Fabry Disease
Conditions
Keywords
alpha-galactosidase A, a-GAL, Fabry, GL-3, Fabrazyme
Brief summary
This is an exploratory study to evaluate changes in glycosphingolipid levels and other (exploratory) Fabry disease parameters in male Fabry disease participants who were previously treated with agalsidase alfa (Replagal®) 0.2 milligram per kilogram (mg/kg) every two weeks (q2w) and who are being switched to agalsidase beta (Fabrazyme®) 1.0 mg/kg q2w.
Interventions
BIOLOGICALAgalsidase beta
Commercially available agalsidase beta 1.0 mg/kg administered as an intravenous infusion q2w up to Month 6.
Sponsors
Genzyme, a Sanofi Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Healthy volunteers
No
Inclusion criteria
* The participant and/or his parent/legal guardian is willing and able to provide signed informed consent, and the participant, if less than (\<) 18 years of age, is willing to provide assent if deemed able to do so * Participant is male and has been treated with agalsidase alfa at 0.2 mg/kg q2w for the 12 months prior to switching to agalsidase beta * The participant has a confirmed diagnosis of Fabry disease by alfa-galactosidase A (alfa-GAL) activity and/or genotyping per local standards * The participant when switched to agalsidase beta receives the labeled dose, that is, 0.9 to 1.1 mg/kg (1 mg/kg) q2w, and must be willing to maintain the labeled dose for the duration of the study
Exclusion criteria
* The participant is on dialysis or is post renal transplantation * The participant is in end-stage cardiac failure * The participant and/or his parent or legal guardian, in the opinion of the investigator, is unable to adhere to the requirements of the study * The participant has been switched from agalsidase alfa to agalsidase beta and does not have historical blood and urine samples
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Plasma Deacylated Globotriaosylceramide (Lyso-GL-3) at Month 2, 4 and 6 | Baseline, Month 2, 4, 6 | Percent change from baseline = (\[post-baseline value minus baseline value\] divided by \[baseline value\]) multiplied by 100. For levels reported as below quantitative limit (BQL), the lower limit of quantitation (LLOQ) value was divided by 2 and used in the calculation to estimate values in samples that were BQL. The LLOQ for plasma lyso-GL-3 was 5.0 nanogram per milliliter (ng/mL). This study is exploratory because little is known about the dose-response of these biomarkers to enzyme replacement therapy (ERT) or about the clinical significance of the biomarkers. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Plasma Globotriaosylceramide (GL-3) at Month 2, 4 and 6 | Baseline, Month 2, 4, 6 | Percent change from baseline = (\[post-baseline value minus baseline value\] divided by \[baseline value\]) multiplied by 100. For levels reported as BQL, the LLOQ value was divided by 2 and used in the calculation to estimate values in samples that were BQL. The LLOQ for plasma GL-3 was 2.0 microgram per milliliter (mcg/mL). This study is exploratory because little is known about the dose-response of these biomarkers to ERT or about the clinical significance of the biomarkers. |
| Percent Change From Baseline in Urine GL-3 at Month 2, 4, and 6 | Baseline, Month 2, 4, 6 | Percent change from baseline = (\[post-baseline value minus baseline value\] divided by \[baseline value\]) multiplied by 100. For levels reported as BQL, the LLOQ value was divided by 2 and used in the calculation to estimate values in samples that were BQL. The LLOQ for urine GL-3 was 0.2 mcg/mL. The absolute values were calculated in microgram per millimole (mcg/mmol) of creatinine by dividing GL-3 (mcg/mL) by creatinine (mg/mL) and multiplying by 113.13 (mg/mmol), the molecular weight of creatinine. For levels reported BQL, the absolute values were calculated in microgram per millimole (mcg/mmol) of creatinine by dividing 0.1 (mcg/mL) by creatinine (mg/mL) and multiplying by 133.13 (mg/mmol). This study is exploratory because little is known about the dose-response of these biomarkers to ERT or about the clinical significance of the biomarkers. |
| Percent Change From Baseline in Gastrointestinal (GI) Symptoms (Abdominal Pain, Abdominal Distention, and Bowel Irregularities) at Month 2, 4, and 6 | Baseline, Month 2, 4, 6 | Gastrointestinal symptoms (abdominal pain, abdominal distention, and irregular bowel movements) were to be assessed by a modified version of the Irritable Bowel Syndrome (IBS) Severity Scoring System. The modified IBS Severity Scoring System is a 7-item questionnaire. The severity score calculated by summing the scores of 5 of the 7 questions. Each of the 5 questions were scored on a scale of 0 to 100, leading to a total possible score range of 0 to 500, where higher scores indicate more severe gastrointestinal symptoms. The data for this outcome measure was exploratory and to be collected in individual participant listing only. |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 6 centers in the United States of America between April 30, 2012 and March 15, 2013.
Pre-assignment details
A total of 16 participants were screened of which 1 participant was screen failure. A total of 15 participants were enrolled in this study.
Participants by arm
| Arm | Count |
|---|---|
| Agalsidase Beta Commercially available agalsidase beta 1.0 mg/kg administered as an intravenous infusion q2w up to Month 6. | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Agalsidase Beta |
|---|---|
| Age, Continuous | 28.5 years STANDARD_DEVIATION 16.11 |
| Duration of Fabry Disease | 9.3 years FULL_RANGE 4.73 |
| Method of Diagnosis of Fabry Disease Genotype | 14 participants |
| Method of Diagnosis of Fabry Disease Leukocyte alfa-galactosidase A (GAL) activity | 11 participants |
| Method of Diagnosis of Fabry Disease Plasma alfa-GAL activity | 9 participants |
| Race/Ethnicity, Customized Caucasian | 13 participants |
| Race/Ethnicity, Customized Hispanic | 1 participants |
| Race/Ethnicity, Customized Other | 1 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 1 / 15 |
| serious Total, serious adverse events | 0 / 15 |
Outcome results
Primary
Percent Change From Baseline in Plasma Deacylated Globotriaosylceramide (Lyso-GL-3) at Month 2, 4 and 6
Percent change from baseline = (\[post-baseline value minus baseline value\] divided by \[baseline value\]) multiplied by 100. For levels reported as below quantitative limit (BQL), the lower limit of quantitation (LLOQ) value was divided by 2 and used in the calculation to estimate values in samples that were BQL. The LLOQ for plasma lyso-GL-3 was 5.0 nanogram per milliliter (ng/mL). This study is exploratory because little is known about the dose-response of these biomarkers to enzyme replacement therapy (ERT) or about the clinical significance of the biomarkers.
Time frame: Baseline, Month 2, 4, 6
Population: All enrolled participants were included in the analysis. Here, 'n' signifies participants with plasma Lyso-GL-3 assessment at the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Agalsidase Beta | Percent Change From Baseline in Plasma Deacylated Globotriaosylceramide (Lyso-GL-3) at Month 2, 4 and 6 | Month 2 (n=14) | -31.71 percent change | Standard Deviation 22.54 |
| Agalsidase Beta | Percent Change From Baseline in Plasma Deacylated Globotriaosylceramide (Lyso-GL-3) at Month 2, 4 and 6 | Month 4 (n=12) | -39.04 percent change | Standard Deviation 22.28 |
| Agalsidase Beta | Percent Change From Baseline in Plasma Deacylated Globotriaosylceramide (Lyso-GL-3) at Month 2, 4 and 6 | Month 6 (n=14) | -39.54 percent change | Standard Deviation 23.567 |
Comparison: Baseline versus Month 2: Analysis was performed using one sample t-test.p-value: 0.0002One sample t-test
Comparison: Baseline versus Month 4: Analysis was performed using one sample t-test.p-value: <0.0001One sample t-test
Comparison: Baseline versus Month 6: Analysis was performed using one sample t-test.p-value: <0.0001One sample t-test
Secondary
Percent Change From Baseline in Gastrointestinal (GI) Symptoms (Abdominal Pain, Abdominal Distention, and Bowel Irregularities) at Month 2, 4, and 6
Gastrointestinal symptoms (abdominal pain, abdominal distention, and irregular bowel movements) were to be assessed by a modified version of the Irritable Bowel Syndrome (IBS) Severity Scoring System. The modified IBS Severity Scoring System is a 7-item questionnaire. The severity score calculated by summing the scores of 5 of the 7 questions. Each of the 5 questions were scored on a scale of 0 to 100, leading to a total possible score range of 0 to 500, where higher scores indicate more severe gastrointestinal symptoms. The data for this outcome measure was exploratory and to be collected in individual participant listing only.
Time frame: Baseline, Month 2, 4, 6
Population: The data for this outcome measure was exploratory and to be collected in individual participant listing only. Analysis of this data was planned only if baseline data was collected on a large number of enrolled participants. This was not the case and therefore interpretation of these results were not possible.
Secondary
Percent Change From Baseline in Plasma Globotriaosylceramide (GL-3) at Month 2, 4 and 6
Percent change from baseline = (\[post-baseline value minus baseline value\] divided by \[baseline value\]) multiplied by 100. For levels reported as BQL, the LLOQ value was divided by 2 and used in the calculation to estimate values in samples that were BQL. The LLOQ for plasma GL-3 was 2.0 microgram per milliliter (mcg/mL). This study is exploratory because little is known about the dose-response of these biomarkers to ERT or about the clinical significance of the biomarkers.
Time frame: Baseline, Month 2, 4, 6
Population: All enrolled participants were included in the analysis. Here, 'n' signifies participants with plasma GL-3 assessment at the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Agalsidase Beta | Percent Change From Baseline in Plasma Globotriaosylceramide (GL-3) at Month 2, 4 and 6 | Month 2 (n=12) | -10.33 percent change | Standard Deviation 21.087 |
| Agalsidase Beta | Percent Change From Baseline in Plasma Globotriaosylceramide (GL-3) at Month 2, 4 and 6 | Month 4 (n=10) | -12.80 percent change | Standard Deviation 23.388 |
| Agalsidase Beta | Percent Change From Baseline in Plasma Globotriaosylceramide (GL-3) at Month 2, 4 and 6 | Month 6 (n=12) | -17.89 percent change | Standard Deviation 25.291 |
Comparison: Baseline versus Month 2: Analysis was performed using one sample t-test.p-value: 0.1178One sample t-test
Comparison: Baseline versus Month 4: Analysis was performed using one sample t-test.p-value: 0.1176One sample t-test
Comparison: Baseline versus Month 6: Analysis was performed using one sample t-test.p-value: 0.0322One sample t-test
Secondary
Percent Change From Baseline in Urine GL-3 at Month 2, 4, and 6
Percent change from baseline = (\[post-baseline value minus baseline value\] divided by \[baseline value\]) multiplied by 100. For levels reported as BQL, the LLOQ value was divided by 2 and used in the calculation to estimate values in samples that were BQL. The LLOQ for urine GL-3 was 0.2 mcg/mL. The absolute values were calculated in microgram per millimole (mcg/mmol) of creatinine by dividing GL-3 (mcg/mL) by creatinine (mg/mL) and multiplying by 113.13 (mg/mmol), the molecular weight of creatinine. For levels reported BQL, the absolute values were calculated in microgram per millimole (mcg/mmol) of creatinine by dividing 0.1 (mcg/mL) by creatinine (mg/mL) and multiplying by 133.13 (mg/mmol). This study is exploratory because little is known about the dose-response of these biomarkers to ERT or about the clinical significance of the biomarkers.
Time frame: Baseline, Month 2, 4, 6
Population: All enrolled participants were included in the analysis. Here, 'n' signifies participants with urine GL-3 assessment at the specified time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Agalsidase Beta | Percent Change From Baseline in Urine GL-3 at Month 2, 4, and 6 | Month 2 (n=13) | -44.71 percent change |
| Agalsidase Beta | Percent Change From Baseline in Urine GL-3 at Month 2, 4, and 6 | Month 4 (n=12) | -41.49 percent change |
| Agalsidase Beta | Percent Change From Baseline in Urine GL-3 at Month 2, 4, and 6 | Month 6 (n=12) | -33.75 percent change |
Comparison: Baseline versus Month 2: Analysis was performed using one sample test of median (sign test). The percent change and absolute change from baseline in urine GL-3 levels were not normally distributed and thus medians were evaluated.p-value: 0.5811One sample test of median (sign test)
Comparison: Baseline versus Month 4: Analysis was performed using one sample test of median (sign test). The percent change and absolute change from baseline in urine GL-3 levels were not normally distributed and thus medians were evaluated.p-value: 0.7744One sample test of median (sign test)
Comparison: Baseline versus Month 6: Analysis was performed using one sample test of median (sign test). The percent change and absolute change from baseline in urine GL-3 levels were not normally distributed and thus medians were evaluated.p-value: 0.3877One sample test of median (sign test)