Exploratory Muscle Biopsy Assessment Study in Patients With Late-Onset Pompe Disease Treated With Alglucosidase Alfa

• Sponsor: Genzyme, a Sanofi Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01288027
• Collaborator: (none)
• Enrollment: 16
• Locations: 15
• Arm: 1
• Duration (Months): 30
• Patients Per Site: 1.1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This is an open-label, multicenter study of participants with late-onset Pompe disease naive to treatment with enzyme replacement therapy (ERT). The primary objective of this study is to evaluate glycogen clearance in muscle tissue samples collected pre and post alglucosidase alfa treatment in participants with Late-Onset Pompe disease.

The secondary objectives are to characterize the disease burden in participants with late-onset Pompe disease and explore imaging, histologic, and functional assessments in these participants and to explore potential plasma or urine biomarkers relative to late-onset Pompe disease and participant's response to treatment with alglucosidase alfa (Myozyme®/Lumizyme®/GZ419829).

Condition or Disease	Intervention/Treatment	Phase
Pompe Disease (Late-Onset); Glycogen Storage Disease Type II (GSD II); Glycogenesis 2 Acid Maltase Deficiency	Biological: Alglucosidase Alfa	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 4 Prospective Exploratory Muscle Biopsy, Biomarker, and Imaging Assessment Study in Patients With Late-Onset Pompe Disease Treated With Alglucosidase Alfa
• Study Start Date: Jun 1, 2011
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Alglucosidase Alfa	Biological: Alglucosidase Alfa; Alglucosidase alfa intravenous infusion 20 milligram per kilogram (mg/kg) every other week for 24 weeks.; Other Names: GZ419829 Myozyme® Lumizyme®

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Tissue Glycogen Content in Quadriceps Muscle Biopsy Samples at Week 26 [Baseline, Week 26]

   Tissue glycogen content was measured by quadriceps biopsies as 'percent area of tissue occupied by glycogen'.

Secondary Outcome Measures

1. Glycogen Distribution [Baseline, Week 26]

2. Muscle Fiber Morphology [Baseline, Week 26]

3. Lysosomal Inclusions [Baseline, Week 26]

4. Percent Change From Baseline in Muscle Involvement Using Mercuri Scoring at Week 26 [Baseline, Week 26]

   Muscle involvement was assessed by T1-weighted magnetic resonance imaging (MRI). T1-weighted MRI data was analyzed using the Mercuri scoring in both legs (Total score = 1-4; where 1=Normal appearance, 2=Mild involvement, 3=Moderate involvement, and 4=Severe involvement). For each participants, the average for each the upper (thigh) and lower leg was computed for Mercuri grading.

5. Percent Change From Baseline in Degree of Fatty Infiltration Using 3-Point 3-Dimensional (3D) Dixon at Week 26 [Baseline, Week 26]

   Degree of Fatty Infiltration was assessed by 3-point 3D Dixon acquisition using skeletal muscle MRI in a subset of participants.

6. Percent Change From Baseline in Disease Activity Using T2 Magnetic Resonance Imaging (MRI) at Week 26 [Baseline, Week 26]

   Disease activity (inflammation and/or water content within muscles) was quantitatively assessed by T2 MRI values in a subset of participants. A T2 MRI value of greater than (>) 39 millisecond (ms) was defined as abnormal. T2 estimation normally requires an additional acquisition for computing the B1 spatial deviation however, can still be estimated if this acquisition is missing.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• The participant has confirmed acid alpha-glucosidase (GAA) enzyme deficiency from any tissue source and/or confirmed GAA gene mutations and without known cardiac hypertrophy

• The participant is able to ambulate a distance without stopping and without an assistive device. Use of assistive device for community ambulation is appropriate

• The participant has a certain forced vital capacity (FVC) in upright position

• The participant, if female and of childbearing potential, must have a negative pregnancy test (urine beta-human chorionic gonadotropin [beta-hCG]) at baseline

Exclusion Criteria:

• The participant has had previous treatment with ERT

• The participant is wheelchair dependent

• The participant requires invasive-ventilation (non-invasive ventilation is allowed)

• The participant is participating in another clinical study using investigational treatment

• The participant cannot submit to magnetic resonance imaging (MRI) examination because of a formal contraindication such as a pacemaker, implanted ferromagnetic metals, etc

• The participant, in the opinion of the Investigator, is unable to adhere to the requirements of the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Orange	California	United States
2		Gainesville	Florida	United States
3		Kansas City	Kansas	United States
4		St. Louis	Missouri	United States
5		New York	New York	United States
6		Durham	North Carolina	United States
7		Colombus	Ohio	United States
8		Heshey	Pennsylvania	United States
9		Fairfax	Virginia	United States
10		Mainz		Germany
11		Munster		Germany
12		München		Germany
13		Rotterdam		Netherlands
14		Newcastle upon Tyne		United Kingdom
15		Salford		United Kingdom

Sponsors and Collaborators

• Genzyme, a Sanofi Company

Investigators

• Study Director: Medical Monitor, Genzyme, a Sanofi Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Genzyme, a Sanofi Company
• ClinicalTrials.gov Identifier: NCT01288027
• Other Study ID Numbers: AGLU07310; 2010-020611-36; MSC12823
• First Posted: Feb 2, 2011
• Last Update Posted: Dec 19, 2014
• Last Verified: Dec 1, 2014

• Additional relevant MeSH terms: Glycogen Storage Disease Type II; Glycogen Storage Disease

Study Results

Participant Flow

Recruitment Details	The study was conducted at 11 centers between July 06, 2011 and December 19, 2013.

Arm/Group Title	Alglucosidase Alfa
Arm/Group Description	Alglucosidase alfa intravenous infusion 20 milligram per kilogram (mg/kg) every other week for 24 weeks.
Period Title: Overall Study
STARTED	16
Full Analysis Set (FAS)	16
COMPLETED	16
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Alglucosidase Alfa
Arm/Group Description	Alglucosidase alfa intravenous infusion 20 milligram per kilogram (mg/kg) every other week for 24 weeks.
Overall Participants	16
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.6 (13.69)
Sex: Female, Male (Count of Participants)
Female	9 56.3%
Male	7 43.8%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Tissue Glycogen Content in Quadriceps Muscle Biopsy Samples at Week 26
Description	Tissue glycogen content was measured by quadriceps biopsies as 'percent area of tissue occupied by glycogen'.
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

FAS population included all participants who received at least one complete infusion of alglucosidase alfa. Here, n = number of participants with both Baseline and Week 26 assessment of tissue glycogen content.

Arm/Group Title	Alglucosidase Alfa
Arm/Group Description	Alglucosidase alfa intravenous infusion 20 milligram per kilogram (mg/kg) every other week for 24 weeks.
Measure Participants	16
Baseline (n=14)	5.3 (4.59)
Change at Week 26 (n=13)	-1.6 (4.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alglucosidase Alfa
	Comments	Statistical significance for change from Baseline was measured using one sample t-test
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1860
	Comments
	Method	one sample t-test
	Comments

2. Secondary Outcome

Title	Glycogen Distribution
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

No quantitative data could be reported for this outcome as the assessment was qualitative in nature.

Arm/Group Title	Alglucosidase Alfa
Arm/Group Description	Alglucosidase alfa intravenous infusion 20 milligram per kilogram (mg/kg) every other week for 24 weeks.
Measure Participants	0

3. Secondary Outcome

Title	Muscle Fiber Morphology
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

No quantitative data could be reported for this outcome as the assessment was qualitative in nature.

Arm/Group Title	Alglucosidase Alfa
Arm/Group Description	Alglucosidase alfa intravenous infusion 20 milligram per kilogram (mg/kg) every other week for 24 weeks.
Measure Participants	0

4. Secondary Outcome

Title	Lysosomal Inclusions
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

No quantitative data could be reported for this outcome as the assessment was qualitative in nature.

Arm/Group Title	Alglucosidase Alfa
Arm/Group Description	Alglucosidase alfa intravenous infusion 20 milligram per kilogram (mg/kg) every other week for 24 weeks.
Measure Participants	0

5. Secondary Outcome

Title	Percent Change From Baseline in Muscle Involvement Using Mercuri Scoring at Week 26
Description	Muscle involvement was assessed by T1-weighted magnetic resonance imaging (MRI). T1-weighted MRI data was analyzed using the Mercuri scoring in both legs (Total score = 1-4; where 1=Normal appearance, 2=Mild involvement, 3=Moderate involvement, and 4=Severe involvement). For each participants, the average for each the upper (thigh) and lower leg was computed for Mercuri grading.
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

FAS population included all participants who received at least one complete infusion of alglucosidase alfa. Here, Number of participants analyzed= participants with both Baseline and Week 26 assessment of muscle involvement, n= number of participants with both Baseline and Week 26 assessment of muscle involvement for specified category.

Arm/Group Title	Alglucosidase Alfa
Arm/Group Description	Alglucosidase alfa intravenous infusion 20 milligram per kilogram (mg/kg) every other week for 24 weeks.
Measure Participants	14
Mercuri Scoring - Upper Leg (n=13)	2.6 (9.24)
Mercuri Scoring - Lower Leg (n=14)	0.0 (0.0)

6. Secondary Outcome

Title	Percent Change From Baseline in Degree of Fatty Infiltration Using 3-Point 3-Dimensional (3D) Dixon at Week 26
Description	Degree of Fatty Infiltration was assessed by 3-point 3D Dixon acquisition using skeletal muscle MRI in a subset of participants.
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

FAS population included all participants who received at least one complete infusion of alglucosidase alfa. Here, number of participants analyzed = number of participants with both Baseline and Week 26 assessment of degree of fatty infiltration.

Arm/Group Title	Alglucosidase Alfa
Arm/Group Description	Alglucosidase alfa intravenous infusion 20 milligram per kilogram (mg/kg) every other week for 24 weeks.
Measure Participants	3
Mean (Standard Deviation) [percent change]	2.0 (12.83)

7. Secondary Outcome

Title	Percent Change From Baseline in Disease Activity Using T2 Magnetic Resonance Imaging (MRI) at Week 26
Description	Disease activity (inflammation and/or water content within muscles) was quantitatively assessed by T2 MRI values in a subset of participants. A T2 MRI value of greater than (>) 39 millisecond (ms) was defined as abnormal. T2 estimation normally requires an additional acquisition for computing the B1 spatial deviation however, can still be estimated if this acquisition is missing.
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

FAS population included all participants who received at least one complete infusion of alglucosidase alfa. Here Number of participants analyzed = number of participants with both baseline and Week 26 assessment of disease activity.

Arm/Group Title	Alglucosidase Alfa
Arm/Group Description	Alglucosidase alfa intravenous infusion 20 milligram per kilogram (mg/kg) every other week for 24 weeks.
Measure Participants	6
T2 with B1	8.1 (14.19)
T2 without B1	7.2 (13.58)

Adverse Events

Time Frame	From signature of the informed consent form up to the final visit (Week 26)
Adverse Event Reporting Description	In the event a single participant has experienced both serious and non-serious form of the same adverse event (AE), individual has been included in numerator of both AE tables. Analysis was performed on the safety population: all participant who received any amount of alglucosidase alfa. AEs are listed independent of relationship to treatment.
Arm/Group Title	Alglucosidase Alfa
Arm/Group Description	Alglucosidase alfa intravenous infusion 20 milligram per kilogram (mg/kg) every other week for 24 weeks.
All Cause Mortality
	Alglucosidase Alfa
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Alglucosidase Alfa
	Affected / at Risk (%)	# Events
Total	1/16 (6.3%)
Eye disorders
Retinal vascular thrombosis	1/16 (6.3%)
Other (Not Including Serious) Adverse Events
	Alglucosidase Alfa
	Affected / at Risk (%)	# Events
Total	15/16 (93.8%)
Cardiac disorders
Bradycardia	1/16 (6.3%)
Ear and labyrinth disorders
Deafness	1/16 (6.3%)
Tympanic membrane perforation	1/16 (6.3%)
Eye disorders
Ocular hyperaemia	1/16 (6.3%)
Gastrointestinal disorders
Abdominal discomfort	1/16 (6.3%)
Diarrhoea	2/16 (12.5%)
Nausea	1/16 (6.3%)
Vomiting	1/16 (6.3%)
General disorders
Adverse drug reaction	1/16 (6.3%)
Fatigue	2/16 (12.5%)
Feeling cold	1/16 (6.3%)
Influenza like illness	1/16 (6.3%)
Injection site extravasation	1/16 (6.3%)
Malaise	1/16 (6.3%)
Infections and infestations
Bronchitis	2/16 (12.5%)
Ear infection	1/16 (6.3%)
Nasopharyngitis	5/16 (31.3%)
Rhinitis	1/16 (6.3%)
Subcutaneous abscess	1/16 (6.3%)
Upper respiratory tract infection	2/16 (12.5%)
Injury, poisoning and procedural complications
Arthropod bite	1/16 (6.3%)
Ligament sprain	1/16 (6.3%)
Procedural pain	3/16 (18.8%)
Investigations
Heart rate increased	1/16 (6.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/16 (12.5%)
Back pain	2/16 (12.5%)
Muscle spasms	1/16 (6.3%)
Myalgia	1/16 (6.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic naevus	1/16 (6.3%)
Nervous system disorders
Dizziness	3/16 (18.8%)
Headache	4/16 (25%)
Muscle contractions involuntary	1/16 (6.3%)
Paraesthesia	1/16 (6.3%)
Sciatica	1/16 (6.3%)
Psychiatric disorders
Insomnia	2/16 (12.5%)
Reproductive system and breast disorders
Epididymitis	1/16 (6.3%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/16 (6.3%)
Nasal congestion	1/16 (6.3%)
Oropharyngeal pain	2/16 (12.5%)
Pharyngeal oedema	1/16 (6.3%)
Tachypnoea	1/16 (6.3%)
Skin and subcutaneous tissue disorders
Dry skin	1/16 (6.3%)
Rash	2/16 (12.5%)
Urticaria	1/16 (6.3%)
Vascular disorders
Flushing	2/16 (12.5%)
Hypotension	1/16 (6.3%)
Peripheral coldness	1/16 (6.3%)
Thrombosis	1/16 (6.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.