Pharmacokinetics of Alglucosidase Alfa in Patients With Pompe Disease

Study Overview
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Brief Summary
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The primary objective of this study was to characterize the pharmacokinetics (PK) of alglucosidase alfa manufactured at the 4000 L scale in participants who had a confirmed diagnosis of Pompe disease. A secondary objective of this study was to evaluate and explore the relationship between anti-recombinant human acid alpha-glucosidase antibody titers and the PK of alglucosidase alfa.

Detailed Description
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The total study duration per participant was 4 to 8 weeks that consisted of a screening period (from 2 days to 4 weeks), treatment visit (1 day), and a follow up call (greater than or equal to 30 days). Two participants enrolled prior to protocol amendment 2 (dated 17 December 2015), which changed the study to single-dose, and were treated for 26 weeks, with a 4-week follow up.

Official Title
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A Phase 3/4 Prospective Study to Characterize the Pharmacokinetics of Alglucosidase Alfa in Patients With Pompe Disease

Conditions
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Pompe Disease, Glycogen Storage Disease Type II (GSD II)

Intervention / Treatment
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* Biological: alglucosidase alfa


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A participant was to meet all of the following criteria to be eligible for this study: The participant and/or the participant's parent/legal guardian was willing and able to provide signed informed consent. The participant had a confirmed acid alpha-glucosidase (GAA) enzyme deficiency from skin, blood, or muscle tissue and/or 2 confirmed GAA gene mutations. Infant and toddler Pompe disease participants could be included in the study only under condition (minimal body weight) that the trial-related blood loss (including any losses in the maneuver) would not exceed 3 percent (%) of the total blood volume during a period of 4 weeks and would not exceed 1 % at any single time. The participant, if female and of childbearing potential, must have had a negative pregnancy test (urine beta-human chorionic gonadotropin) at screening. Note: All female participants of childbearing potential and sexually mature males must have agreed to use a medically accepted method of contraception throughout the study. For participants previously treated with alglucosidase alfa the participant had received alglucosidase alfa for at least 6 months. Exclusion Criteria: A participant who met any of the following criteria was excluded from this study: The participant was participating in another clinical study using an investigational product. The participant, in the opinion of the Investigator, was unable to adhere to the requirements of the study. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Sexes Eligible for Study
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All

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: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alglucosidase alfa<br>Participants received intravenous (IV) infusion of Alglucosidase alfa 20 milligrams per kilogram (mg/kg) body weight on Day 1. Infusion was administered at an initial rate of approximately 1 milligram per kilogram per hour (mg/kg/hr) with allowed rate increased of 2 mg/kg/hr every 30 minutes, if there were no signs of infusion-associated reactions (IARs), until a maximum rate of approximately 7 mg/kg/hr was reached. | Biological: alglucosidase alfa<br>* Intravenous (IV) infusion of 20mg/kg body weight every other week (qow)<br>* Other names: Lumizyme;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of Alglucosidase Alfa | Cmax was defined as maximum observed plasma concentration. | Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1 | 
| Pharmacokinetics: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alglucosidase Alfa | Tmax was defined as time to reach maximum observed plasma concentration. | Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1 | 
| Pharmacokinetics: Area Under the Plasma Concentration-Time Curve (AUC) of Alglucosidase Alfa | AUC was defined as area under the plasma concentration-time curve from time 0 to 24 hours post-dose. | Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1 | 
| Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Alglucosidase Alfa | AUC0-last was defined as area under the concentration-time curve from time 0 to the time of the last quantifiable concentration. | Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1 | 
| Pharmacokinetics: Terminal Elimination Half-life (T1/2) of Alglucosidase Alfa | T1/2 was defined as the time taken by drug to reduce to half of its initial plasma concentration. | Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1 | 
| Pharmacokinetics: Total Systemic Clearance (CL) of Alglucosidase Alfa | CL of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. | Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1 | 
| Pharmacokinetics: Volume of Distribution at Steady State (Vss) of Alglucosidase Alfa | Volume of distribution (Vd) is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss is the apparent volume of distribution at steady-state. | Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics: Maximum Observed Plasma Concentration of Alglucosidase Alfa in Anti-Recombinant Human Acid Alpha-Glucosidase Antibody Positive and Negative Participants | Cmax was defined as maximum observed plasma concentration. | Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1 | 
| Pharmacokinetics: Time to Reach Maximum Observed Plasma Concentration in Anti-rhGAA Antibody Positive and Negative Participants | Tmax was defined as time to reach maximum observed plasma concentration. | Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1 | 
| Pharmacokinetics: Terminal Elimination Half-life of Alglucosidase Alfa in Anti-rhGAA Antibody Positive and Negative Participants | T1/2 was defined as the time taken by drug to reduce to half of its initial plasma concentration. | Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1 | 
| Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration of Alglucosidase Alfa in Anti-rhGAA Antibody Positive and Negative Participants | AUC0-last was defined as area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration. | Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1 | 
| Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 and Extrapolated to Infinite Time (AUC0-inf) in Anti-rhGAA Antibody Positive and Negative Participants | AUC0-inf was defined as area under the concentration-time curve from time 0 extrapolated to infinite time. | Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1 | 
| Pharmacokinetics: Total Systemic Clearance in Anti-rhGAA Antibody Positive and Negative Participants | CL of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. | Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1 | 
| Pharmacokinetics: Volume of Distribution in Anti-rhGAA Antibody Positive and Negative Participants | Vd is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss is the apparent volume of distribution at steady-state. | Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1 |