Clinical Trial Results:
A Phase 3/4 Prospective Study to Characterize the Pharmacokinetics of Alglucosidase Alfa in Patients with Pompe Disease
Summary
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EudraCT number |
2010-022231-11 |
Trial protocol |
DE GB |
Global end of trial date |
20 Nov 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
02 Jun 2021
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First version publication date |
02 Jun 2021
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
AGLU07710
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01410890 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Genzyme, a Sanofi Company
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Sponsor organisation address |
500 Kendall Street, Cambridge, United States, 02142
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Public contact |
Trial Transparency Team, Genzyme, a Sanofi Company, Contact-US@sanofi.com
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Scientific contact |
Trial Transparency Team, Genzyme, a Sanofi Company, Contact-US@sanofi.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
16 Dec 2020
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
20 Nov 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To characterise the pharmacokinetics (PK) of alglucosidase alfa manufactured at the 4000 L scale in subjects who had a confirmed diagnosis of Pompe disease.
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Protection of trial subjects |
The study was conducted by investigators experienced in the treatment of paediatric and adult subjects. The parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimised. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anesthesia might have been used to minimise distress and discomfort. Adult subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
03 Nov 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
India: 4
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Country: Number of subjects enrolled |
Russian Federation: 2
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Country: Number of subjects enrolled |
Ukraine: 2
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Country: Number of subjects enrolled |
United States: 6
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Country: Number of subjects enrolled |
Bulgaria: 1
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Country: Number of subjects enrolled |
United Kingdom: 6
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Worldwide total number of subjects |
21
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EEA total number of subjects |
1
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
2
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Children (2-11 years) |
7
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Adolescents (12-17 years) |
1
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Adults (18-64 years) |
11
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted at 12 sites in 6 countries. A total of 27 subjects were screened between 03-Nov-2014 and 23-Sep-2020, of whom 6 subjects were screen failures and 21 subjects were enrolled in the study. | ||||||||||||
Pre-assignment
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Screening details |
Out of 21 subjects, 1 subject signed the informed consent, but due to health status did not continue in the study to the treatment visit. | ||||||||||||
Period 1
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Period 1 title |
Overall (overall period)
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Alglucosidase Alfa: <18 Years | ||||||||||||
Arm description |
Subjects with less than (<) 18 years of age 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 milligrams 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. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Alglucosidase Alfa
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Investigational medicinal product code |
GZ419829
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Single IV infusion of Alglucosidase alfa 20 mg/kg body weight on Day 1.
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Arm title
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Alglucosidase Alfa: >=18 Years | ||||||||||||
Arm description |
Subjects with greater than or equal to (>=) 18 years of age received IV infusion of Alglucosidase alfa 20 mg/kg body weight on Day 1. Infusion was administered at an initial rate of approximately 1 mg/kg/hr with allowed rate increased of 2 mg/kg/hr every 30 minutes, if there were no signs of IARs, until a maximum rate of approximately 7 mg/kg/hr was reached. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Alglucosidase Alfa
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Investigational medicinal product code |
GZ419829
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Single IV infusion of Alglucosidase alfa 20 mg/kg body weight on Day 1.
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Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: 1 subject signed the informed consent, but due to health status did not continue in the study to the treatment visit. |
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Baseline characteristics reporting groups
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Reporting group title |
Alglucosidase Alfa: <18 Years
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Reporting group description |
Subjects with less than (<) 18 years of age 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 milligrams 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Alglucosidase Alfa: >=18 Years
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Reporting group description |
Subjects with greater than or equal to (>=) 18 years of age received IV infusion of Alglucosidase alfa 20 mg/kg body weight on Day 1. Infusion was administered at an initial rate of approximately 1 mg/kg/hr with allowed rate increased of 2 mg/kg/hr every 30 minutes, if there were no signs of IARs, until a maximum rate of approximately 7 mg/kg/hr was reached. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Alglucosidase Alfa: <18 Years
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Reporting group description |
Subjects with less than (<) 18 years of age 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 milligrams 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. | ||
Reporting group title |
Alglucosidase Alfa: >=18 Years
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Reporting group description |
Subjects with greater than or equal to (>=) 18 years of age received IV infusion of Alglucosidase alfa 20 mg/kg body weight on Day 1. Infusion was administered at an initial rate of approximately 1 mg/kg/hr with allowed rate increased of 2 mg/kg/hr every 30 minutes, if there were no signs of IARs, until a maximum rate of approximately 7 mg/kg/hr was reached. | ||
Subject analysis set title |
Anti-rhGAA Antibody Negative Subjects
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Subjects with negative anti-rhGAA IgG antibody status at Baseline received IV infusion of Alglucosidase alfa 20 mg/kg body weight on Day 1. Infusion was administered at an initial rate of approximately 1 mg/kg/hr with allowed rate increased of 2 mg/kg/hr every 30 minutes, if there were no signs of IARs, until a maximum rate of approximately 7 mg/kg/hr was reached.
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Subject analysis set title |
Anti-rhGAA Antibody Positive Subjects
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Subjects with positive anti-rhGAA IgG antibody status at Baseline received IV infusion of Alglucosidase alfa 20 mg/kg body weight on Day 1. Infusion was administered at an initial rate of approximately 1 mg/kg/hr with allowed rate increased of 2 mg/kg/hr every 30 minutes, if there were no signs of IARs, until a maximum rate of approximately 7 mg/kg/hr was reached.
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End point title |
Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Alglucosidase Alfa [1] | ||||||||||||
End point description |
Cmax was defined as maximum observed plasma concentration. Analysis was performed on all subjects who received any amount of alglucosidase alfa.
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End point type |
Primary
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End point timeframe |
Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
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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: As the endpoint is descriptive in nature, no statistical analysis is provided. |
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alglucosidase Alfa [2] | ||||||||||||
End point description |
Tmax was defined as time to reach maximum observed plasma concentration. Analysis was performed on all subjects who received any amount of alglucosidase alfa.
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End point type |
Primary
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End point timeframe |
Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
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Notes [2] - 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: As the endpoint is descriptive in nature, no statistical analysis is provided. |
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics: Area Under the Plasma Concentration-Time Curve (AUC) of Alglucosidase Alfa [3] | ||||||||||||
End point description |
AUC was defined as area under the plasma concentration-time curve from time 0 to 24 hours post-dose. Analysis was performed on all subjects who received any amount of alglucosidase alfa.
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End point type |
Primary
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End point timeframe |
Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
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Notes [3] - 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: As the endpoint is descriptive in nature, no statistical analysis is provided. |
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Alglucosidase Alfa [4] | ||||||||||||
End point description |
AUC0-last was defined as area under the concentration-time curve from time 0 to the time of the last quantifiable concentration. Analysis was performed on all subjects who received any amount of alglucosidase alfa.
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End point type |
Primary
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End point timeframe |
Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
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Notes [4] - 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: As the endpoint is descriptive in nature, no statistical analysis is provided. |
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics: Terminal Elimination Half-life (T1/2) of Alglucosidase Alfa [5] | ||||||||||||
End point description |
T1/2 was defined as the time taken by drug to reduce to half of its initial plasma concentration. Analysis was performed on all subjects who received any amount of alglucosidase alfa.
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End point type |
Primary
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End point timeframe |
Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
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Notes [5] - 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: As the endpoint is descriptive in nature, no statistical analysis is provided. |
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics: Total Systemic Clearance (CL) of Alglucosidase Alfa [6] | ||||||||||||
End point description |
CL of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Analysis was performed on all subjects who received any amount of alglucosidase alfa.
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End point type |
Primary
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End point timeframe |
Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
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Notes [6] - 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: As the endpoint is descriptive in nature, no statistical analysis is provided. |
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics: Volume of Distribution at Steady State (Vss) of Alglucosidase Alfa [7] | ||||||||||||
End point description |
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. Analysis was performed on all subjects who received any amount of alglucosidase alfa.
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End point type |
Primary
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End point timeframe |
Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
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Notes [7] - 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: As the endpoint is descriptive in nature, no statistical analysis is provided. |
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics: Maximum Observed Plasma Concentration of Alglucosidase Alfa in Anti-Recombinant Human Acid Alpha-Glucosidase Antibody Positive and Negative Subjects | ||||||||||||
End point description |
Cmax was defined as maximum observed plasma concentration. Analysis was performed on full analysis set (FAS) that included subjects who received any amount of alglucosidase alfa. Here, number of subjects analysed = subjects with available data for this endpoint.
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End point type |
Secondary
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End point timeframe |
Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics: Time to Reach Maximum Observed Plasma Concentration in Anti-rhGAA Antibody Positive and Negative Subjects | ||||||||||||
End point description |
Tmax was defined as time to reach maximum observed plasma concentration. Analysis was performed on FAS that included all subjects who received any amount of alglucosidase alfa. Here, number of subjects analysed = subjects with available data for this endpoint.
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End point type |
Secondary
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End point timeframe |
Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics: Terminal Elimination Half-life of Alglucosidase Alfa in Anti-rhGAA Antibody Positive and Negative Subjects | ||||||||||||
End point description |
T1/2 was defined as the time taken by drug to reduce to half of its initial plasma concentration. Analysis was performed on FAS that included subjects who received any amount of alglucosidase alfa. Here, number of subjects analysed = subjects with available data for this endpoint.
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End point type |
Secondary
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End point timeframe |
Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
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No statistical analyses for this end point |
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End point title |
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 Subjects | ||||||||||||
End point description |
AUC0-last was defined as area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration. Analysis was performed on FAS that included subjects who received any amount of alglucosidase alfa. Here, number of subjects analysed = subjects with available data for this endpoint.
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End point type |
Secondary
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End point timeframe |
Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 and Extrapolated to Infinite Time (AUC0-inf) in Anti-rhGAA Antibody Positive and Negative Subjects | ||||||||||||
End point description |
AUC0-inf was defined as area under the concentration-time curve from time 0 extrapolated to infinite time. Analysis was performed on FAS that included subjects who received any amount of alglucosidase alfa. Here, number of subjects analysed = subjects with available data for this endpoint.
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End point type |
Secondary
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End point timeframe |
Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics: Total Systemic Clearance in Anti-rhGAA Antibody Positive and Negative Subjects | ||||||||||||
End point description |
CL of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Analysis was performed on FAS that included subjects who received any amount of alglucosidase alfa. Here, number of subjects analysed = subjects with available data for this endpoint.
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End point type |
Secondary
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End point timeframe |
Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics: Volume of Distribution in Anti-rhGAA Antibody Positive and Negative Subjects | ||||||||||||
End point description |
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. Analysis was performed on FAS that included subjects who received any amount of alglucosidase alfa. Here, number of subjects analysed = subjects with available data for this endpoint.
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End point type |
Secondary
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End point timeframe |
Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
All Adverse Events (AEs) were collected from signature of the informed consent form up to Week 4.
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Adverse event reporting additional description |
Reported AEs and deaths were treatment-emergent (TEAEs) that developed/worsened in grade/became serious during 'TEAE period' (i.e., from signature of the informed consent form up to Week 4. Analysis was performed on FAS that included all subjects who received any amount of alglucosidase alfa.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.1
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Reporting groups
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Reporting group title |
Alglucosidase Alfa: <18 Years
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Reporting group description |
Subjects with <18 years of age received IV infusion of Alglucosidase alfa 20 mg/kg body weight on Day 1. Infusion was administered at an initial rate of approximately 1 mg/kg/hr with allowed rate increased of 2 mg/kg/hr every 30 minutes, if there were no signs of IARs, until a maximum rate of approximately 7 mg/kg/hr was reached. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Alglucosidase Alfa: >=18 Years
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Reporting group description |
Subjects with >=18 years of age received IV infusion of Alglucosidase alfa 20 mg/kg body weight on Day 1. Infusion was administered at an initial rate of approximately 1 mg/kg/hr with allowed rate increased of 2 mg/kg/hr every 30 minutes, if there were no signs of IARs, until a maximum rate of approximately 7 mg/kg/hr was reached. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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05 May 2011 |
Following changes were made: Updated study personnel information; clarified the timing of the 30-day follow-up visit, which was the subjects last study visit; updated language for contraception requirements and pregnancy testing for consistency within the protocol and added urine pregnancy tests and use of contraception; reevaluated sample assay requirements to minimise burden on subjects. The PK sampling timepoints were extended out to 48 hours after the end of infusion to increase assurance of characterising the half-life of the second phase of the alglucosidase alfa concentration-time curve. Adjusted PK sampling timepoints to include samples immediately before each scheduled infusion rate change to make sure the true Cmax was not missed; unified text with language of approved label, where applicable; added text that dose increase and dose reduction was not permitted unless it was due to an AE; standardised collection of complete medical history and surgical procedure information; clarified that additional testing was needed only for IARs suggestive of hypersensitivity reactions. Window for testing was expanded based on experience across the program; revised the schedule of assessments to allow sufficient time between the last study infusion and last study IgG assessment to see if there was a change in IgG titer. Required that the follow-up visit be an office visit to allow collection of an IgG sample. |
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17 Dec 2015 |
Following changes were made: Modified inclusion criteria to remove the upper age limit of 18 years as a means to remedy the unsatisfactory number of subjects enrolled to date. Approximately 10 subjects <18 years old and 10 subjects >=18 years old was the target for enrollment; inclusion criteria was added and exclusion criteria was deleted to allow inclusion of subjects previously treated with alglucosidase alfa for at least 6 months; reduced number of infusions from 14 to 1, reducing study duration from approximately 30 weeks to approximately 4 to 9 weeks to enhance subjects recruitment into the study; limited collection of blood samples for PK assessment to infusion Day 1 and samples at 30, 36,
42, and 48 hours after the end of infusion were eliminated to enhance subjects recruitment into the study; eliminated determination of the exploratory biomarker urine hex4 level as a consequence of the reduced study duration; eliminated exploratory assessment of GAA activity in dried blood spot with the more focused emphasis on PK and immunology assessment. |
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18 Jul 2016 |
Following changes were made: modified Inclusion criteria to remove the lower age limit of 8 years of age to add the possibility to characterise PK in subjects <8 years old. Approximately 10 subjects <18 years old and 10 subjects >=18 years old remained the target for enrollment. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |