A Study of Two Fabrazyme (Agalsidase Beta) Dosing Regimens in Treatment-naïve, Male Pediatric Patients Without Severe Symptoms

Study Overview
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Brief Summary
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The purpose of this study was to determine whether 2 alternative dosing regimens of Fabrazyme (Agalsidase beta) (1.0 mg/kg every 4 weeks or 0.5 mg/kg every 2 weeks) were effective in treatment-naïve pediatric participants without severe symptoms. Participants were to be treated for 5 years.

Official Title
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A Randomized, Multicenter, Multinational, Phase 3B, Open-Label, Parallel-Group Study of Fabrazyme (Agalsidase Beta) in Treatment-Naïve Male Pediatric Patients With Fabry Disease Without Severe Symptoms

Conditions
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Fabry Disease

Intervention / Treatment
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* Biological: Agalsidase beta
* Biological: Agalsidase beta


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The participant and/or participant's parent(s)/legal guardian(s) must provide written informed assent/consent prior to any protocol-related procedures being performed. The participant must had a confirmed diagnosis of Fabry disease as documented by leukocyte α-Galactosidase A (αGAL) activity of <4 nmol/hr/mg leukocyte (preferred assay; resulted from a central laboratory). If the leukocyte αGAL activity assay was difficult to obtain, the participant might be enrolled based on documented plasma αGAL <1.5 nmol/hr/mL, with the agreement of the Medical Monitor (resulted from a central laboratory). The participant must had evidence of globotriaosylceramide (GL-3) accumulation as documented by plasma GL-3 (>7.0 µg/mL) or urinary GL-3 (>0.3 mg GL-3/mmol creatinine) levels (results from a central laboratory). The participant must be male ≥5 and ≤18 years of age. Exclusion Criteria: Participant had albuminuria (first morning void urinary albumin/creatinine ratio >30 mg/g on at least 2 out of 3 consecutive samples, each at least 1 week apart). Participant had a Glomerular Filtration Rate (GFR) by iohexol <90 L/min/1.73m^2. In case of properly documented low protein intake, values as low as 80 mL/min/1.73 m^2 might be acceptable, after consultation with the Medical Monitor. Participant had documented evidence of stroke or transient ischemic attack (TIA), or if a brain magnetic resonance imaging (MRI) had been performed, bright lesions >2 mm on T2- or fluid attenuated inversion recovery (FLAIR)- weighted images within the white matter or the basal ganglia. Participant had severe and recurrent acroparesthesia, judged by the physician as frequent (more than once a week) pain episodes for at least 3 months that influenced daily activities, irrespective of medication. Participant had an end-diastolic left ventricular posterior wall thickness (LVPWTd) and/or an end-diastolic interventricular septum thickness (IVSTd)≥2 standard deviations (SD) compared to normal (based on body surface area [BSA] normal ranges from Kampmann, et al 2000) as read at the study site. Participant had received prior treatment specific to Fabry Disease. Participant had participated in a study employing an investigational drug within 30 days of the start of their participation in this study. Participant had any medical condition or extenuating circumstance, which in the opinion of the Study Investigator, could interfere with study compliance. Participant had any medical condition or extenuating circumstance, for example diabetes mellitus, which in the opinion of the Study Investigator, could interfere with the interpretation of study results. Participant was on treatment with angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs). Participant had any contra-indication mentioned in the labeling of Fabrazyme and/or iohexol (Omnipaque). Participant or parent(s)/legal guardian(s) was unwilling to comply with the requirements of the protocol.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fabrazyme 0.5 mg/kg<br>Fabrazyme 0.5 mg/kg was administered every 2 weeks (up to 131 infusion) up to 260 weeks, the total infusion time was not less than 45 minutes. In case of significant progression of Fabry disease, the dose was increased to 1.0 mg/kg every 2 weeks. | Biological: Agalsidase beta<br>* Powder for concentrate for solution for infusion 1.0 mg/kg/4 weeks<br>* Other names: Recombinant human α-galactosidase A (r-hαGAL);|
| Experimental: Fabrazyme 1.0 mg/kg<br>Fabrazyme 1.0 mg/kg was administered every 4 weeks (up to 66 infusion) up to 260 weeks, the total infusion time was not less than 90 minutes. In case of significant progression of Fabry disease, the dose was increased to 1.0 mg/kg every 2 weeks. | Biological: Agalsidase beta<br>* Powder for concentrate for solution for infusion 0.5 mg/kg/2 weeks<br>* Other names: Recombinant human α-galactosidase A (r-hαGAL);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Skin Globotriaosylceramide (GL-3) Clearance From Superficial Skin Capillary Endothelium | Skin biopsies were taken at Baseline, Week 52, Week 156 and Week 260 or early withdrawal and analyzed for cellular GL-3 accumulation (inclusions) by light microscopy. Each biopsy was scored for GL-3 accumulation on a severity score-scale of none, mild, moderate, severe (0-1-2-3). Scores are categorized as normal (score = 0) or abnormal (score = 1, 2 or 3). Data was summarized in terms of number of participants with none/trace, mild, moderate and severe biopsy scores. | Baseline, Week 52, Week 156 and Week 260 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in GL-3 Clearance From Plasma | Plasma samples were assayed for GL-3 clearance using a validated tandem mass spectrometry with an upper limit of normal plasma GL-3 level of 7.0 μg/mL. Number of participants analyzed=participants with both baseline and post-baseline GL-3 plasma clearance assessment. Here 'n' signifies number of participants with available data for specified category. | Baseline, Week 12, 28, 40, 52, 80, 104, 132, 156, 184, 208, 236 and 260 | 
| Percent Change From Baseline in GL-3 Clearance From Urine | Plasma samples were assayed for total urine GL-3 clearance using a validated tandem mass spectrometry with an upper limit of normal of <0.030 mg/mmoL of creatinine. Number of participants analyzed=participants with both baseline and post-baseline GL-3 urine clearance assessment. Here 'n' signifies number of participants with available data for specified category. | Baseline, Week 12, 28, 40, 52, 80, 104, 132, 156, 184, 208, 236 and 260 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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α-GAL, α-Galactosidase-A, r-hαGAL