Fabry Disease
Conditions
Keywords
Replagal
Brief summary
This study is designed to evaluate safety and PK/PD in Canadian Fabry patients.
Detailed description
In 2008, a change in the agalsidase alfa drug substance manufacturing process was made. There are no changes to the drug product formulation, manufacturing site, manufacturing process, or container closure. An agalsidase alfa bioreactor manufacturing process (agalAF1) utilizing animal component-free media replaced the previous roller bottle (RB) process. This study is designed to provide PD/PK and safety data. The assessment schedule is designed to capture the PK profile of drug uptake in the blood as well the pharmacologic effect which manifests over the course of weeks. Each patient will serve as his own control.
Interventions
BIOLOGICALagalsidase alfa
Sponsors
Shire
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. The patient must be diagnosed with Fabry disease using the following criteria: The patient is a hemizygous male with Fabry disease as confirmed by a deficiency of α-galactosidase A activity measured in serum, leukocytes, or fibroblasts or has a confirmed mutation of the α-galactosidase A gene. 2. Patient is male and between 18 and 65 years of age, inclusive. 3. Patient must be willing to remain in the clinic as required by the study and comply with the procedures and evaluations of the study. 4. At the time of confirmation of study eligibility visit, patients must have received at least 26 weeks of treatment with RB Replagal at a dose of 0.2 mg/kg administered IV EOW. 5. Patient provides informed consent. Patients who are naive to ERT: 1\. Treatment naive patients must have a pretreatment plasma Gb3 level above the normal range (if value is available).
Exclusion criteria
1. Patient is unable to be venipunctured and/or tolerate venous access. 2. Patient has tested positive for anti-agalsidase alfa antibodies either at screening or confirmation of eligibility visit. 3. Patient had pre-ERT plasma Gb3 levels within the normal range (if value is available). 4. Patient is participating in any other Shire HGT investigational study. 5. Patient is currently on dialysis, is expected to begin dialysis during the study, has received a kidney transplant, or is on the renal transplant waiting list. 6. Patient is unable to comply with the protocol (eg, clinical relevant medical condition making implementation of the protocol difficult, unstable social situation, or otherwise unlikely to complete the study) or is, in the opinion of the Investigator, otherwise unsuited for the study. 7. The patient is enrolled in another clinical study that involves clinical investigations or use of any investigational product (drug or device), except for the Canadian Fabry Disease Initiative, within 6 months prior to receiving the first dose of AF Replagal in this study or at any time during the study. 8. The patient has previously received AF Replagal prior to study entry.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline to Week 16 (EOS) in Urine Gb3 Levels | Baseline to EOS |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Dose-normalized Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Sample (AUClast/Dose) | Week 0 to Week 14 | The dose-normalized calculation was performed by dividing the pharmacokinetic parameter by the administered dose. |
| Dose-normalized AUC Extrapolated to Infinity (AUC∞/Dose) | Week 0 to Week 14 | The dose-normalized calculation was performed by dividing the pharmacokinetic parameter by the administered dose. |
| Change From Baseline to Week 16 (EOS) in Plasma Gb3 Levels | Baseline to EOS | — |
| To Assess Safety and Tolerability by Anti-agalsidase Alfa Antibody Status (in Serum) at End of Study | EOS | — |
| Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF) | Week 2 to EOS | To Assess Safety and Tolerability by Anti-agalsidase Alfa Antibody Status, concomitant medication, vital signs and ECG. |
| Dose-normalized Maximum Serum Concentration (Cmax/Dose) | Week 0 to Week 14 | The dose-normalized calculation was performed by dividing the pharmacokinetic parameter by the administered dose. |
Countries
Canada
Participant flow
Recruitment details
The first patient participated in the study on 06 December 2011 and the last patient completed the study procedures on 28 December 2012.
Participants by arm
| Arm | Count |
|---|---|
| Replagal® (0.2 mg/kg, EOW) Patients who had received Replagal RB for at least 26 weeks prior to entering the study REP-082, received 1 dose of Replagal RB at baseline before switching to Replagal AF. They then received 14 weeks of treatment with Replagal AF. | 17 |
| Total | 17 |
Baseline characteristics
| Characteristic | Replagal® (0.2 mg/kg, EOW) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants |
| Age, Continuous | 39.8 Years STANDARD_DEVIATION 13.589 |
| Region of Enrollment CANADA | 17 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 17 Participants |
| Study Specific Characteristic [Plasma Gb3] | 5.276 nmol/mL STANDARD_DEVIATION 1.562 |
| Study Specific Characteristic [Urine Gb3] | 919.27 nmol/g creatinine STANDARD_DEVIATION 990.144 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 12 / 17 |
| serious Total, serious adverse events | 2 / 17 |
Outcome results
Primary
Change From Baseline to Week 16 (EOS) in Urine Gb3 Levels
Time frame: Baseline to EOS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Replagal® (0.2 mg/kg, EOW) | Change From Baseline to Week 16 (EOS) in Urine Gb3 Levels | -28.68 (nmol/g creatinine) | Standard Deviation 192.659 |
Secondary
Change From Baseline to Week 16 (EOS) in Plasma Gb3 Levels
Time frame: Baseline to EOS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Replagal® (0.2 mg/kg, EOW) | Change From Baseline to Week 16 (EOS) in Plasma Gb3 Levels | 0.170 (nmol/mL) | Standard Deviation 0.503 |
Secondary
Dose-normalized Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Sample (AUClast/Dose)
The dose-normalized calculation was performed by dividing the pharmacokinetic parameter by the administered dose.
Time frame: Week 0 to Week 14
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Replagal® (0.2 mg/kg, EOW) | Dose-normalized Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Sample (AUClast/Dose) | Week 14 versus 0 | 0.65 Ratio |
| Replagal® (0.2 mg/kg, EOW) | Dose-normalized Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Sample (AUClast/Dose) | Week 14 versus 2 | 1.05 Ratio |
Secondary
Dose-normalized AUC Extrapolated to Infinity (AUC∞/Dose)
The dose-normalized calculation was performed by dividing the pharmacokinetic parameter by the administered dose.
Time frame: Week 0 to Week 14
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Replagal® (0.2 mg/kg, EOW) | Dose-normalized AUC Extrapolated to Infinity (AUC∞/Dose) | Week 14 versus 0 | 0.67 Ratio |
| Replagal® (0.2 mg/kg, EOW) | Dose-normalized AUC Extrapolated to Infinity (AUC∞/Dose) | Week 14 versus 2 | 1.07 Ratio |
Secondary
Dose-normalized Maximum Serum Concentration (Cmax/Dose)
The dose-normalized calculation was performed by dividing the pharmacokinetic parameter by the administered dose.
Time frame: Week 0 to Week 14
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Replagal® (0.2 mg/kg, EOW) | Dose-normalized Maximum Serum Concentration (Cmax/Dose) | Week 14 versus 0 | 0.81 Ratio |
| Replagal® (0.2 mg/kg, EOW) | Dose-normalized Maximum Serum Concentration (Cmax/Dose) | Week 14 versus 2 | 1.05 Ratio |
Secondary
Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF)
To Assess Safety and Tolerability by Anti-agalsidase Alfa Antibody Status, concomitant medication, vital signs and ECG.
Time frame: Week 2 to EOS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Replagal® (0.2 mg/kg, EOW) | Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF) | No TEAE | 9 participants |
| Replagal® (0.2 mg/kg, EOW) | Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF) | Experienced at least one TEAE | 8 participants |
| Replagal® (0.2 mg/kg, EOW) | Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF) | Deaths | 0 participants |
| Replagal® (0.2 mg/kg, EOW) | Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF) | Discontinued due to a TEAE | 0 participants |
| Replagal® (0.2 mg/kg, EOW) | Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF) | Experienced at least one drug-related TEAE | 3 participants |
| Replagal® (0.2 mg/kg, EOW) | Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF) | Experienced at least one SAE | 0 participants |
| Replagal® (0.2 mg/kg, EOW) | Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF) | At least one severe or life- threatening TEAE | 1 participants |
| Replagal® (0.2 mg/kg, EOW) | Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF) | At least one IRR (infusion related reaction) | 1 participants |
| Replagal AF | Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF) | Deaths | 0 participants |
| Replagal AF | Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF) | At least one severe or life- threatening TEAE | 1 participants |
| Replagal AF | Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF) | Discontinued due to a TEAE | 0 participants |
| Replagal AF | Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF) | Experienced at least one drug-related TEAE | 3 participants |
| Replagal AF | Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF) | Experienced at least one SAE | 2 participants |
| Replagal AF | Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF) | No TEAE | 5 participants |
| Replagal AF | Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF) | Experienced at least one TEAE | 12 participants |
| Replagal AF | Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF) | At least one IRR (infusion related reaction) | 1 participants |
| Overall | Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF) | Deaths | 0 participants |
| Overall | Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF) | Experienced at least one TEAE | 12 participants |
| Overall | Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF) | No TEAE | 5 participants |
| Overall | Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF) | Discontinued due to a TEAE | 0 participants |
| Overall | Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF) | At least one severe or life- threatening TEAE | 1 participants |
| Overall | Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF) | Experienced at least one SAE | 2 participants |
| Overall | Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF) | Experienced at least one drug-related TEAE | 3 participants |
| Overall | Overall Summary of TEAEs by Treatment (Replagal RB and Replagal AF) | At least one IRR (infusion related reaction) | 1 participants |
Secondary
To Assess Safety and Tolerability by Anti-agalsidase Alfa Antibody Status (in Serum) at End of Study
Time frame: EOS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Replagal® (0.2 mg/kg, EOW) | To Assess Safety and Tolerability by Anti-agalsidase Alfa Antibody Status (in Serum) at End of Study | Anti-Agalsidase alfa Antibody Positive (IgG) | 2 participants |
| Replagal® (0.2 mg/kg, EOW) | To Assess Safety and Tolerability by Anti-agalsidase Alfa Antibody Status (in Serum) at End of Study | Anti-Agalsidase alfa Antibody Positive (IgM) | 2 participants |
| Replagal® (0.2 mg/kg, EOW) | To Assess Safety and Tolerability by Anti-agalsidase Alfa Antibody Status (in Serum) at End of Study | Anti-Agalsidase alfa Antibody Negative | 13 participants |