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

An Open-label Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of REPLAGAL® in Treatment-naïve Chinese Subjects With Fabry Disease

The main aim of the study is to assess the safety of REPLAGAL. Study participants will receive REPLAGAL as an intravenous infusion every other week for 52 weeks. Participants will visit their study clinic many times throughout the study.

Study Overview

• Status: Completed
• Conditions: Fabry Disease
• Intervention / Treatment: Biological: REPLAGAL

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Beijing, China, Dongcheng District
    • Peking Union Medical College Hospital
  • Changsha, China, Kaifu District
    • Xiangya Hospital, Central South University
  • Chengdu, China, Wuhou District
    • West China Hospital, Sichuan University
  • Hangzhou, China, Xiacheng District
    • The Children's Hospital of Zhejiang University School of Medicine
  • Jinan, China, Huaiyin District
    • Shandong Provincial Hospital
  • Shanghai, China, Huangpu District
    • Ruijin Hospital, Shanghai Jiaotong Uni. School of Med.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participant and/or legally authorized representative must voluntarily sign an Institutional Review Board/Independent Ethics Committee approved written informed consent form (ICF) after all relevant aspects of the study have been explained and discussed with the participant. For the participants less than (<) 18 years old, participants will give assent AND their parent(s)/legally authorized representative should sign the ICF accordingly.

• The participant has confirmed diagnosis of Fabry disease as determined by the investigator, according to medical record including:

  • For male participant, Fabry disease is confirmed by a deficiency of α-galactosidase A (GLA) activity and a mutation in the GLA gene
  • For female participant, Fabry disease is confirmed by a mutation in the GLA gene.
• The participant is 7 to 65 years of age, inclusive, at screening.
• Female participants of childbearing potential must have a negative pregnancy test at screening.
• Female participants of childbearing potential must agree to use a medically acceptable method of contraception at all times during the study and for at least 14 days after the final investigational product infusion.
• The participant is deemed, as determined by the investigator, to have adequate general health to undergo the specified protocol-related procedures and to have no safety or medical contraindications for participation.
• The participant has not received any treatment (approved or investigational) specific to Fabry disease, such as ERT, chaperone therapy, or substrate reduction therapy.
• The adult participant (greater than or equal to [>=] 18 years old) must have an estimated glomerular filtration rate (eGFR) of 45 to 120 milliliter per minute per 1.73 meter square (mL/min/1.73 m^2) (inclusive). Serum creatinine is tested and the eGFR is calculated by central laboratory using the Chronic Kidney Disease Epidemiology (CKD-EPI) equation.

Exclusion Criteria:

• In the opinion of the investigator, the participant's life expectancy is less than or equal to (<=) 5 years.
• The participant has undergone or is scheduled to undergo kidney transplantation or is currently on dialysis or has any signs or symptoms of end stage renal disease.
• The participant has a urine protein/creatinine ratio of greater than (>) 500 milligram per gram (mg/g).
• The participant has a clinically relevant history of allergy or signs or symptoms of severe hypersensitivity, which in the investigator's judgment, will substantially increase the participant's risk if he or she participates in the study.
• In the opinion of the investigator, the participant has non-Fabry disease-related cause of end organ (renal, cardiovascular, central nervous system) dysfunction/failure or is receiving medications that may affect the rate of disease progression, as assessed by renal measures.
• The participant has a positive test result at screening for hepatitis B surface antigen with detectable hepatitis B viral deoxyribonucleic acid (DNA) load, hepatitis C virus (HCV) antibody with confirmation by HCV ribonucleic acid polymerase chain reaction testing, or human immunodeficiency virus antibody.

• The participant has received prior treatment with any of the following medications, with the exception of non-systemic use:

  • Chloroquine
  • Amiodarone
  • Monobenzone
  • Gentamicin
• The participant is pregnant or lactating.
• The participant has a body mass index >35 kilogram per square meter (kg/m^2).
• The participant is treated or has been treated with any investigational drug for indication other than Fabry disease within 30 days of study start.
• The participant and/or the participant's parent(s)/legal guardian is unable to understand the nature, scope, and possible consequences of the study.
• The participant is unable to comply with the protocol, example, uncooperative with protocol schedule, refusal to agree to all of the study procedures, inability to return for evaluations, or is otherwise unlikely to complete the study, as determined by the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: REPLAGAL; 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.	Biological: REPLAGAL; REPLAGAL IV infusion.; Other Names: Agalsidase Alfa; TAK-675

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Serious Treatment-emergent Adverse Events (TEAEs)	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.	From start of study drug administration up to 14 days after end of treatment (EOT) [up to Week 54]

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With TEAEs	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.	From start of study drug administration up to 14 days after EOT (up to Week 54)
Number of Participants With Infusion-related Reactions (IRRs)	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.	From start of study drug administration up to Week 52
Number of Participants With Positive Anti-drug Antibodies (ADA) to REPLAGAL	Number of participants with positive ADA to REPLAGAL were reported.	Baseline up to Week 52
Number of Participants With Positive Neutralizing Antibodies (NAb) to REPLAGAL	Number of participants with positive NAb to REPLAGAL were reported.	Baseline up to Week 52
Number of Participants With Clinically Meaningful Changes in Laboratory Parameters	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.	From start of study drug administration up to Week 52
Number of Participants With Clinically Meaningful Changes in Vital Signs	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.	From start of study drug administration up to Week 52
Number of Participants With Clinically Meaningful Changes in Electrocardiogram (ECG) Parameters	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.	From start of study drug administration up to Week 52
Renal Function as Assessed by Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 52	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).	Baseline, Week 52
Change From Baseline in eGFR Values at Weeks 8, 16, 28, and 40	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).	Baseline, Weeks 8, 16, 28, and 40
Change From Baseline in Left Ventricular Mass Index (LVMI) at Weeks 16 and 52	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.	Baseline, Weeks 16 and 52
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) at Weeks 16 and 52	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.	Baseline, Weeks 16 and 52
Change From Baseline in Urine Protein/Creatinine Ratio	The change from baseline in urine protein/creatinine ratio was derived from early morning spot urine samples collected at the specified time points.	Baseline, Weeks 8, 16, 28, 40, and 52
Change From Baseline in Brief Pain Inventory (BPI) Short Form Pain Severity Total Score	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.	Baseline, Weeks 8, 16, 28, 40, and 52
Change From Baseline in BPI Short Form Pain Interference Total Score	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.	Baseline, Weeks 8, 16, 28, 40, and 52
Percent Change From Baseline in Plasma Globotriaosylsphingosine (Lyso-Gb3) Level	Plasma lyso-Gb3 determinations were performed at the central laboratory using a validated liquid chromatography-tandem mass spectrometry bioanalytical assay.	Baseline, Weeks 8, 16, 28, 40, and 52
Number of Participants With Hearing Loss as Assessed by Audiology Testing	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.	Baseline up to Week 52
Area Under Serum Concentration-time Curve From the Time of Dosing to the Last Measurable Concentration (AUC0-last) of REPLAGAL		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
Area Under Serum Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of REPLAGAL		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
Serum Clearance of Administered Dose (CL) of REPLAGAL	Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL = dose/AUC.	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
Serum Clearance of Administered Dose Normalized Based on Body Weight of REPLAGAL	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).	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
Maximum Observed Serum Concentration (Cmax) of REPLAGAL		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
Terminal Elimination Half-life (T1/2z) of REPLAGAL	T1/2 is defined as the natural log of 2 divided by the terminal rate constant (ƛz).	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
Time to Reach Maximum Observed Serum Concentration (Tmax) of REPLAGAL		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
Volume of Distribution at Steady State (Vss) of REPLAGAL	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.	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
Volume of Distribution at Steady State Normalized Based on Body Weight of REPLAGAL	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.	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
Dose Normalized Area Under Serum Concentration-time Curve From Time Zero to the Last Sampling Time (AUC0-last/Dose) of REPLAGAL	AUC0-last/Dose was expressed using the unit: (minutes*units per milliliter)/(units per kilogram) [(min*U/mL)/(U/kg)].	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
Dose Normalized Area Under the Serum Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of REPLAGAL		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
Dose Normalized Maximum Observed Serum Concentration (Cmax/Dose) of REPLAGAL	Cmax/Dose was expressed using the unit: (units/milliliter)/(units/kilogram) [(U/mL)/(U/kg)].	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

Collaborators and Investigators

• Sponsor: Takeda
• Investigators: Study Director: Medical Director, Takeda

Publications and helpful links

Helpful Links

• To obtain more information on the study, click here/on this link

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2022
• Primary Completion (Actual): January 3, 2024
• Study Completion (Actual): January 3, 2024

Study Registration Dates

• First Submitted: July 21, 2021
• First Submitted That Met QC Criteria: July 21, 2021
• First Posted (Actual): July 23, 2021

Study Record Updates

• Last Update Posted (Actual): October 8, 2024
• Last Update Submitted That Met QC Criteria: July 2, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Cerebral Small Vessel Diseases; Lipidoses; Lipid Metabolism, Inborn Errors; Fabry Disease
• Other Study ID Numbers: TAK-675-3001; 2022-004246-35 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No