A Study Evaluating Glycosphingolipid Clearance in Patients Treated With Agalsidase Alfa Who Switch to Agalsidase Beta

• Sponsor: Genzyme, a Sanofi Company
• Information provided by (Responsible Party): Sanofi ( Genzyme, a Sanofi Company )

Study Type	Interventional
Study Design	Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition	Fabry Disease
Intervention	Biological: Agalsidase beta
Enrollment	15

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.

Arm/Group Title	Agalsidase Beta
Arm/Group Description	Commercially available agalsidase beta (Fabrazyme ®) 1.0 milligram per kilogram (mg/kg) administered as an intravenous infusion every 2 weeks (q2w) up to Month 6.
Period Title: Overall Study
Started	15
Completed	14
Not Completed	1
Reason Not Completed
Withdrawal by Subject	1

Baseline Characteristics

Arm/Group Title		Agalsidase Beta
Arm/Group Description		Commercially available agalsidase beta 1.0 mg/kg administered as an intravenous infusion q2w up to Month 6.
Overall Number of Baseline Participants		15
Baseline Analysis Population Description		All enrolled participants were included in the analysis.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	15 participants
		28.5 (16.11)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	15 participants
	Female	0 0.0%
	Male	15 100.0%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	15 participants
Caucasian		13
Hispanic		1
Other		1
Duration of Fabry Disease [1]; Median (Full Range); Unit of measure: Years
	Number Analyzed	15 participants
		9.3; (2 to 19)
		[1] Measure Description: Duration of Fabry disease was calculated from date of initial diagnosis of Fabry disease to date of the first study infusion. Number of participants analyzed for this baseline measure were 14, as one participant did not have information on date of initial diagnosis of Fabry disease.
Method of Diagnosis of Fabry Disease [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	15 participants
Genotype		14
Leukocyte alfa-galactosidase A (GAL) activity		11
Plasma alfa-GAL activity		9
		[1] Measure Description: Number of participants with each method (genotype, leukocyte alfa-galactosidase A [GAL] activity, and plasma alfa-GAL activity) are reported. Some participants were diagnosed by more than 1 method, hence reported under more than 1 category.

Outcome Measures

1. Primary Outcome

Title	Percent Change From Baseline in Plasma Deacylated Globotriaosylceramide (Lyso-GL-3) at Month 2, 4 and 6
Description	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

Outcome Measure Data

Analysis Population Description

All enrolled participants were included in the analysis. Here, 'n' signifies participants with plasma Lyso-GL-3 assessment at the specified time point.

Arm/Group Title	Agalsidase Beta
Arm/Group Description:	Commercially available agalsidase beta 1.0 mg/kg administered as an intravenous infusion q2w up to Month 6.
Overall Number of Participants Analyzed	15
Mean (Standard Deviation); Unit of Measure: percent change
Month 2 (n=14)	-31.71 (22.540)
Month 4 (n=12)	-39.04 (22.280)
Month 6 (n=14)	-39.54 (23.567)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Agalsidase Beta
	Comments	Baseline versus Month 2: Analysis was performed using one sample t-test.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0002
	Comments	[Not Specified]
	Method	One sample t-test
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Agalsidase Beta
	Comments	Baseline versus Month 4: Analysis was performed using one sample t-test.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	One sample t-test
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Agalsidase Beta
	Comments	Baseline versus Month 6: Analysis was performed using one sample t-test.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	One sample t-test
	Comments	[Not Specified]

2. Secondary Outcome

Title	Percent Change From Baseline in Plasma Globotriaosylceramide (GL-3) at Month 2, 4 and 6
Description	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

Outcome Measure Data

Analysis Population Description

All enrolled participants were included in the analysis. Here, 'n' signifies participants with plasma GL-3 assessment at the specified time point.

Arm/Group Title	Agalsidase Beta
Arm/Group Description:	Commercially available agalsidase beta 1.0 mg/kg administered as an intravenous infusion q2w up to Month 6.
Overall Number of Participants Analyzed	15
Mean (Standard Deviation); Unit of Measure: percent change
Month 2 (n=12)	-10.33 (21.087)
Month 4 (n=10)	-12.80 (23.388)
Month 6 (n=12)	-17.89 (25.291)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Agalsidase Beta
	Comments	Baseline versus Month 2: Analysis was performed using one sample t-test.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1178
	Comments	[Not Specified]
	Method	One sample t-test
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Agalsidase Beta
	Comments	Baseline versus Month 4: Analysis was performed using one sample t-test.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1176
	Comments	[Not Specified]
	Method	One sample t-test
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Agalsidase Beta
	Comments	Baseline versus Month 6: Analysis was performed using one sample t-test.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0322
	Comments	[Not Specified]
	Method	One sample t-test
	Comments	[Not Specified]

3. Secondary Outcome

Title	Percent Change From Baseline in Urine GL-3 at Month 2, 4, and 6
Description	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

Outcome Measure Data

Analysis Population Description

All enrolled participants were included in the analysis. Here, 'n' signifies participants with urine GL-3 assessment at the specified time point.

Arm/Group Title	Agalsidase Beta
Arm/Group Description:	Commercially available agalsidase beta 1.0 mg/kg administered as an intravenous infusion q2w up to Month 6.
Overall Number of Participants Analyzed	15
Median (Full Range); Unit of Measure: percent change
Month 2 (n=13)	-44.71; (-98.4 to 1068.2)
Month 4 (n=12)	-41.49; (-96.5 to 464.9)
Month 6 (n=12)	-33.75; (-97.1 to 1116.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Agalsidase Beta
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5811
	Comments	[Not Specified]
	Method	One sample test of median (sign test)
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Agalsidase Beta
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7744
	Comments	[Not Specified]
	Method	One sample test of median (sign test)
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Agalsidase Beta
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3877
	Comments	[Not Specified]
	Method	One sample test of median (sign test)
	Comments	[Not Specified]

4. Secondary Outcome

Title	Percent Change From Baseline in Gastrointestinal (GI) Symptoms (Abdominal Pain, Abdominal Distention, and Bowel Irregularities) at Month 2, 4, and 6
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Agalsidase Beta
Arm/Group Description:	Commercially available agalsidase beta 1.0 mg/kg administered as an intravenous infusion q2w up to Month 6.
Overall Number of Participants Analyzed	0

No data displayed because Outcome Measure has zero total analyzed.

Adverse Events

Time Frame	Baseline up to end of study (Month 6) or early withdrawal
Adverse Event Reporting Description	All enrolled participants were included in the analysis.
Arm/Group Title	Agalsidase Beta
Arm/Group Description	Commercially available agalsidase beta 1.0 mg/kg administered as an intravenous infusion every 2 weeks up to Month 6.
All-Cause Mortality
	Agalsidase Beta
	Affected / at Risk (%)
Total	--/--
Serious Adverse Events
	Agalsidase Beta
	Affected / at Risk (%)
Total	0/15 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Agalsidase Beta
	Affected / at Risk (%)
Total	1/15 (6.67%)
General disorders
Infusion-associated reactions * 1	1/15 (6.67%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA 16.0

Limitations and Caveats

This is considered to be an exploratory study for the following reasons: it was based on a small number of participants and has been designed as an open-label, single-arm study as opposed to a two-arm crossover design.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.

Results Point of Contact

Name/Title: Trial Transparency Team

Organization: Sanofi

EMail: Contact-us@sanofi.com

Responsible Party:	Sanofi ( Genzyme, a Sanofi Company )
ClinicalTrials.gov Identifier:	NCT01650779 History of Changes
Other Study ID Numbers:	AGAL19412
First Submitted:	July 24, 2012
First Posted:	July 26, 2012
Results First Submitted:	June 9, 2014
Results First Posted:	July 10, 2014
Last Update Posted:	July 10, 2014