrolled participants who had received at least 1 dose of investigational product and completed at least 1 post-baseline efficacy assessment of the endpoints. 'n' denotes the number of participants with data available for analysis at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 16 and 52
    End point values
    		 REPLAGAL
    Number of subjects analysed
    19
    Units: grams per meter (g/m)^2.7
    arithmetic mean (standard deviation)
        Week 16 (n=14)
    -0.4696 ( 6.81928 )
        Week 52 (n=12)
    -1.7261 ( 9.87836 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Urine Protein/Creatinine Ratio

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    End point title
    		 Change From Baseline in Urine Protein/Creatinine Ratio
    End point description
    The change from baseline in urine protein/creatinine ratio was derived from early morning spot urine samples collected at the specified time points. mITT Set included all enrolled participants who had received at least 1 dose of investigational product and completed at least 1 post-baseline efficacy assessment of the endpoints. 'n' denotes the number of participants with data available for analysis at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 8, 16, 28, 40, and 52
    End point values
    		 REPLAGAL
    Number of subjects analysed
    19
    Units: gram per gram
    arithmetic mean (standard deviation)
        Week 8 (n=18)
    0.0759 ( 0.17486 )
        Week 16 (n=18)
    0.1061 ( 0.21743 )
        Week 28 (n=16)
    0.0711 ( 0.16049 )
        Week 40 (n=14)
    0.0830 ( 0.16333 )
        Week 52 (n=17)
    0.0627 ( 0.16508 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Left Ventricular Ejection Fraction (LVEF) at Weeks 16 and 52

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    End point title
    		 Change From Baseline in Left Ventricular Ejection Fraction (LVEF) at Weeks 16 and 52
    End point description
    LVEF is the central measure of left ventricular systolic function. LVEF is the fraction of chamber volume ejected in systole (stroke volume) in relation to the volume of the blood in the ventricle at the end of diastole (end-diastolic volume). This was measured by echocardiography at the clinical sites. mITT Set included all enrolled participants who had received at least 1 dose of investigational product and completed at least 1 post-baseline efficacy assessment of the endpoints. 'n' denotes the number of participants with data available for analysis at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 16 and 52
    End point values
    		 REPLAGAL
    Number of subjects analysed
    19
    Units: percent of LVEF
    arithmetic mean (standard deviation)
        Week 16 (n=14)
    -1.1 ( 7.29 )
        Week 52 (n=12)
    0.8 ( 3.28 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Brief Pain Inventory (BPI) Short Form Pain Severity Total Score

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    End point title
    		 Change From Baseline in Brief Pain Inventory (BPI) Short Form Pain Severity Total Score
    End point description
    The BPI short form is a numeric rating scale that assesses the severity of pain (severity scale), its impact on daily functioning (Pain Interference scale). BPI short form pain severity scale has been reported here. Pain severity scale has 4 questions that assess pain intensity (worst, least, average, right now) on 10-point rating scales (0=No pain to 10=Pain as bad as you can imagine). The pain severity score is calculated as the average of questions, with a total score ranging from 0 to 10 with higher scores indicating more pain. A negative change from baseline indicates better outcome. mITT Set included all enrolled participants who had received at least 1 dose of investigational product and completed at least 1 post-baseline efficacy assessment of the endpoints. Subjects analyzed is the number of participants with pain at baseline. 'n' denotes the number of participants with data available for analysis at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 8, 16, 28, 40, and 52
    End point values
    		 REPLAGAL
    Number of subjects analysed
    7
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 8 (n=7)
    -1.607 ( 2.8572 )
        Week 16 (n=7)
    -2.214 ( 2.4041 )
        Week 28 (n=6)
    -1.833 ( 2.6957 )
        Week 40 (n=6)
    -1.375 ( 2.8007 )
        Week 52 (n=6)
    -0.958 ( 3.3370 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in BPI Short Form Pain Interference Total Score

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    End point title
    		 Change From Baseline in BPI Short Form Pain Interference Total Score
    End point description
    BPI short form is numeric rating scale that assesses severity of pain(severity scale), its impact on daily functioning(Pain Interference scale). BPI short form pain interference scale has been reported here. Pain interference scale has 7 questions that assess impact of pain on daily functions(general activity,mood,walking ability,normal work,relations with other people,sleep,enjoyment of life)on 10-point rating scales as(0=Does not interfere to 10=Completely interferes).Pain interference score=average of questions, with total score ranging from 0-10 with higher scores indicating more interference. Negative change from baseline indicates better outcome. mITT Set included all enrolled participants who had received at least 1 dose of investigational product & completed at least 1 post-baseline efficacy assessment of endpoints. Subjects analyzed is number of participants with pain at baseline. 'n' denotes number of participants with data available for analysis at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 8, 16, 28, 40, and 52
    End point values
    		 REPLAGAL
    Number of subjects analysed
    7
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 8 (n=7)
    -2.286 ( 3.6636 )
        Week 16 (n=7)
    -3.571 ( 3.9812 )
        Week 28 (n=6)
    -4.738 ( 4.3221 )
        Week 40 (n=6)
    -3.810 ( 3.8222 )
        Week 52 (n=6)
    -3.643 ( 5.7020 )
    No statistical analyses for this end point

    Secondary: Number of Participants With Hearing Loss as Assessed by Audiology Testing

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    End point title
    		 Number of Participants With Hearing Loss as Assessed by Audiology Testing
    End point description
    Hearing loss was assessed in participants with the age <18 years old by audiology testing. Audiology testing included pure tone conduction and bone conduction for each ear using 4 different pure tone frequencies (500 hertz [Hz], 1000 Hz, 2000 Hz, and 4000 Hz). Any changes in threshold were to be categorized as conductive, sensorineural, or unknown. mITT Set included all enrolled participants who had received at least 1 dose of investigational product and completed at least 1 post-baseline efficacy assessment of the endpoints. Subjects analyzed is the number of participants with age <18 years old.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 REPLAGAL
    Number of subjects analysed
    6
    Units: participants
    0
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Plasma Globotriaosylsphingosine (Lyso-Gb3) Level

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    End point title
    		 Percent Change From Baseline in Plasma Globotriaosylsphingosine (Lyso-Gb3) Level
    End point description
    Plasma lyso-Gb3 determinations were performed at the central laboratory using a validated liquid chromatography-tandem mass spectrometry bioanalytical assay. mITT Set included all enrolled participants who had received at least 1 dose of investigational product and completed at least 1 post-baseline efficacy assessment of the endpoints. 'n' denotes the number of participants with data available for analysis at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 8, 16, 28, 40, and 52
    End point values
    		 REPLAGAL
    Number of subjects analysed
    19
    Units: percent change
    arithmetic mean (standard deviation)
        Week 8 (n=18)
    -36.236 ( 24.7056 )
        Week 16 (n=18)
    -38.147 ( 24.7376 )
        Week 28 (n=17)
    -37.764 ( 25.8314 )
        Week 40 (n=17)
    -35.565 ( 27.7874 )
        Week 52 (n=17)
    -37.072 ( 27.5659 )
    No statistical analyses for this end point

    Secondary: Area Under Serum Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of REPLAGAL

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    End point title
    		 Area Under Serum Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of REPLAGAL
    End point description
    Intensive PK Set included participants in the PK Set who provided intensive sampling.
    End point type
    Secondary
    End point timeframe
    Pre-infusion (0 minutes), during infusion (20 minutes) and end of infusion (40 minutes), and post-infusion at 50, 60, 90, 120, 240, and 360 minutes at Weeks 0 and 28
    End point values
    		 REPLAGAL
    Number of subjects analysed
    10
    Units: min*U/mL
    arithmetic mean (standard deviation)
        Week 0
    233700 ( 49553 )
        Week 28
    309500 ( 157460 )
    No statistical analyses for this end point

    Secondary: Area Under Serum Concentration-time Curve From the Time of Dosing to the Last Measurable concentration (AUC0-last) of REPLAGAL

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    End point title
    		 Area Under Serum Concentration-time Curve From the Time of Dosing to the Last Measurable concentration (AUC0-last) of REPLAGAL
    End point description
    Intensive Pharmacokinetic (PK) Set included participants in the PK Set who provided intensive sampling.
    End point type
    Secondary
    End point timeframe
    Pre-infusion (0 minutes), during infusion (20 minutes) and end of infusion (40 minutes), and post-infusion at 50, 60, 90, 120, 240, and 360 minutes at Weeks 0 and 28
    End point values
    		 REPLAGAL
    Number of subjects analysed
    10
    Units: minutes*units per milliliter (min*U/mL)
    arithmetic mean (standard deviation)
        Week 0
    229000 ( 48768 )
        Week 28
    297300 ( 139640 )
    No statistical analyses for this end point

    Secondary: Serum Clearance of Administered Dose (CL) of REPLAGAL

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    End point title
    		 Serum Clearance of Administered Dose (CL) of REPLAGAL
    End point description
    Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL = dose/AUC. Intensive PK Set included participants in the PK Set who provided intensive sampling.
    End point type
    Secondary
    End point timeframe
    Pre-infusion (0 minutes), during infusion (20 minutes) and end of infusion (40 minutes), and post-infusion at 50, 60, 90, 120, 240, and 360 minutes at Weeks 0 and 28
    End point values
    		 REPLAGAL
    Number of subjects analysed
    10
    Units: milliliters per minute (mL/min)
    arithmetic mean (standard deviation)
        Week 0
    187.4 ( 35.770 )
        Week 28
    195.5 ( 226.52 )
    No statistical analyses for this end point

    Secondary: Serum Clearance of Administered Dose Normalized Based on Body Weight of REPLAGAL

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    End point title
    		 Serum Clearance of Administered Dose Normalized Based on Body Weight of REPLAGAL
    End point description
    Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL normalized for body weight was reported. CL= (dose/AUC)/ body weight. Clearance was expressed using the unit: milliliters/minute/kilogram (mL/min/kg). Intensive PK Set included participants in the PK Set who provided intensive sampling.
    End point type
    Secondary
    End point timeframe
    Pre-infusion (0 minutes), during infusion (20 minutes) and end of infusion (40 minutes), and post-infusion at 50, 60, 90, 120, 240, and 360 minutes at Weeks 0 and 28
    End point values
    		 REPLAGAL
    Number of subjects analysed
    10
    Units: mL/min/kg
    arithmetic mean (standard deviation)
        Week 0
    3.234 ( 0.78070 )
        Week 28
    3.183 ( 3.5632 )
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Concentration (Cmax) of REPLAGAL

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    End point title
    		 Maximum Observed Serum Concentration (Cmax) of REPLAGAL
    End point description
    Intensive PK Set included participants in the PK Set who provided intensive sampling.
    End point type
    Secondary
    End point timeframe
    Pre-infusion (0 minutes), during infusion (20 minutes) and end of infusion (40 minutes), and post-infusion at 50, 60, 90, 120, 240, and 360 minutes at Weeks 0 and 28
    End point values
    		 REPLAGAL
    Number of subjects analysed
    10
    Units: units per milliliter (U/mL)
    arithmetic mean (standard deviation)
        Week 0
    4620.55 ( 1046.889 )
        Week 28
    4507.99 ( 1682.041 )
    No statistical analyses for this end point

    Secondary: Terminal Elimination Half-life (T1/2z) of REPLAGAL

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    End point title
    		 Terminal Elimination Half-life (T1/2z) of REPLAGAL
    End point description
    T1/2 is defined as the natural log of 2 divided by the terminal rate constant (ƛz). Intensive PK Set included participants in the PK Set who provided intensive sampling.
    End point type
    Secondary
    End point timeframe
    Pre-infusion (0 minutes), during infusion (20 minutes) and end of infusion (40 minutes), and post-infusion at 50, 60, 90, 120, 240, and 360 minutes at Weeks 0 and 28
    End point values
    		 REPLAGAL
    Number of subjects analysed
    10
    Units: minutes
    arithmetic mean (standard deviation)
        Week 0
    45.36 ( 23.058 )
        Week 28
    66.34 ( 27.272 )
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Observed Serum Concentration (Tmax) of REPLAGAL

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    End point title
    		 Time to Reach Maximum Observed Serum Concentration (Tmax) of REPLAGAL
    End point description
    Intensive PK Set included participants in the PK Set who provided intensive sampling.
    End point type
    Secondary
    End point timeframe
    Pre-infusion (0 minutes), during infusion (20 minutes) and end of infusion (40 minutes), and post-infusion at 50, 60, 90, 120, 240, and 360 minutes at Weeks 0 and 28
    End point values
    		 REPLAGAL
    Number of subjects analysed
    10
    Units: hours
    median (full range (min-max))
        Week 0
    40.000 (20.00 to 40.00)
        Week 28
    40.000 (20.00 to 41.00)
    No statistical analyses for this end point

    Secondary: Volume of Distribution at Steady State Normalized Based on Body Weight of REPLAGAL

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    End point title
    		 Volume of Distribution at Steady State Normalized Based on Body Weight of REPLAGAL
    End point description
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Vss normalized for body weight was reported. V(ss) = [(dose/AUC)*MRT]/ body weight, where MRT is mean residence time. Intensive PK Set included participants in the PK Set who provided intensive sampling.
    End point type
    Secondary
    End point timeframe
    Pre-infusion (0 minutes), during infusion (20 minutes) and end of infusion (40 minutes), and post-infusion at 50, 60, 90, 120, 240, and 360 minutes at Weeks 0 and 28
    End point values
    		 REPLAGAL
    Number of subjects analysed
    10
    Units: milliliters per kilogram (mL/kg)
    arithmetic mean (standard deviation)
        Week 0
    135.9 ( 34.530 )
        Week 28
    202.1 ( 267.74 )
    No statistical analyses for this end point

    Secondary: Volume of Distribution at Steady State (Vss) of REPLAGAL

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    End point title
    		 Volume of Distribution at Steady State (Vss) of REPLAGAL
    End point description
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. V(ss) = (dose/AUC)*MRT, where MRT is mean residence time. Intensive PK Set included participants in the PK Set who provided intensive sampling.
    End point type
    Secondary
    End point timeframe
    Pre-infusion (0 minutes), during infusion (20 minutes) and end of infusion (40 minutes), and post-infusion at 50, 60, 90, 120, 240, and 360 minutes at Weeks 0 and 28
    End point values
    		 REPLAGAL
    Number of subjects analysed
    10
    Units: milliliters (mL)
    arithmetic mean (standard deviation)
        Week 0
    7834 ( 1625.9 )
        Week 28
    12310 ( 16988 )
    No statistical analyses for this end point

    Secondary: Dose Normalized Maximum Observed Serum Concentration (Cmax/Dose) of REPLAGAL

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    End point title
    		 Dose Normalized Maximum Observed Serum Concentration (Cmax/Dose) of REPLAGAL
    End point description
    Cmax/Dose was expressed using the unit: (units/milliliter)/(units/kilogram) [(U/mL)/(U/kg)]. Intensive PK Set included participants in the PK Set who provided intensive sampling.
    End point type
    Secondary
    End point timeframe
    Pre-infusion (0 minutes), during infusion (20 minutes) and end of infusion (40 minutes), and post-infusion at 50, 60, 90, 120, 240, and 360 minutes at Weeks 0 and 28
    End point values
    		 REPLAGAL
    Number of subjects analysed
    10
    Units: (U/mL)/(U/kg)
    arithmetic mean (standard deviation)
        Week 0
    0.0001092 ( 0.000021579 )
        Week 28
    0.0001197 ( 0.000040471 )
    No statistical analyses for this end point

    Secondary: Dose Normalized Area Under the Serum Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of REPLAGAL

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    End point title
    		 Dose Normalized Area Under the Serum Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of REPLAGAL
    End point description
    Intensive PK Set included participants in the PK Set who provided intensive sampling.
    End point type
    Secondary
    End point timeframe
    Pre-infusion (0 minutes), during infusion (20 minutes) and end of infusion (40 minutes), and post-infusion at 50, 60, 90, 120, 240, and 360 minutes at Weeks 0 and 28
    End point values
    		 REPLAGAL
    Number of subjects analysed
    10
    Units: (min*U/mL)/(U/kg)
    arithmetic mean (standard deviation)
        Week 0
    0.005520 ( 0.0010993 )
        Week 28
    0.008489 ( 0.0051204 )
    No statistical analyses for this end point

    Secondary: Dose Normalized Area Under Serum Concentration-time Curve From Time Zero to the Last Sampling Time (AUC0-last/Dose) of REPLAGAL

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    End point title
    		 Dose Normalized Area Under Serum Concentration-time Curve From Time Zero to the Last Sampling Time (AUC0-last/Dose) of REPLAGAL
    End point description
    AUC0-last/Dose was expressed using the unit: (minutes*units per milliliter)/(units per kilogram) [(min*U/mL)/(U/kg)]. Intensive PK Set included participants in the PK Set who provided intensive sampling.
    End point type
    Secondary
    End point timeframe
    Pre-infusion (0 minutes), during infusion (20 minutes) and end of infusion (40 minutes), and post-infusion at 50, 60, 90, 120, 240, and 360 minutes at Weeks 0 and 28
    End point values
    		 REPLAGAL
    Number of subjects analysed
    10
    Units: (min*U/mL)/(U/kg)
    arithmetic mean (standard deviation)
        Week 0
    0.005411 ( 0.0010847 )
        Week 28
    0.008119 ( 0.0044732 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study drug administration up to 14 days after EOT (up to Week 54)
    Adverse event reporting additional description
    Safety Analysis Set included all participants in the ITT Set who received at least 1 dose of REPLAGAL.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    REPLAGAL
    Reporting group description
    		 Participants received REPLAGAL 0.2 mg/kg body weight, IV infusion, EOW from Day 1 (Week 0) up to Week 52.

    Serious adverse events
    		 REPLAGAL
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 20 (10.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Pregnancy, puerperium and perinatal conditions
    Ectopic pregnancy
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 REPLAGAL
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 20 (90.00%)
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Oedema peripheral
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Pyrexia
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    6
    Eye disorders
    Corneal opacity
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 20 (30.00%)
         occurrences all number
    6
    Renal and urinary disorders
    Albuminuria
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Haematuria
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Bone metabolism disorder
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Infections and infestations
    COVID-19
         subjects affected / exposed
    13 / 20 (65.00%)
         occurrences all number
    13
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    14

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Feb 2022
    The following changes were made as per Amendment 1: 1) Added cardiac LVMI and LVEF assessed by echocardiography test as one of the efficacy assessments. 2) Updated inclusion and exclusion criteria. 3) Added and clarified that the mITT analysis set will be used for efficacy analyses, instead of the ITT set. 4) Updated time points for height and weight measurement. 5) Removed the requirement that participants need to fast for at least 8 hours prior to the blood draw for plasma lyso-Gb3 assessment.
    23 May 2023
    The following changes were made as per Amendment 2: 1) Added EudraCT number. 2) Updated inclusion criteria. 3) Modified the ITT definition to include all participants enrolled in the study. 4) Added description of BMI calculation. 5) Added ‘physical examination finding’ to the list of clinical assessments.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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