A Study of REPLAGAL® in Treatment-naive Chinese Participants With Fabry Disease

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.

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.

Number of participants with positive ADA to REPLAGAL were reported.

Number of participants with positive NAb to REPLAGAL were reported.

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.

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.

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.

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).

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).

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.

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.

The change from baseline in urine protein/creatinine ratio was derived from early morning spot urine samples collected at the specified time points.

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.

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 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). The pain interference score is calculated as the average of questions, with a total score ranging from 0 to 10 with higher scores indicating more interference. A negative change from baseline indicates better outcome.

Plasma lyso-Gb3 determinations were performed at the central laboratory using a validated liquid chromatography-tandem mass spectrometry bioanalytical assay.

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.

Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL = dose/AUC.

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).

T1/2 is defined as the natural log of 2 divided by the terminal rate constant (ƛz).

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.

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.

AUC0-last/Dose was expressed using the unit: (minutes*units per milliliter)/(units per kilogram) [(min*U/mL)/(U/kg)].

Cmax/Dose was expressed using the unit: (units/milliliter)/(units/kilogram) [(U/mL)/(U/kg)].